Richard G. Wise

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.

Current clinical and experimental literature strongly supports the phenomenon of reduced pain perception whilst attention is distracted away from noxious stimuli.This study used functional MRI to elucidate the underlying neural systems and mechanisms involved.An analogue of the Stroop task, the counting Stroop, was used as a cognitive distraction task whilst subjects received intermittent painful thermal stimuli.Pain intensity scores were signi®cantly reduced when subjects took part in the more cognitively demanding interference task of the counting Stroop than in the less demanding neutral task.When subjects were distracted during painful stimulation, brain areas associated with the affective division of the anterior cingulate cortex (ACC) and orbitofrontal regions showed increased activation.In contrast, many areas of the pain matrix (i.e.thalamus, insula, cognitive division of the ACC) displayed reduced activation, supporting the behavioural results of reduced pain perception.

It is common clinical experience that anxiety about pain can exacerbate the pain sensation. Using event-related functional magnetic resonance imaging (FMRI), we compared activation responses to noxious thermal stimulation while perceived pain intensity was manipulated by changes in either physical intensity or induced anxiety. One visual signal, which reliably predicted noxious stimulation of moderate intensity, came to evoke low anxiety about the impending pain. Another visual signal was followed by the same, moderate-intensity stimulation on most of the trials, but occasionally by discriminably stronger noxious stimuli, and came to evoke higher anxiety. We found that the entorhinal cortex of the hippocampal formation responded differentially to identical noxious stimuli, dependent on whether the perceived pain intensity was enhanced by pain-relevant anxiety. During this emotional pain modulation, entorhinal responses predicted activity in closely connected, affective (perigenual cingulate), and intensity coding (mid-insula) areas. Our finding suggests that accurate preparatory information during medical and dental procedures alleviates pain by disengaging the hippocampus. It supports the proposal that during anxiety, the hippocampal formation amplifies aversive events to prime behavioral responses that are adaptive to the worst possible outcome.

Significance Lysergic acid diethylamide (LSD), the prototypical “psychedelic,” may be unique among psychoactive substances. In the decades that followed its discovery, the magnitude of its effect on science, the arts, and society was unprecedented. LSD produces profound, sometimes life-changing experiences in microgram doses, making it a particularly powerful scientific tool. Here we sought to examine its effects on brain activity, using cutting-edge and complementary neuroimaging techniques in the first modern neuroimaging study of LSD. Results revealed marked changes in brain blood flow, electrical activity, and network communication patterns that correlated strongly with the drug’s hallucinatory and other consciousness-altering properties. These results have implications for the neurobiology of consciousness and for potential applications of LSD in psychological research.

Carbon dioxide is a potent cerebral vasodilator. We have identified a significant source of low-frequency variation in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal at 3 T arising from spontaneous fluctuations in arterial carbon dioxide level in volunteers at rest. Fluctuations in the partial pressure of end-tidal carbon dioxide (PetCO2) of ±1.1 mm Hg in the frequency range 0–0.05 Hz were observed in a cohort of nine volunteers. Correlating with these fluctuations were significant generalized grey and white matter BOLD signal fluctuations. We observed a mean (±standard error) regression coefficient across the group of 0.110 ± 0.033% BOLD signal change per mm Hg CO2 for grey matter and 0.049 ± 0.022% per mm Hg in white matter. PetCO2-related BOLD signal fluctuations showed regional differences across the grey matter, suggesting variability of the responsiveness to carbon dioxide at rest. Functional magnetic resonance imaging (fMRI) results were corroborated by transcranial Doppler (TCD) ultrasound measurements of the middle cerebral artery (MCA) blood velocity in a cohort of four volunteers. Significant PetCO2-correlated fluctuations in MCA blood velocity were observed with a lag of 6.3 ± 1.2 s (mean ± standard error) with respect to PetCO2 changes. This haemodynamic lag was adopted in the analysis of the BOLD signal. Doppler ultrasound suggests that a component of low-frequency BOLD signal fluctuations is mediated by CO2-induced changes in cerebral blood flow (CBF). These fluctuations are a source of physiological noise and a potentially important confounding factor in fMRI paradigms that modify breathing. However, they can also be used for mapping regional vascular responsiveness to CO2.

Functional neuroimaging studies in humans have shown that nociceptive stimuli elicit activity in a wide network of cortical areas commonly labeled as the “pain matrix” and thought to be preferentially involved in the perception of pain. Despite the fact that this “pain matrix” has been used extensively to build models of where and how nociception is processed in the human brain, convincing experimental evidence demonstrating that this network is specifically related to nociception is lacking. The aim of the present study was to determine whether there is at least a subset of the “pain matrix” that responds uniquely to nociceptive somatosensory stimulation. In a first experiment, we compared the fMRI brain responses elicited by a random sequence of brief nociceptive somatosensory, non-nociceptive somatosensory, auditory and visual stimuli, all presented within a similar attentional context. We found that the fMRI responses triggered by nociceptive stimuli can be largely explained by a combination of (1) multimodal neural activities (i.e., activities elicited by all stimuli regardless of sensory modality) and (2) somatosensory-specific but not nociceptive-specific neural activities (i.e., activities elicited by both nociceptive and non-nociceptive somatosensory stimuli). The magnitude of multimodal activities correlated significantly with the perceived saliency of the stimulus. In a second experiment, we compared these multimodal activities to the fMRI responses elicited by auditory stimuli presented using an oddball paradigm. We found that the spatial distribution of the responses elicited by novel non-target and novel target auditory stimuli resembled closely that of the multimodal responses identified in the first experiment. Taken together, these findings suggest that the largest part of the fMRI responses elicited by phasic nociceptive stimuli reflects non nociceptive-specific cognitive processes.

Random amplified polymorphic DNA (RAPD) analysis appears to offer a cost- and time-effective alternative to restriction fragment-length polymorphism (RFLP) analysis. However, concerns about the ability to compare RAPD results from one laboratory to another have not been addressed effectively. DNA fragments that were amplified by five primers and shown to be reproducibly polymorphic between two oat cultivars (within the Ottawa laboratory) were tested in six other laboratories in North America. Four of the six participants amplified very few or no fragments using the Ottawa protocol. These same participants were able to generate a considerable number of amplified fragments by using their own protocols. The reproducibility of results among laboratories was affected by two factors. First, different laboratories amplified different size ranges of DNA fragments, and, consequently, small and large polymorphic fragments were not always reproduced. Second, although reproducible results were obtained with four of the primers, reproducible results were not obtained with the fifth primer, using the same reaction conditions. It is suggested that if the overall temperature profiles (especially the annealing temperature) inside the tubes are identical among the laboratories, then RAPD fragments are likely to be reproducible.

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very different functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, independent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

Little is known about the neurobiology of bipolar II disorder. While bipolar I disorder is associated with abnormally elevated activity in response to reward in the ventral striatum, a key component of reward circuitry, no studies have compared reward circuitry function in bipolar I and bipolar II disorders. Furthermore, associations among reward circuitry activity, reward sensitivity, and striatal volume remain underexplored in bipolar and healthy individuals. The authors examined reward activity in the ventral striatum in participants with bipolar I and II disorders and healthy individuals, the relationships between ventral striatal activity and reward sensitivity across all participants, and between-group differences in striatal gray matter volume and relationships with ventral striatal activity across all participants.Twenty healthy comparison subjects and 32 euthymic bipolar I (N=17) and bipolar II (N=15) patients underwent a neuroimaging reward paradigm during functional MRI scanning, structural scanning, and completed psychometric and clinical assessments.Region-of-interest analyses revealed significant ventral striatal activity in all participants during reward anticipation that was significantly greater in bipolar II patients compared with the other groups. Ventral striatal activity during reward anticipation correlated positively with reward sensitivity and fun seeking across all participants. Bipolar II patients had significantly greater left putamen volume than bipolar I patients, and left putamen volume correlated positively with left ventral striatal activity to reward anticipation in all participants.Abnormally elevated ventral striatal activity during reward anticipation may be a potential biomarker of bipolar II disorder. These findings highlight the importance of adopting a dimensional approach in the study of neural mechanisms supporting key pathophysiological processes that may cut across psychiatric disorders.

Psilocybin is a classic psychedelic drug that has a history of use in psychotherapy. One of the rationales for its use was that it aids emotional insight by lowering psychological defences.To test the hypothesis that psilocybin facilitates access to personal memories and emotions by comparing subjective and neural responses to positive autobiographical memories under psilocybin and placebo.Ten healthy participants received two functional magnetic resonance imaging scans (2 mg intravenous psilocybin v. intravenous saline), separated by approximately 7 days, during which they viewed two different sets of 15 positive autobiographical memory cues. Participants viewed each cue for 6 s and then closed their eyes for 16 s and imagined re-experiencing the event. Activations during this recollection period were compared with an equivalent period of eyes-closed rest. We split the recollection period into an early phase (first 8 s) and a late phase (last 8 s) for analysis.Robust activations to the memories were seen in limbic and striatal regions in the early phase and the medial prefrontal cortex in the late phase in both conditions (P<0.001, whole brain cluster correction), but there were additional visual and other sensory cortical activations in the late phase under psilocybin that were absent under placebo. Ratings of memory vividness and visual imagery were significantly higher after psilocybin (P<0.05) and there was a significant positive correlation between vividness and subjective well-being at follow-up (P<0.01).Evidence that psilocybin enhances autobiographical recollection implies that it may be useful in psychotherapy either as a tool to facilitate the recall of salient memories or to reverse negative cognitive biases.

Defining language lateralization is important to minimize morbidity in patients treated surgically for temporal lobe epilepsy (TLE). Functional magnetic resonance imaging (fMRI) offers a promising, noninvasive, alternative strategy to the Wada test. Here we have used fMRI to study healthy controls and patients with TLE in order to (i) define language-related activation patterns and their reproducibility; (ii) compare lateralization determined by fMRI with those from of the Wada test; and (iii) contrast different methods of assessing fMRI lateralization. Twelve healthy right-handed controls and 19 right-handed preoperative patients with TLE (12 left- and seven right-TLE) were studied at 3T using fMRI and a verbal fluency paradigm. A Wada test also was performed on each of the patients. Greater activation was found in several areas in the right hemisphere for the left-TLE group relative to controls or right-TLE patients. Relative hemispheric activations calculated based on either the extent or the mean signal change gave consistent results showing a more bihemispheric language representation in the left-TLE patients. There was good agreement between the Wada and fMRI results, although the latter were more sensitive to involvement of the nondominant right hemisphere. The reproducibility of the fMRI values was lowest for the more bihemispherically represented left-TLE patients. Overall, our results further demonstrate that noninvasive fMRI measures of language-related lateralization may provide a practical and reliable alternative to invasive testing for presurgical language lateralization in patients with TLE. The high proportion (33%) of left-TLE patients showing bilateral or right hemispheric language-related lateralization suggests that there is considerable plasticity of language representation in the brains of patients with intractable TLE.

Animal studies have established a role for the brainstem reticular formation, in particular the rostral ventromedial medulla (RVM), in the development and maintenance of central sensitisation and its clinical manifestation, secondary hyperalgesia. Similar evidence in humans is lacking, as neuroimaging studies have mainly focused on cortical changes. To fully characterise the supraspinal contributions to central sensitisation in humans, we used whole-brain functional magnetic resonance imaging at 3 T, to record brain responses to punctate mechanical stimulation in an area of secondary hyperalgesia. We used the heat/capsaicin sensitisation model to induce secondary hyperalgesia on the right lower leg in 12 healthy volunteers. A paired t-test was used to compare activation maps obtained during punctate stimulation of the secondary hyperalgesia area and those recorded during control punctate stimulation (same body site, untreated skin, separate session). The following areas showed significantly increased activation (Z>2.3, corrected P<0.01) during hyperalgesia: contralateral brainstem, cerebellum, bilateral thalamus, contralateral primary and secondary somatosensory cortices, bilateral posterior insula, anterior and posterior cingulate cortices, right middle frontal gyrus and right parietal association cortex. Brainstem activation was localised to two distinct areas of the midbrain reticular formation, in regions consistent with the location of nucleus cuneiformis (NCF) and rostral superior colliculi/periaqueductal gray (SC/PAG). The PAG and the NCF are the major sources of input to the RVM, and therefore in an ideal position to modulate its output. These results suggest that structures in the mesencephalic reticular formation, possibly the NCF and PAG, are involved in central sensitisation in humans.

Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os , in a single administration. We found that ( i ) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; ( ii ) gabapentin reduced the activation in the brainstem, only during central sensitization; ( iii ) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.

Evidence from both human and animal studies has demonstrated a key role for brainstem centers in the control of ascending nociceptive input. Nuclei such as the rostral ventromedial medulla and periaqueductal gray (PAG) are able to both inhibit and facilitate the nociceptive response. It has been proposed that altered descending modulation may underlie many of the chronic pain syndromes (both somatic and visceral). We used functional magnetic resonance imaging to image the neural correlates of visceral and somatic pain within the brainstem. Ten healthy subjects were scanned twice at 3 tesla, during which they received matched, moderately painful, electrical stimuli to either the midline lower abdomen or rectum. Significant activation was observed in regions consistent with the PAG, nucleus cuneiformis (NCF), ventral tegmental area/substantia nigra, parabrachial nuclei/nucleus ceruleus, and red nucleus bilaterally to both stimuli. Marked spatial similarities in activation were observed for visceral and somatic pain, although significantly greater activation of the NCF (left NCF, p = 0.02; right NCF, p = 0.01; Student's paired t test, two-tailed) was observed in the visceral pain group compared with the somatic group. Right PAG activity correlated with anxiety during visceral stimulation (r = 0.74; p < 0.05, Pearson's r, two-tailed) but not somatic stimulation. We propose that the differences in NCF and right PAG activation observed may represent a greater nocifensive response and greater emotive salience of visceral over somatic pain.

Spinal cord functional imaging allows assessment of activity in primary synaptic connections made by sensory neurons relaying information about the state of the body. However, reported human data based on gradient-echo techniques have been largely inconsistent, with no clear patterns of activation emerging. One reason for this variability is the influence of physiological noise, which is typically not corrected for. By acquiring single-slice resting data from the spinal cord with a conventional gradient-echo EPI pulse sequence at TR=200 ms (critically sampled) and TR=3 s (under-sampled), we have characterised various sources of physiological noise. In 8 healthy subjects, the presence of physiologically dependent signal was explored using probabilistic independent component analysis (PICA). Based on the insights provided by PICA, we defined a new physiological noise model (PNM) based on retrospective image correction (RETROICOR), which uses independent physiological measurements taken from the subject to model sources of noise. Statistical significance of individual components included in the PNM was assessed by F-tests, which demonstrated that the optimal PNM included cardiac, respiratory, interaction and low-frequency regressors. In a group of 10 healthy subjects, activation data were acquired from the cervical spinal region (T1 to C5) during painful thermal stimulation of the right and left hands. The improvement obtained when using a PNM in estimating spinal cord activation was reflected in a reduction of false-positive activation (active voxels in the CSF space surrounding the cord), when compared to conventional GLM modelling without a PNM.

In the past decade the use of blood oxygen level-dependent (BOLD) fMRI to investigate the effect of diseases and pharmacological agents on brain activity has increased greatly. BOLD fMRI does not measure neural activity directly, but relies on a cascade of physiological events linking neural activity to the generation of MRI signal. However, most of the disease and pharmacological studies performed so far have interpreted changes in BOLD fMRI as "brain activation," ignoring the potential confounds that can arise through drug- or disease-induced modulation of events downstream of the neural activity. This issue is especially serious in diseases (like multiple sclerosis, brain tumours and stroke) and drugs (like anaesthetics or those with a vascular action) that are known to influence these physiological events. Here we provide evidence that, to extract meaningful information on brain activity in patient and pharmacological BOLD fMRI studies, it is important to identify, characterise and possibly correct these influences that potentially confound the results. We suggest a series of experimental measures to improve the interpretability of BOLD fMRI studies. We have ranked these according to their potential information and current practical feasibility. First-line, necessary improvements consist of (1) the inclusion of one or more control tasks, and (2) the recording of physiological parameters during scanning and subsequent correction of possible between-group differences. Second-line, highly recommended important aim to make the results of a patient or drug BOLD study more interpretable and include the assessment of (1) baseline brain perfusion, (2) vascular reactivity, (3) the inclusion of stimulus-related perfusion fMRI and (4) the recording of electrophysiological responses to the stimulus of interest. Finally, third-line, desirable improvements consist of the inclusion of (1) simultaneous EEG-fMRI, (2) cerebral blood volume and (3) rate of metabolic oxygen consumption measurements and, when relevant, (4) animal studies investigating signalling between neural cells and blood vessels.

While ubiquitous, pharmacological manipulation of consciousness remains poorly defined and incompletely understood (Prys-Roberts, 1987). This retards anesthetic drug development, confounds interpretation of animal studies conducted under anesthesia, and limits the sensitivity of clinical monitors of cerebral function to intact perception. Animal and human studies propose a functional "switch" at the level of the thalamus, with inhibition of thalamo-cortical transmission characterizing loss of consciousness (Alkire et al., 2000; Mashour, 2006). We investigated the effects of propofol, widely used for anesthesia and sedation, on spontaneous and evoked cerebral activity using functional magnetic resonance imaging (fMRI). A series of auditory and noxious stimuli was presented to eight healthy volunteers at three behavioral states: awake, "sedated" and "unresponsive." Performance in a verbal task and the absence of a response to verbal stimulation, rather than propofol concentrations, were used to define these states clinically. Analysis of stimulus-related blood oxygenation level-dependent signal changes identified reductions in cortical and subcortical responses to auditory and noxious stimuli in sedated and unresponsive states. A specific reduction in activity within the putamen was noted and further investigated with functional connectivity analysis. Progressive failure to perceive or respond to auditory or noxious stimuli was associated with a reduction in the functional connectivity between the putamen and other brain regions, while thalamo-cortical connectivity was relatively preserved. This result has not been previously described and suggests that disruption of subcortical thalamo-regulatory systems may occur before, or even precipitate, failure of thalamo-cortical transmission with the induction of unconsciousness.

Pharmacological functional (phMRI) studies are making a significant contribution to our understanding of drug-effects on brain systems. Pharmacological fMRI has an additional contribution to make in the translation of disease models and candidate compounds from preclinical to clinical investigation and in the early clinical stages of drug development. Here it can demonstrate a proof-of-concept of drug action in a small human cohort and thus contribute substantially to decision-making in drug development. We review the methods underlying pharmacological fMRI studies and the links that can be made between animal and human investigations. We discuss the potential fMRI markers of drug effect, experimental designs and caveats in interpreting hemodynamic fMRI data as reflective of changes in neuronal activity. Although there are no current published examples of fMRI applied to novel compounds, we illustrate the potential of fMRI across a range of applications and with specific reference to processing of pain in the human brain and pharmacological analgesia. Pharmacological fMRI is developing to meet the neuroscientific challenges. Electrophysiological methods can be used to corroborate the drug effects measured hemodynamically with fMRI. In future, pharmacological fMRI is likely to extend to examinations of the spinal cord and into pharmacogenetics to relate genetic polymorphisms to differential responses of the brain to drugs.

We present a method for investigating the dynamic pharmacological modulation of pain-related brain activity, measured by BOLD-contrast fMRI. Noxious thermal stimulation was combined with a single infusion and washout of remifentanil, a short-acting opioid analgesic agent. The temporal profile of the effect site concentration of remifentanil, estimated from a pharmacokinetic model, was incorporated into a linear model of the fMRI data. The methodology was tested in nine healthy male subjects. During each imaging session the subjects received noxious thermal stimulation to the back of the left hand, prior to infusion, during infusion to a remifentanil effect site concentration of 1.0 ng/ml, and during washout of the remifentanil. Infusions were repeated with saline. Remifentanil-induced analgesia was confirmed from subjective pain intensity scores. Pain-related brain activity was identified in a matrix of regions using a linear model of the transient BOLD responses to noxious stimulation. Of those regions, there was a significant fractional reduction in the amplitude of the pain-related BOLD response in the insular cortex contralateral to the stimulus, the ipsilateral insular cortex, and the anterior cingulate cortex. Statistical parametric mapping of the component of pain-related BOLD responses that was linearly scaled by remifentanil concentration confirmed the contralateral insular cortex as the pain-processing region most significantly modulated by remifentanil compared to saline. The mapping of specific modulation of pain-related brain activity is directly relevant for understanding pharmacological analgesia. The method of examining time-dependent pharmacological modulation of specific brain activity may be generalized to other drugs that modulate brain activity other than that associated with pain.

Graded levels of supplemental inspired oxygen were investigated for their viability as a noninvasive method of obtaining intravascular magnetic resonance image contrast. Administered hyperoxia has been shown to be effective as a blood oxygenation level-dependent contrast agent for magnetic resonance imaging (MRI); however, it is known that high levels of inspired fraction of oxygen result in regionally decreased perfusion in the brain potentially confounding the possibility of using hyperoxia as a means of measuring blood flow and volume. Although the effects of hypoxia on blood flow have been extensively studied, the hyperoxic regime between normoxia and 100% inspired oxygen has been only intermittently studied. Subjects were studied at four levels of hyperoxia induced during a single session while perfusion was measured using arterial spin labelling MRI. Reductions in regional perfusion of grey matter were found to occur even at moderate levels of hyperoxia; however, perfusion changes at all oxygen levels were relatively mild (less than 10%) supporting the viability of hyperoxia-induced contrast.

The estimation of changes in CMRO2 using functional MRI involves an essential calibration step using a vasoactive agent to induce an isometabolic change in CBF. This calibration procedure is performed most commonly using hypercapnia as the isometabolic stimulus. However, hypercapnia possesses a number of detrimental side effects. Here, a new method is presented using hyperoxia to perform the same calibration step. This procedure requires independent measurement of PaO2, the BOLD signal, and CBF. We demonstrate that this method yields results that are comparable to those derived using other methods. Further, the hyperoxia technique is able to provide an estimate of the calibration constant that has lower overall intersubject and intersession variability compared to the hypercapnia approach.

Abstract Purpose To estimate the importance of respiratory and cardiac effects on signal variability found in functional magnetic resonance imaging data recorded from the brainstem. Materials and Methods A modified version of the retrospective image correction (RETROICOR) method (Glover et al, [2000] Magn Reson Med 44:162–167) was implemented on resting brainstem echo‐planar imaging (EPI) data in 12 subjects. Fourier series were fitted to image data based on cardiac and respiratory recordings (pulseoximetry and respiratory turbine), including multiplicative terms that accounted for interactions between cardiac and respiratory signals. F‐tests were performed on residuals produced by regression analysis. Additionally, we evaluated whether modified RETROICOR improved detection of brainstem activation (in 11 subjects) during a finger opposition task. Results The optimal model, containing three cardiac (C) and four respiratory (R) harmonics, and one multiplicative (X) term, “3C4R1X,” significantly reduced signal variability without overfitting to noise. The application of modified RETROICOR to activation data increased group Z‐statistics and reduced putative false‐positive activation. Conclusion In addition to cardiac and respiratory effects, their interaction was also a significant source of physiological noise. The modified RETROICOR model improved detection of brainstem activation and would be usefully applied to any study examining this brain region. J. Magn. Reson. Imaging 2008;28:1337–1344. © 2008 Wiley‐Liss, Inc.

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem.

Intense itch and urge to scratch are the major symptoms of many chronic skin ailments, which are increasingly common. Vicious itch-scratch cycles are readily established and may diminish quality of life for those afflicted. We investigated peripheral and central processing of two types of itch sensation elicited by skin-prick tests of histamine and allergen solutions. Itch-related skin blood flow changes were measured by laser Doppler in 14 subjects responsive to type I allergens and 14 nonatopic subjects. In addition, this study examined central processing of both types of itch using functional magnetic resonance imaging (fMRI). Itch perception and blood flow changes were significantly greater when itch was induced by allergens compared with histamine. Both types of itch correlated significantly with activity in the genual anterior cingulate, striatum, and thalamus. Moreover, itch elicited by allergens activated orbitofrontal, supplementary motor, and posterior parietal areas. Histamine-induced itch also significantly correlated with activation in the insula bilaterally. The identification of limbic and ventral prefrontal activation in two types of itch processing likely reflects the subjects' desire to relieve the itch sensation by scratching, and these regions have been repeatedly associated with motivation processing. A dysfunction of the striato-thalamo-orbitofrontal circuit is believed to underlie the failure to regulate motivational drive in disorders associated with strong urges, e.g., addiction and obsessive compulsive disorder. The patterns of itch-induced activation reported here may help explain why chronic itch sufferers frequently self-harm through uncontrollable itch-scratch cycles.

Despite widespread damage associated with multiple sclerosis (MS) pathology, recovery of function can occur, driven by adaptive plasticity in brain networks. Tomassini et al. review the mechanisms underlying functional recovery in MS, and discuss interventions that might promote this process. Methodological considerations for imaging neuroplasticity using functional MRI are also highlighted. The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain's recovery from damage, generating novel hypotheses about potential targets and modes of intervention, and laying the foundation for development of scientifically informed recovery-promoting strategies in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms that can be modulated by interventions and the development of robust measurements of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use to obtain reliable markers of the effects of interventions.

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is most commonly used in a semi-quantitative manner to infer changes in brain activity. Despite the basis of the image contrast lying in the cerebral venous blood oxygenation level, quantification of absolute cerebral metabolic rate of oxygen consumption (CMRO2) has only recently been demonstrated. Here we examine two approaches to the calibration of fMRI signal to measure absolute CMRO2 using hypercapnic and hyperoxic respiratory challenges. The first approach is to apply hypercapnia and hyperoxia separately but interleaved in time and the second is a combined approach in which we apply hyperoxic challenges simultaneously with different levels of hypercapnia. Eleven healthy volunteers were studied at 3 T using a dual gradient-echo spiral readout pulsed arterial spin labelling (ASL) imaging sequence. Respiratory challenges were conducted using an automated system of dynamic end-tidal forcing. A generalised BOLD signal model was applied, within a Bayesian estimation framework, that aims to explain the effects of modulation of CBF and arterial oxygen content to estimate venous deoxyhaemoglobin concentration ([dHb]0). Using CBF measurements combined with the estimated oxygen extraction fraction (OEF), absolute CMRO2 was calculated. The interleaved approach to hypercapnia and hyperoxia, as well as yielding estimates of CMRO2 and OEF demonstrated a significant increase in regional CBF, venous oxygen saturation (SvO2) (a decrease in OEF) and absolute CMRO2 in visual cortex in response to a continuous (20 min) visual task, demonstrating the potential for the method in measuring long term changes in CMRO2. The combined approach to oxygen and carbon dioxide modulation, as well as taking less time to acquire data, yielded whole brain grey matter estimates of CMRO2 and OEF of 184 ± 45 μmol/100 g/min and 0.42 ± 0.12 respectively, along with additional estimates of the vascular parameters α = 0.33 ± 0.06, the exponent relating relative increases in CBF to CBV, and β = 1.35 ± 0.13, the exponent relating deoxyhaemoglobin concentration to the relaxation rate R2*. Maps of cerebrovascular and cerebral metabolic parameters were also calculated. We show that combined modulation of oxygen and carbon dioxide can offer an experimentally more efficient approach to estimating OEF and absolute CMRO2 along with the additional vascular parameters that form an important part of the commonly used calibrated fMRI signal model.

Inter-subject differences in local cerebral blood flow (CBF) and cerebral blood volume (CBV) contribute to differences in BOLD signal reactivity and, therefore, unmodelled variance in group level fMRI analyses. A simple way of elevating blood CO2 concentrations to characterise subject differences in vascular reactivity is through breath-holds but two aspects of this measure are often neglected: (1) breath-holds are usually modelled as blocks even though CO2 accumulates over time and (2) increases in CO2 differ between subjects. This study demonstrates that the BOLD breath-hold response is best modelled by convolving the end-tidal CO2 trace with a standard haemodynamic response function and including its temporal derivative. Inclusion of the BOLD breath-hold response as a voxel-dependent covariate in a group level analysis increases the spatial extent of activation in stimulus evoked and resting state datasets. By expressing the BOLD breath-hold response as a percentage signal increase with respect to an absolute change in the partial pressure of CO2 (expressed in mmHg), the spatial extent of stimulus-evoked activation is further improved. This demonstrates that individual end-tidal CO2 increases to breath-hold should be accounted for to provide an accurate measure of vascular reactivity resulting in more statistically active voxels in group level analyses.

Abstract It has previously been demonstrated that there is a negative correlation between the amplitude of the BOLD response and resting γ amino‐butyric acid (GABA) concentration in visual cortex. The work here is the first to empirically characterize individual variability in the haemodynamic response functions (HRFs) in response to a simple visual stimulus and baseline GABA concentration in a population of young adult males ( n = 15, aged 20–28 years). The results demonstrate that GABA concentration is negatively correlated with BOLD response amplitude ( r = −0.64, P &lt; 0.02) and positively correlated with HRF width ( r = 0.67, P &lt; 0.002), that is, individuals with higher resting GABA concentration tend to exhibit smaller and wider HRFs. No correlations were observed with resting cerebral blood flow and GABA concentration and similarly, no correlations were observed between GABA and the proportional tissue content of the MRS voxel. We argue that correlation of the height of the HRF is supportive of the view that the previously observed correlations between BOLD amplitudes and GABA are reflective of differences in neuronal activity. However, the changes in HRF shape in individuals with higher baseline GABA levels are suggestive that differing vascular response characteristics may also make a significant contribution. Our results reinforce the view that variability in endogenous factors, such as neurotransmitter concentration, can have a profound effect on the vascular haemodynamic response. This has important implications for between‐cohort fMRI studies in which variation in parameters such as GABA concentration may lead to group differences in the BOLD signal. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.

The therapeutic effects of centrally acting pharmaceuticals can manifest gradually and unreliably in patients, making the drug discovery process slow and expensive. Biological markers providing early evidence for clinical efficacy could help prioritize development of the more promising drug candidates. A potential source of such markers is functional magnetic resonance imaging (fMRI), a noninvasive imaging technique that can complement molecular imaging. fMRI has been used to characterize how drugs cause changes in brain activity. However, variation in study protocols and analysis techniques has made it difficult to identify consistent associations between subtle modulations of brain activity and clinical efficacy. We present and validate a general protocol for functional imaging-based assessment of drug activity in the central nervous system. The protocol uses machine learning methods and data from multiple published studies to identify reliable associations between drug-related activity modulations and drug efficacy, which can then be used to assess new data. A proof-of-concept version of this approach was developed and is shown here for analgesics (pain medication), and validated with eight separate studies of analgesic compounds. Our results show that the systematic integration of multistudy data permits the generalized inferences required for drug discovery. Multistudy integrative strategies of this type could help optimize the drug discovery and validation pipeline.

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.

Neoadjuvant chemo-radiotherapy (CRT) followed by total mesorectal excision (TME) represents the standard treatment for patients with locally advanced (≥ T3 or N+) rectal cancer (LARC). Approximately 15% of patients with LARC shows a complete response after CRT. The use of pre-treatment MRI as predictive biomarker could help to increase the chance of organ preservation by tailoring the neoadjuvant treatment. We present a novel machine learning model combining pre-treatment MRI-based clinical and radiomic features for the early prediction of treatment response in LARC patients. MRI scans (3.0 T, T2-weighted) of 72 patients with LARC were included. Two readers independently segmented each tumor. Radiomic features were extracted from both the "tumor core" (TC) and the "tumor border" (TB). Partial least square (PLS) regression was used as the multivariate, machine learning, algorithm of choice and leave-one-out nested cross-validation was used to optimize hyperparameters of the PLS. The MRI-Based "clinical-radiomic" machine learning model properly predicted the treatment response (AUC = 0.793, p = 5.6 × 10-5). Importantly, the prediction improved when combining MRI-based clinical features and radiomic features, the latter extracted from both TC and TB. Prospective validation studies in randomized clinical trials are warranted to better define the role of radiomics in the development of rectal cancer precision medicine.

BOLD fMRI signal has been used in conjunction with vasodilatory stimulation as a marker of cerebrovascular reactivity (CVR): the relative change in cerebral blood flow (CBF) arising from a unit change in the vasodilatory stimulus. Using numerical simulations, we demonstrate that the variability in the relative BOLD signal change induced by vasodilation is strongly influenced by the variability in deoxyhemoglobin-containing cerebral blood volume (CBV), as this source of variability is likely to be more prominent than that of CVR. It may, therefore, be more appropriate to describe the relative BOLD signal change induced by an isometabolic vasodilation as a proxy of deoxygenated CBV (CBVdHb) rather than CVR. With this in mind, a new method was implemented to map a marker of CBVdHb, termed BOLD-CBV, based on the normalization of voxel-wise BOLD signal variation by an estimate of the intravascular venous BOLD signal from voxels filled with venous blood. The intravascular venous BOLD signal variation, recorded during repeated breath-holding, was extracted from the superior sagittal sinus in a cohort of 27 healthy volunteers and used as a regressor across the whole brain, yielding maps of BOLD-CBV. In the same cohort, we demonstrated the potential use of BOLD-CBV for the normalization of stimulus-evoked BOLD fMRI by comparing group-level BOLD fMRI responses to a visuomotor learning task with and without the inclusion of voxel-wise vascular covariates of BOLD-CBV and the BOLD signal change per mmHg variation in end-tidal carbon dioxide (BOLD-CVR). The empirical measure of BOLD-CBV accounted for more between-subject variability in the motor task-induced BOLD responses than BOLD-CVR estimated from end-tidal carbon dioxide recordings. The new method can potentially increase the power of group fMRI studies by including a measure of vascular characteristics and has the strong practical advantage of not requiring experimental measurement of end-tidal carbon dioxide, unlike traditional methods to estimate BOLD-CVR. It also more closely represents a specific physiological characteristic of brain vasculature than BOLD-CVR, namely blood volume.

BOLD contrast is the most commonly used functional MRI method for studies of brain activity. However, the underlying physiological processes giving rise to measured BOLD signal changes (which include contribution from changes in cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2)) vary substantially between sessions and subjects. To determine whether direct CBF measurement is a more reliable technique, we compared the localisation of activation and reproducibility of relative signal change measured by optimised BOLD versus CBF measured using the arterial spin labelling (ASL) technique. Data were collected within the primary sensorimotor cortex in normal healthy controls performing a simple finger-tapping task over three imaging sessions (two on same day and one on a different day). The displacement between the foci of BOLD and CBF activation was less than the linear dimension of one voxel (2.4 mm), however, BOLD activation was significantly closer to the nearest draining vein compared to CBF activation (P = 0.030). For the relative signal change measurement, we found that CBF has a lower inter-subject variation than BOLD (P < 0.05), enabling a smaller sample size for any given effect size, although the intra-subject variation across sessions for CBF was not significantly different from BOLD. BOLD imaging provides the optimal contrast for exploratory brain activation mapping, however, for a single time-point group study, CBF has reduced variance. In addition, the reduction of variance over time using CBF measurements (non-significant) suggests it could potentially provide a more useful approach when assessing longitudinal activation changes.

Simultaneous recording of event-related electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) responses has the potential to provide information on how the human brain reacts to an external stimulus with unique spatial and temporal resolution. However, in most studies combining the two techniques, the acquisition of functional MR images has been interleaved with the recording of evoked potentials. In this study we investigated the feasibility of recording pain-related evoked potentials during continuous and simultaneous collection of blood oxygen level-dependent (BOLD) functional MR images at 3 T. Brain potentials were elicited by selective stimulation of cutaneous Adelta and C nociceptors using brief radiant laser pulses (laser-evoked potentials, LEPs). MR-induced artifacts on EEG data were removed using a novel algorithm. Latencies, amplitudes, and scalp distribution of LEPs recorded during fMRI were not significantly different from those recorded in a control session outside of the MR scanner using the same equipment and experimental design. Stability tests confirmed that MR-image quality was not impaired by the evoked potential recording, beyond signal loss related to magnetic susceptibility differences local to the electrodes. fMRI results were consistent with our previous studies of brain activity in response to nociceptive stimulation. These results demonstrate the feasibility of recording reliable pain-related LEPs and fMRI responses simultaneously. Because LEPs collected during fMRI and those collected in a control session show remarkable similarity, for many experimental designs the integration of LEP and fMRI data collected in separate, single-modality acquisitions may be appropriate. Truly simultaneous recording of LEPs and fMRI is still desirable in specific experimental conditions, such as single-trial, learning, and pharmacological studies.

Visceral and somatic pain perception differs in several aspects: poor localization of visceral pain and the ability of visceral pain to be referred to somatic structures. The perception of pain intensity and affect in visceral and somatic pain syndromes is often different, with visceral pain reported as more unpleasant. To determine whether these behavioral differences are due to differences in the central processing of visceral and somatic pain, non-invasive imaging tools are required to examine the neural correlates of visceral and somatic events when the behavior has been isolated and matched for either unpleasantness or pain intensity. In this study we matched the unpleasantness of somatic and visceral sensations and imaged the neural representation of this perception using functional magnetic resonance imaging in 10 healthy right-handed subjects. Each subject received noxious thermal stimuli to the left foot and midline lower back and balloon distension of the rectum while being scanned. Stimuli were matched to the same unpleasantness rating, producing mild-moderate pain intensity for somatic stimuli but an intensity below the pain threshold for the visceral stimuli. Visceral stimuli induced deactivation of the perigenual cingulate bilaterally with a relatively greater activation of the right anterior insula-i.e. regions encoding affect. Somatic pain induced left dorso-lateral pre-frontal cortex and bilateral inferior parietal cortex activation i.e. regions encoding spatial orientation and assessing perceptual valence of the stimulus. We believe that the observed patterns of activation represent the differences in cortical process of interoceptive (visceral) and exteroceptive (somatic) stimuli when matched for unpleasantness.

Anatomic sites within the brain, which activate in response to noxious stimuli, can be identified with the use of functional magnetic resonance imaging. The aim of this study was to determine whether the analgesic effects of ketamine could be imaged.Ketamine was administered to eight healthy volunteers with use of a target-controlled infusion to three predicted plasma concentrations: 0 (saline), 50 (subanalgesic), and 200 ng/ml (analgesic, subanesthetic). Volunteers received noxious thermal stimuli and auditory stimuli and performed a motor task within a 3-T human brain imaging magnet. Activation of brain regions in response to noxious and auditory stimuli and during the motor task was compared with behavioral measures.The analgesic subanesthetic dose of ketamine significantly reduced the pain scores, and this matched a decrease in activity within brain regions that activate in response to noxious stimuli, in particular, the insular cortex and thalamus. A different pattern of activation was observed in response to an auditory task. In comparison, smaller behavioral and imaging changes were found for the motor paradigm. The lower dose of ketamine gave similar but smaller nonsignificant effects.The analgesic effect can be measured within a more global effect of ketamine as shown by auditory and motor tasks, and the analgesia produced by ketamine occurs with a smaller degree of cortical processing in pain-related regions.

Investigations into the blood oxygenation level-dependent (BOLD) functional MRI signal have used respiratory challenges with the aim of probing cerebrovascular physiology. Such challenges have altered the inspired partial pressures of either carbon dioxide or oxygen, typically to a fixed and constant level (fixed inspired challenge (FIC)). The resulting end-tidal gas partial pressures then depend on the subject's metabolism and ventilatory responses. In contrast, dynamic end-tidal forcing (DEF) rapidly and independently sets end-tidal oxygen and carbon dioxide to desired levels by altering the inspired gas partial pressures on a breath-by-breath basis using computer-controlled feedback. This study implements DEF in the MRI environment to map BOLD signal reactivity to CO 2 . We performed BOLD (T2*) contrast FMRI in four healthy male volunteers, while using DEF to provide a cyclic normocapnichypercapnic challenge, with each cycle lasting 4 mins (Pet CO2 mean±s.d., from 40.9 ± 1.8 to 46.4 ± 1.6 mm Hg). This was compared with a traditional fixed-inspired (Fi CO2 = 5%) hypercapnic challenge (Pet CO2 mean±s.d., from 38.2 ± 2.1 to 45.6 ± 1.4 mm Hg). Dynamic end-tidal forcing achieved the desired target Pet CO2 for each subject while maintaining Pet CO2 constant. As a result of CO 2 -induced increases in ventilation, the FIC showed a greater cyclic fluctuation in Pet CO2 . These were associated with spatially widespread fluctuations in BOLD signal that were eliminated largely by the control of Pet CO2 during DEF. The DEF system can provide flexible, convenient, and physiologically well-controlled respiratory challenges in the MRI environment for mapping dynamic responses of the cerebrovasculature.

To understand and exploit centrally acting drugs requires reliable measures of their time course of action in the human brain. Functional magnetic resonance imaging (fMRI) is able to measure noninvasively, drug-induced changes in task-related brain activity. Here, we have characterized, in a specific region of the brain, the time of onset of action and the half-life of action of a clinically relevant dose of a potent opioid analgesic agent, remifentanil. These times were established from the temporal variation of the amplitude of the blood oxygen level-dependent response in the insular cortex contralateral to a painfully hot thermal stimulus, in volunteers receiving a remifentanil infusion. The insular cortex has repeatedly been reported as activated by noxious thermal stimulation. The times of onset and offset of drug action were each characterized by a half-life for changes in fMRI signal from within the insula. These characteristic times agreed with the observed drug-induced analgesia and previous pharmacokinetic–pharmacodynamic measurements for remifentanil. We have successfully measured, for the first time using fMRI, temporal pharmacological parameters for a CNS-active drug based on its effect on task-related activity in a specific brain region. Comparison of the time course of regional brain activity with pain perception could reveal those regions engaged in drug-induced analgesia.

Cerebrospinal fluid (CSF) provides hydraulic suspension for the brain. The general concept of bulk CSF production, circulation, and reabsorption is well established, but the mechanisms of momentary CSF volume variation corresponding to vasoreactive changes are far less understood. Nine individuals were studied in a 3T MR scanner with a protocol that included visual stimulation using a 10-Hz reversing checkerboard and administration of a 5% CO(2) mix in air. We acquired PRESS-localized spin-echoes (TR = 12 sec, TE = 26 ms to 1.5 sec) from an 8-mL voxel located in the visual cortex. Echo amplitudes were fitted to a two-compartmental model of relaxation to estimate the partial volume of CSF and the T(2) relaxation times of the tissues. CSF signal contributed 10.7 +/- 3% of the total, with T(2,csf) = 503.0 +/- 64.3 [ms], T(2,brain) = 61.0 +/- 2 [ms]. The relaxation time of tissue increased during physiological stimulation, while the fraction of signal contributed by CSF decreased significantly by 5-6% with visual stimulation (P < 0.03) and by 3% under CO(2) inhalation (P < 0.08). The CSF signal fraction is shown to represent well the volume changes under viable physiological scenarios. In conclusion, CSF plays a significant role in buffering the changes in cerebral blood volume, especially during rapid functional stimuli.

Combined blood oxygenation level-dependent (BOLD) and arterial spin labeling (ASL) functional MRI (fMRI) was performed for simultaneous investigation of neurovascular coupling in the primary visual cortex (PVC), primary motor cortex (PMC), and supplementary motor area (SMA). The hypercapnia-calibrated method was employed to estimate the fractional change in cerebral metabolic rate of oxygen consumption (CMR(O2)) using both a group-average and a per-subject calibration. The group-averaged calibration showed significantly different CMR(O2)-CBF coupling ratios in the three regions (PVC: 0.34 +/- 0.03; PMC: 0.24 +/- 0.03; and SMA: 0.40 +/- 0.02). Part of this difference emerges from the calculated values of the hypercapnic calibration constant M in each region (M(PVC) = 6.6 +/- 3.4, M(PMC) = 4.3 +/- 3.5, and M(SMA) = 7.2 +/- 4.1), while a relatively minor part comes from the spread and shape of the sensorimotor BOLD-CBF responses. The averages of the per-subject calibrated CMR(O2)-CBF slopes were 0.40 +/- 0.04 (PVC), 0.31 +/- 0.03 (PMC), and 0.44 +/- 0.03 (SMA). These results are 10-30% higher than group-calibrated values, and are potentially more useful for quantifying individual differences in focal functional responses. The group-average calibrated motor coupling value is increased to 0.28 +/- 0.03 when stimulus-correlated increases in end-tidal CO(2) are included. Our results support the existence of regional differences in neurovascular coupling, and argue for the importance of achieving optimal accuracy in hypercapnia calibrations to resolve method-dependent variations in published results.

Arterial spin labelling (ASL) has proved to be a promising magnetic resonance imaging (MRI) technique to measure brain perfusion. In this study, volumetric three-dimensional (3D) gradient and spin echo (GRASE) ASL was used to produce cerebral blood flow (CBF) and arterial arrival time (AAT) maps during rest and during an infusion of remifentanil. Gradient and spin echo ASL perfusion-weighted images were collected at multiple inflow times (500 to 2,500 ms in increments of 250 ms) to accurately fit an ASL perfusion model. Fit estimates were assessed using z-statistics, allowing voxels with a poor fit to be excluded from subsequent analyses. Nonparametric permutation testing showed voxels with a significant difference in CBF and AAT between conditions across a group of healthy participants (N=10). Administration of remifentanil produced an increase in end-tidal CO(2), an increase in CBF from 57+/-12.0 to 77+/-18.4 mL/100 g tissue per min and a reduction in AAT from 0.73+/-0.073 to 0.64+/-0.076 sec. Within grey matter, remifentanil produced a cerebrovascular response of 5.7+/-1.60 %CBF per mm Hg. Significant differences between physiologic conditions were observed in both CBF and AAT maps, indicating that 3D GRASE-ASL has the sensitivity to study changes in physiology at a voxel level.

Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (&lt;0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices.

HomeCirculation ResearchVol. 119, No. 12Is High Blood Pressure Self-Protection for the Brain? Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBIs High Blood Pressure Self-Protection for the Brain? Esther A.H. Warnert, Jonathan C.L. Rodrigues, Amy E. Burchell, Sandra Neumann, Laura E.K. Ratcliffe, Nathan E. Manghat, Ashley D. Harris, Zoe Adams, Angus K. Nightingale, Richard G. Wise, Julian F.R. Paton and Emma C. Hart Esther A.H. WarnertEsther A.H. Warnert From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Jonathan C.L. RodriguesJonathan C.L. Rodrigues From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Amy E. BurchellAmy E. Burchell From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Sandra NeumannSandra Neumann From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Laura E.K. RatcliffeLaura E.K. Ratcliffe From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Nathan E. ManghatNathan E. Manghat From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Ashley D. HarrisAshley D. Harris From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Zoe AdamsZoe Adams From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Angus K. NightingaleAngus K. Nightingale From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Richard G. WiseRichard G. Wise From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). , Julian F.R. PatonJulian F.R. Paton From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). and Emma C. HartEmma C. Hart From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children’s Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.). Originally published26 Sep 2016https://doi.org/10.1161/CIRCRESAHA.116.309493Circulation Research. 2016;119:e140–e151Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 9, 2016: Previous Version 1 AbstractRationale:Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular variants of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the pathogenesis of essential hypertension, which remains enigmatic in 95% of patients.Objective:To evaluate the role of the cerebral circulation in the pathophysiology of hypertension.Methods and Results:We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia, and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow, and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving antihypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension, suggesting that it may be a novel prognostic or diagnostic marker (n=126).Conclusions:Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore, lowering blood pressure may worsen cerebral perfusion in susceptible individuals.IntroductionHigh blood pressure (BP) affects ≈25% of the world’s population and is the largest single contributor to global mortality.1 Hypertension represents a significant economic burden to public healthcare providers, where the global cost of nonoptimal BP is estimated to be US$370 billion (10% of healthcare expenditure).2 Remarkably, despite the availability of many pharmacological treatments, BP is poorly controlled with a recent report stating that only 53% of patients prescribed antihypertensive medication have BP controlled.3 This reflects the well-known heterogeneity of the syndrome, including epigenetic and inherited factors contributing to the unknown causes in 95% of patients.4Editorial, see p 1267In This Issue, see p 1255Despite the devastating consequences of hypertension (eg, stroke, kidney failure, coronary heart disease, and death1,2), the mechanisms that lead to the onset of hypertension in humans are poorly understood. It is well established that elevated sympathetic nerve activity (SNA) contributes to the development of hypertension in most humans,5–7 but what initiates this remains unclear. Experimental data from hypertensive rats and observations in postmortem human studies suggest that blood flow to the brain might be important in setting the operating level of SNA and, thus, systemic arterial pressure.8,9 Evidence from Dickinson10 showed that the vertebral arteries in hypertensive patients were narrower than those observed in normotensive individuals. Dickinson and Thomason9 demonstrated that high vertebral artery resistance correlated with higher BP; importantly, a weaker relationship was found in other arteries, including femoral, renal, and internal carotid arteries. They proposed that narrowing of the vertebral arteries with subsequent brain stem hypoperfusion might be a cause of hypertension, rather than being a consequence, but had no evidence to support causality. This has been termed Cushing’s mechanism or the selfish brain hypothesis of hypertension.11 The mechanism may trigger elevations in SNA and BP, thereby maintaining cerebral blood flow.8,12 Evidence from spontaneously hypertensive rats at a prehypertensive age supports this notion: Cates et al8 demonstrated that vertebrobasilar artery hypertrophy occurred before the onset of hypertension in these animals. The authors also showed that brain stem ischemia caused by bilateral vertebral artery clamping, generated a greater increase in SNA in prehypertensive spontaneously hypertensive rats compared with age-matched normotensive animals.8 In addition, the brain stem of hypertensive rats is hypoxic, and this is accentuated when BP is normalized.13We have addressed the issue of whether Cushing’s mechanism is involved in the development of hypertension in humans. This may have a significant impact on the diagnosis and treatment of hypertension, whilst potentially aiding prevention of early-onset vascular dementia in hypertensive humans.14 Thus, we have evaluated the temporal relationship of changes in cerebral vascular structure and cerebral blood flow with both the onset of hypertension and raised SNA in humans. We performed a series of retrospective and mechanistic case–control studies in a range of participants with different levels of BP and classifications of hypertension. Uniquely, we show that congenital cerebral vascular variants, vascular resistance, and blood flow are tightly coupled to the development of hypertension in humans.MethodsRetrospective StudyWe first measured whether there were anatomic differences in the cerebral circulation of hypertensive patients compared with controls. We specifically focused on vertebral artery hypoplasia (VAH; a congenital anatomic variant of the posterior circulation that occurs in the general population), which is associated with lower posterior cerebral territory blood flow15 and variations in the anatomy of the circle of Willis (CoW). We hypothesized that the occurrence of anatomic variants in the vertebral arteries and CoW would be higher in the hypertensive population compared with that reported for healthy controls.Study PopulationA total of 133 patients with essential hypertension referred to the Bristol Heart Institute tertiary hypertension clinic between February 2012 and April 2015 were included in the retrospective analyses (secondary causes of hypertension had been excluded in clinic). The local Research Ethics committee confirmed that the study conformed to the governance arrangements for research ethics committees. All patients provided written informed consent. Online Table I shows patient characteristics. Cases included were from consecutive referrals by the hypertension clinic to the Cardiovascular Magnetic Resonance Unit in the NIHR Bristol Cardiovascular Biomedical Research Unit in the Bristol Heart Institute.BP MeasurementsAverage office systolic BP and diastolic BP were measured from both arms after seated rest, using standard automated sphygmomanometry with an appropriate sized cuff.16 In a subgroup of patients (n=84), 24-hour ambulatory BP monitoring was completed17 (Online Table I).Magnetic Resonance Imaging Procedures3-Dimensional (3D) time-of-flight magnetic resonance angiography at 1.5T (Avanto, Siemens, Erlangen, Germany) with a dedicated head coil was used to measure arterial anatomy (repetition time=38 ms, echo time=5.28 ms, flip angle=25°, voxel size=0.7×0.5×0.8 mm3, field of view=200 mm, covering major arteries feeding into the CoW). See Online Data Supplement for further information about angiogram analyses.Briefly, VAH was defined as a diameter <2 mm uniformly throughout the vessel.15 Anterior and posterior CoW anatomy was reviewed as previously described.18 VAH was compared with the data previously reported from 306 healthy controls.15 CoW morphology was classified according to the normal reference standards.18Case–Control StudyParticipantsFollowing approval by the National Health Service (NHS) Research Ethics Committee (11/SW/0207) and local R&D approval, 142 participants were prospectively recruited and enrolled at a single site (University Hospitals Bristol NHS Foundation Trust). Participants gave their written informed consent to participate in this study. Sixteen volunteers were excluded because of screen failure or early termination of magnetic resonance imaging (MRI) scan because of discomfort or unforeseen technical difficulties. See Online Data Supplement for inclusion and exclusion criteria. Table 1 outlines participant characteristics and the number and classes of antihypertensive medications being taken. One patient in this study had received renal denervation, which was successful in treating their hypertension.Table 1. Characteristics of Participants in the Case–Control StudyNormotensive (n=49)Hypertensive (n=77)Demographics Female sex, %5758 Age, y52±257±2 Height, cm171±1172±1 Weight, kg71±282±2 Body mass index, kg/m225.2±0.827.7±0.5* Family history of hypertension, %1748‡Office SBP, mm Hg122±2148±2† DBP, mm Hg75±189±2† MBP, mm Hg91±1109±2† HR, bpm65±266±1ABPM daytime SBP, mm Hg119±2139±2† DBP, mm Hg76±185±2† MBP, mm Hg90±1101±2† HR, bpm75±274±1ABPM night SBP, mm Hg107±2122±2† DBP, mm Hg64±172±1† MBP, mm Hg79±189±1† HR, bpm65±264±1 Antihypertensive medications (n)01 (0–6) ACEi, %023 ARB, %015 CCB, %020 Diuretic, %019 β-blocker, %08 α-blocker, %02 I1-blocker, %02Brain volumes, CBF and CVR White matter, %38.6138.33 Gray matter, %40.4941.74§ Gray/white matter ratio1.051.09§Total CBF, mL/min per 100 mL tissue54.4±1.161.8±1.4†Total CVR, mL/min per 100 mL/mm Hg1.91±0.051.28±0.03†Family history of hypertension in first-order relatives is self-reported. Data are mean±SEM or median (IQR). ABPM indicates ambulatory blood pressure monitoring; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CBF, cerebral blood flow; CCB, calcium channel blocker; CVR, cerebral vascular resistance; DBP, diastolic blood pressure; HR, heart rate; MBP, mean blood pressure; and SBP, systolic blood pressure.*P<0.001 (unpaired Student t test), §P<0.01, †P<0.0001 (1-way ANCOVA, body mass index as covariate). ‡P<0.001; Fisher exact test.Six specific BP subgroups were prospectively recruited: young normotensive (age <35 years; Table 2 for characteristics), older normotensive (age >35 years), borderline/prehypertensive, untreated hypertensive, treated-controlled hypertensive (taking antihypertensive medication and BP controlled), and treated-uncontrolled hypertensive groups (taking antihypertensive medications, but BP uncontrolled). Borderline hypertension was defined as an office BP of 135 to 140/85 to 90 mm Hg and a daytime ambulatory BP of 130 to 135/80 to 85 mm Hg.Table 2. Characteristics of NTN and HTN SubgroupsYoung NTN (n=20)Older NTN (n=28)Borderline HTN (n=20)Untreated HTN (n=20)Treated HTN (n=19)Uncontrolled HTN (n=18)Demographics Age, y28±0.852±2*51±3*56±2*58±2*59±2* Sex, % women505045505546 BMI, kg/m224.0±0.824.5±0.628.3±1.1*†28.0±1.228.7±1.0*†31.0±0.9*†Family history HTN, %52255†59†58†56†Office SBP, mm Hg121±3123±2138±2*169±5*,†,‡,§138±3163±5*,†,‡,§ DBP, mm Hg73±276±184±299±3*,†,‡,§82±293±2*,†,‡,§ MBP, mm Hg89±292±1103±1122±4*,†,‡,§102±2116±3*,†,‡,§ HR, bpm67±364±264±267±268±368±3ABPM daytime SBP, mm Hg121±2118±2132±2*,†150±4*,†,‡,§127±2146±2*,†,‡,§ DBP, mm Hg78±276±182±1†93±3*,†,‡,§80±288±2*,†,‡,§ MBP, mm Hg90±290±197±2*,†111±3*,†,‡,§95±1106±2*,†,‡,§ HR, bpm77±374±272±276±276±270±3ABPM night SBP, mm Hg114±3105±2118±2*,†126±3*,†,‡,§115±2128±3*,†,‡,§ DBP, mm Hg66±363±170±2†76±2*,†70±274±2† MBP, mm Hg82±378±186±2†93±2*,†84±290±4*,† HR, bpm68±464±264±265±276±263±3 Antihypertensive medications (n)00002.0 (1.0–2.0)3.0 (1.5–2.5) ACEi, %00004263 ARB, %00003237 CCB, %00002663 Diuretic, %00004247 β-blocker, %00001621 α-blocker, %0000011 I1-blocker, %000055Data are mean±SEM or median (interquartile range). ABPM indicates ambulatory blood pressure monitoring; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; HTN, hypertensive; MBP, mean blood pressure; NTN, normotensive; and SBP, systolic blood pressure.*P<0.05 vs young NTN, †P<0.05 vs older NTN, ‡P<0.05 vs borderline HTN, and §P<0.05 vs treated HTN (1-way ANCOVA with Bonferroni test for multiple comparisons or χ2 test where appropriate).Screening BPParticipants attended a screening session, where office BP was measured using an automated cuff (Omron, The Netherlands), in line with the European Society of Hypertension guidelines.19 Participants were fitted with an ambulatory BP monitor (Spacelabs, OSI Systems Company, Englewood, CO). Their 24-hour BP was measured twice per hour during the daytime and once per hour during the night.MicroneurographyPeroneal microneurography was completed to measure multiunit muscle sympathetic nerve activity (MSNA). For full methods, see Online Data Supplement. After instrumentation, 5 to 10 minutes of baseline data were collected in all patients. Heart rate, BP, and MSNA were measured and recorded continuously using a data acquisition program on a study laptop (LabChart, AD instruments).MRI AcquisitionAll study participants were scanned using 3-T MRI (GE HDx, Milwaukee, WI). The protocol consisted of a high-resolution T1-weighted fast spoiled gradient echo (3D-FSPGR) structural scan, 3D time-of-flight angiography to measure arterial anatomy, phase-contrast pulse sequences to measure blood flow in the internal carotid, and basilar arteries at baseline and in response to 5% CO2, and pseudocontinuous arterial spin labeling to measure regional cerebral blood flow. BP (automated cuff), heart rate (pulse oximeter), and end-tidal CO2 (capnograph) were monitored throughout all acquisitions. See Online Data Supplement for imaging parameters.Because poor cerebral vascular reactivity is linked to the risk of developing hypertension, we hypothesized that the hypertensive group would have impaired cerebral vascular reactivity. In a subgroup of participants, cerebral vascular reactivity to isoxic hypercapnia (5% CO2) and to a strong visual stimulus (flashing checkerboard,20 using a dual echo blood oxygen level dependent [BOLD] and ASL MRI acquisition) was measured (Online Data Supplement for MRI parameters).MRI AnalysesAll data analyses were blinded and completed by separate investigators. Please see Online Data Supplement for details about the methodology for MRI analyses. In short, to measure blood flow in the right and left internal carotid and basilar arteries, phase-contrast images were analyzed using Segment (version 1.9, Medviso, Sweden).21 Total cerebral blood flow was estimated as the sum of blood flow in these vessels and scaled for parenchymal tissue volumes. Cerebral vascular resistance was calculated as the brachial mean arterial pressure (measured during the phase-contrast acquisition) divided by average flow in each vessel. This method assumes that intracranial pressure and venous pressure are normal and similar between groups, and therefore that mean arterial pressure is an accurate estimation of cerebral perfusion pressure in different groups. The method has been used in multiple studies to calculate cerebral vascular resistance.22,23 Regional cerebral perfusion was measured from the pseudo continuous arterial spin labeling images using the standard Buxton model.24 Cerebral vascular reactivity to hypercapnia (5% CO2) was calculated as the change in total cerebral blood flow (calculated as the sum of blood flow in the internal carotid and basilar arteries, measured using phase contrast MRI) from the normocapnic condition. Blood flow was scaled for changes in end-tidal CO2 and BP. Finally, positive and negative changes in cerebral blood flow and BOLD signal, in response to the flashing checkerboard stimulus, were measured in the visual cortex.Statistical AnalysesAll data analysis was blinded. An unpaired Student t test was used to test for differences in participant’s characteristics/demographics between normotensive and hypertensive groups. A 1-way ANCOVA was used to test for differences in total cerebral blood flow, regional cerebral blood flow, and MSNA between hypertensive and normotensive groups, using body mass index (BMI) as a covariate. Binary logistic regression (enter method) was used to test for differences in the prevalence of anatomic variations (VAH, incomplete posterior CoW or VAH with an incomplete posterior CoW) between hypertensive and normotensive groups. To test for differences in cerebral blood flow and cerebral vascular resistance, between hypertensive and normotensive participants with and without anatomic variants, a 1-way ANCOVA (BMI as a covariate) was used with a Bonferroni test for multiple comparisons. Participants subgrouped into specific normotensive and hypertensive groups; a 1-way ANCOVA (BMI as covariate) with a Bonferroni test for multiple comparisons was used to test for differences in demographics, BP, cerebral blood flow, cerebral vascular resistance, and MSNA.To predict which variables might be better predictors of hypertension (ie, is cerebral vascular resistance a stronger predictor of hypertension than BMI?), conditional forward binary logistic regression was completed, where diagnosis of hypertension was the dependent variable. The independent variables were age, BMI, cerebral blood flow, cerebral vascular resistance, VAH plus an incomplete posterior CoW, and MSNA. All statistical tests were 2-tailed. α was set at 0.05, where appropriate data are reported as mean±SEM, median with interquartile range, or as percentage with 95% confidence intervals.ResultsRetrospective StudyAnatomic Variations in the Cerebral VasculaturePatient characteristics are outlined in the Online Table I. Fisher exact test showed that VAH and an incomplete posterior CoW were highly prevalent in the hypertensive population (hypertensive versus normotensive15,18: 53% versus 27% and 64% versus 36%, respectively; P<0.0001; Figure 1). The odds ratios indicated that individuals with VAH or those with an incomplete posterior CoW were 2.8 (95% CI, 1.8–4.3) and 3.1 (95% CI, 1.6–6.1) times more likely to have hypertension. There were no differences in the prevalence of an incomplete anterior CoW between our hypertensive cohort and that reported in a healthy control population18 (32% versus 25%, respectively; P=0.26).Download figureDownload PowerPointFigure 1. Congenital cerebrovascular variants of the posterior cerebral circulation are more prevalent in people with hypertension compared with normotensive controls. A and B, Examples of vertebral artery hypoplasia (VAH; right image) and an incomplete posterior circle of Willis (iCoW; no posterior communicating arteries; pCoA; right image). C, Retrospective study (n=133), prevalence of VAH and iCoW is higher in patients with hypertension compared with the prevalence in controls. There were no differences in age (51±2 vs 51±2 years, P=0.93), sex (males; 56% vs 50%, P=0.50), systolic blood pressure (169±3 vs 170.1±3 mm Hg, P=0.87), or diastolic blood pressure (97±2 vs 96±5 mm Hg, P=0.72) between hypertensive patients with VAH and those without this anatomic variant. D, Case–control study (n=136), prevalence of VAH and VAH with an incomplete posterior CoW in hypertensives and normotensive controls. The retrospective study is compared with data previously described by Park et al.15 **P=0.006 (binary logistic regression), ****P<0.0001 (Fisher exact test). HTN indicates hypertensive; and NTN, normotensive.During the retrospective analysis, we noted that there was also a high prevalence of VAH with an incomplete posterior CoW (27%). The prevalence of having both variants has not been compared in healthy controls previously. We were interested in whether the prevalence was higher in t

FMRI BOLD responses to changes in neural activity are influenced by the reactivity of the vasculature. By complementing a task-related BOLD acquisition with a vascular reactivity measure obtained through breath-holding or hypercapnia, this unwanted variance can be statistically reduced in the BOLD responses of interest. Recently, it has been suggested that vascular reactivity can also be estimated using a resting state scan. This study aimed to compare three breath-hold based analysis approaches (block design, sine-cosine regressor and CO2 regressor) and a resting state approach (CO2 regressor) to measure vascular reactivity. We tested BOLD variance explained by the model and repeatability of the measures. Fifteen healthy participants underwent a breath-hold task and a resting state scan with end-tidal CO2 being recorded during both. Vascular reactivity was defined as CO2-related BOLD percent signal change/mmHg change in CO2. Maps and regional vascular reactivity estimates showed high repeatability when the breath-hold task was used. Repeatability and variance explained by the CO2 trace regressor were lower for the resting state data based approach, which resulted in highly variable measures of vascular reactivity. We conclude that breath-hold based vascular reactivity estimations are more repeatable than resting-based estimates, and that there are limitations with replacing breath-hold scans by resting state scans for vascular reactivity assessment.

A decade of research and development in resting-state functional MRI (RSfMRI) has opened new translational and clinical research frontiers. This review aims to bridge between technical and clinical researchers who seek reliable neuroimaging biomarkers for studying drug interactions with the brain. About 85 pharma-RSfMRI studies using BOLD signal (75% of all) or arterial spin labeling (ASL) were surveyed to investigate the acute effects of psychoactive drugs. Experimental designs and objectives include drug fingerprinting dose-response evaluation, biomarker validation and calibration, and translational studies. Common biomarkers in these studies include functional connectivity, graph metrics, cerebral blood flow and the amplitude and spectrum of BOLD fluctuations. Overall, RSfMRI-derived biomarkers seem to be sensitive to spatiotemporal dynamics of drug interactions with the brain. However, drugs cause both central and peripheral effects, thus exacerbate difficulties related to biological confounds, structured noise from motion and physiological confounds, as well as modeling and inference testing. Currently, these issues are not well explored, and heterogeneities in experimental design, data acquisition and preprocessing make comparative or meta-analysis of existing reports impossible. A unifying collaborative framework for data-sharing and data-mining is thus necessary for investigating the commonalities and differences in biomarker sensitivity and specificity, and establishing guidelines. Multimodal datasets including sham-placebo or active control sessions and repeated measurements of various psychometric, physiological, metabolic and neuroimaging phenotypes are essential for pharmacokinetic/pharmacodynamic modeling and interpretation of the findings. We provide a list of basic minimum and advanced options that can be considered in design and analyses of future pharma-RSfMRI studies. Hum Brain Mapp 38:2276-2325, 2017. © 2017 Wiley Periodicals, Inc.

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.

Long-term exercise interventions have been shown to be a potent trigger for both neurogenesis and vascular plasticity. However, little is known about the underlying temporal dynamics and specifically when exercise-induced vascular adaptations first occur, which is vital for therapeutic applications. In this study, we investigated whether a single session of moderate-intensity exercise was sufficient to induce changes in the cerebral vasculature. We employed arterial spin labeling magnetic resonance imaging to measure global and regional cerebral blood flow (CBF) before and after 20 min of cycling. The blood vessels' ability to dilate, measured by cerebrovascular reactivity (CVR) to CO2 inhalation, was measured at baseline and 25-min postexercise. Our data showed that CBF was selectively increased by 10-12% in the hippocampus 15, 40, and 60 min after exercise cessation, whereas CVR to CO2 was unchanged in all regions. The absence of a corresponding change in hippocampal CVR suggests that the immediate and transient hippocampal adaptations observed after exercise are not driven by a mechanical vascular change and more likely represents an adaptive metabolic change, providing a framework for exploring the therapeutic potential of exercise-induced plasticity (neural, vascular, or both) in clinical and aged populations.

Counter-stimulation reduces pain perception; however, the role of attention during this process is rarely discussed despite attention itself being a well known modulator of pain perception. This study investigated the effect of attentional modulation on pain perception during counter-stimulation using fMRI. Subjects received a noxious thermal stimulus together with an innocuous vibratory counter-stimulus. Subjects directed their attention towards either pain, vibration, or a neutral visual stimulus. During painful and counter-stimulation all subjects reported a reduction in pain perception when attending to counter-stimulation compared with attending to pain. Imaging data supported this behavioural finding showing reduced activity in pain processing areas (anterior cingulate, insula, thalamus). These results suggest attention plays an important part in the pain relief experienced from counter-stimulation.

Recent work has suggested that diffusion-weighted functional magnetic resonance imaging (FMRI) with strong diffusion weighting (high b value) detects neuronal swelling that is directly related to neuronal firing. This would constitute a much more direct measure of brain activity than current methods and represent a major advance in neuroimaging. However, it has not been firmly established that the observed signal changes do not reflect residual vascular effects, which are known to exist at low b value. This study measures the vascular component of diffusion FMRI directly by using hypercapnia, which induces blood flow changes in the absence of a change in neuronal firing. Hypercapnia elicits a similar diffusion FMRI response to a visual stimulus including a rise in percent signal change with increasing b value, which was reported for visual activation. Analysis of the response timing found no evidence for an early response at high b value, which has been reported as evidence for a nonhemodynamic response. These results suggest that a large component of the diffusion FMRI signal at high b value is vascular rather than neuronal.

Prior hypotheses in functional brain imaging are often formulated by constraining the data analysis to regions of interest (ROIs). In this context, this approach yields higher sensitivity than whole brain analyses, which could be particularly important in drug development studies and clinical decision making. Here we systematically examine the effects of different ROI definition criteria on the results inferred from a hypothesis-driven pharmacological fMRI experiment, with the aim of maximising sensitivity and providing a recommended procedure for similar studies. In order to achieve this, we compared different criteria for selecting both anatomical and functional ROIs. Anatomical ROIs were defined (i) specifically for each subject, (ii) at group level, and (iii) using a Talairach-like atlas, in order to assess the effects of inter-subject anatomical variability. Functional ROIs (fROIs) were defined, both for each subject and at group level, by (i) selecting the voxels with the highest Z-score from each study session, and (ii) selecting an inclusive union of significantly active voxels across all sessions. A single value was used to summarise the response within each ROI. For anatomical ROIs we used the mean of the parameter estimates (β values) of either all voxels or the top 20% active voxels. For fROIs we used the mean β value of all voxels constituting the ROI. The results were assessed in terms of the achieved sensitivity in detecting the experimental effect. The use of single-subject anatomical ROIs combined with a summary value calculated from the top 20% fraction of active voxels was the most reliable and sensitive approach for detecting the experimental effect. The use of fROIs from individual sessions introduced unacceptable biases in the results, while the use of union fROIs yielded a lower sensitivity than anatomical ROIs. For these reasons, fROIs should be employed with caution when it is not possible to make clear anatomical prior hypotheses.

We recorded auditory-evoked potentials (AEPs) during simultaneous, continuous fMRI and identified trial-to-trial correlations between the amplitude of electrophysiological responses, characterised in the time domain and the time–frequency domain, and the hemodynamic BOLD response. Cortical AEPs were recorded from 30 EEG channels within the 3 T MRI scanner with and without the collection of simultaneous BOLD fMRI. Focussing on the Cz (vertex) EEG response, single-trial AEP responses were measured from time-domain waveforms. Furthermore, a novel method was used to characterise the single-trial AEP response within three regions of interest in the time–frequency domain (TF-ROIs). The latency and amplitude values of the N1 and P2 AEP peaks during fMRI scanning were not significantly different from the Control session (p > 0.16). BOLD fMRI responses to the auditory stimulation were observed in bilateral secondary auditory cortices as well as in the right precentral and postcentral gyri, anterior cingulate cortex (ACC) and supplementary motor cortex (SMC). Significant single-trial correlations were observed with a voxel-wise analysis, between (1) the magnitude of the EEG TF-ROI1 (70–800 ms post-stimulus, 1–5 Hz) and the BOLD response in right primary (Heschl's gyrus) and secondary (STG, planum temporale) auditory cortex; and (2) the amplitude of the P2 peak and the BOLD response in left pre- and postcentral gyri, the ACC and SMC. No correlation was observed with single-trial N1 amplitude on a voxel-wise basis. An fMRI-ROI analysis of functionally-identified auditory responsive regions identified further single-trial correlations of BOLD and EEG responses. The TF amplitudes in TF-ROI1 and TF-ROI2 (20–400 ms post-stimulus, 5–15 Hz) were significantly correlated with the BOLD response in all bilateral auditory areas investigated (planum temporale, superior temporal gyrus and Heschl's gyrus). However the N1 and P2 peak amplitudes, occurring at similar latencies did not show a correlation in these regions. N1 and P2 peak amplitude did correlate with the BOLD response in bilateral precentral and postcentral gyri and the SMC. Additionally P2 and TF-ROI1 both correlated with the ACC. TF-ROI3 (400–900 ms post-stimulus, 4–10 Hz) correlations were only observed in the ACC and SMC. Across the group, the subject-mean N1 peak amplitude correlated with the BOLD response amplitude in the primary and secondary auditory cortices bilaterally, as well as the right precentral gyrus and SMC. We confirm that auditory-evoked EEG responses can be recorded during continuous and simultaneous fMRI. We have presented further evidence of an empirical single-trial coupling between the EEG and BOLD fMRI responses, and show that a time–frequency decomposition of EEG signals can yield additional BOLD fMRI correlates, predominantly in auditory cortices, beyond those found using the evoked response amplitude alone.

Erythropoietin (Epo) has neuroprotective and neurotrophic effects and is a promising candidate for treatment of neurodegenerative and psychiatric disorder. Recently, we demonstrated that Epo modulates memory-relevant hippocampal response and fear processing in human models of antidepressant drug action 1 week post-administration, and improves self-reported mood for 3 days immediately following administration. The present study explored the effects of Epo (40 000 IU) vs saline on self-reported mood and on neural and cognitive function in healthy volunteers 3 days post-administration to test the reliability of the rapid mood improvement and its neuropsychological basis. Neuronal responses during the processing of happy and fearful faces were investigated using functional magnetic resonance imaging (fMRI); facial expression recognition performance was assessed after the fMRI scan. Daily ratings of mood were obtained for 3 days after Epo/saline administration. During faces processing Epo enhanced activation in the left amygdala and right precuneus to happy and fearful expressions. This was paired with improved recognition of all facial expressions, in particular of low intensity happiness and fear. This is similar to behavioral effects observed with acute administration of serotonergic antidepressants. Consistent with our previous finding, Epo improved self-reported mood for all 3 days post-administration. Together, these results suggest that characterization of the effects of Epo in a clinically depressed group is warranted.

Failure of adaptive plasticity with increasing pathology is suggested to contribute to progression of disability in multiple sclerosis (MS). However, functional impairments can be reduced with practice, suggesting that brain plasticity is preserved even in patients with substantial damage.. Here, functional magnetic resonance imaging (fMRI) was used to probe systems-level mechanisms of brain plasticity associated with improvements in visuomotor performance in MS patients and related to measures of microstructural damage.23 MS patients and 12 healthy controls underwent brain fMRI during the first practice session of a visuomotor task (short-term practice) and after 2 weeks of daily practice with the same task (longer-term practice). Participants also underwent a structural brain MRI scan.Patients performed more poorly than controls at baseline. Nonetheless, with practice, patients showed performance improvements similar to controls and independent of the extent of MRI measures of brain pathology. Different relationships between performance improvements and activations were found between groups: greater short-term improvements were associated with lower activation in the sensorimotor, posterior cingulate, and parahippocampal cortices for patients, whereas greater long-term improvements correlated with smaller activation reductions in the visual cortex of controls.Brain plasticity for visuomotor practice is preserved in MS patients despite a high burden of cerebral pathology. Cognitive systems different from those acting in controls contribute to this plasticity in patients. These findings challenge the notion that increasing pathology is accompanied by an outright failure of adaptive plasticity, supporting a neuroscientific rationale for recovery-oriented strategies even in chronically disabled patients.

The effects of caffeine are mediated through its non-selective antagonistic effects on adenosine A1 and A2A adenosine receptors resulting in increased neuronal activity but also vasoconstriction in the brain. Caffeine, therefore, can modify BOLD FMRI signal responses through both its neural and its vascular effects depending on receptor distributions in different brain regions. In this study we aim to distinguish neural and vascular influences of a single dose of caffeine in measurements of task-related brain activity using simultaneous EEG–FMRI. We chose to compare low-level visual and motor (paced finger tapping) tasks with a cognitive (auditory oddball) task, with the expectation that caffeine would differentially affect brain responses in relation to these tasks. To avoid the influence of chronic caffeine intake, we examined the effect of 250 mg of oral caffeine on 14 non and infrequent caffeine consumers in a double-blind placebo-controlled cross-over study. Our results show that the task-related BOLD signal change in visual and primary motor cortex was significantly reduced by caffeine, while the amplitude and latency of visual evoked potentials over occipital cortex remained unaltered. However, during the auditory oddball task (target versus non-target stimuli) caffeine significantly increased the BOLD signal in frontal cortex. Correspondingly, there was also a significant effect of caffeine in reducing the target evoked response potential (P300) latency in the oddball task and this was associated with a positive potential over frontal cortex. Behavioural data showed that caffeine also improved performance in the oddball task with a significantly reduced number of missed responses. Our results are consistent with earlier studies demonstrating altered flow-metabolism coupling after caffeine administration in the context of our observation of a generalised caffeine-induced reduction in cerebral blood flow demonstrated by arterial spin labelling (19% reduction over grey matter). We were able to identify vascular effects and hence altered neurovascular coupling through the alteration of low-level task FMRI responses in the face of a preserved visual evoked potential. However, our data also suggest a cognitive effect of caffeine through its positive effect on the frontal BOLD signal consistent with the shortening of oddball EEG response latency. The combined use of EEG–FMRI is a promising methodology for investigating alterations in brain function in drug and disease studies where neurovascular coupling may be altered on a regional basis.

Stimulus-induced gamma oscillations in the 30–80 Hz range have been implicated in a wide number of functions including visual processing, memory and attention. While occipital gamma-band oscillations can be pharmacologically modified in animal preparations, pharmacological modulation of stimulus-induced visual gamma oscillations has yet to be demonstrated in non-invasive human recordings. Here, in fifteen healthy humans volunteers, we probed the effects of the GABAA agonist and sedative propofol on stimulus-related gamma activity recorded with magnetoencephalography, using a simple visual grating stimulus designed to elicit gamma oscillations in the primary visual cortex. During propofol sedation as compared to the normal awake state, a significant 60% increase in stimulus-induced gamma amplitude was seen together with a 94% enhancement of stimulus-induced alpha suppression and a simultaneous reduction in the amplitude of the pattern-onset evoked response. These data demonstrate, that propofol-induced sedation is accompanied by increased stimulus-induced gamma activity providing a potential window into mechanisms of gamma-oscillation generation in humans.

Previous studies have reported low repeatability of BOLD activation measures during emotion processing tasks. It is not clear, however, whether low repeatability is a result of changes in the underlying neural signal over time, or due to insufficient reliability of the acquired BOLD signal caused by noise contamination. The aim of this study was to investigate the influence of “cleaning” the BOLD signal, by correcting for physiological noise and for differences in BOLD responsiveness, on measures of repeatability. Fifteen healthy volunteers were scanned on two different occasions, performing an emotion provocation task with faces (neutral, 50% fearful, 100% fearful) followed by a breath-hold paradigm to provide a marker of BOLD responsiveness. Repeatability of signal distribution (spatial repeatability) and repeatability of signal amplitude within two regions of interest (amygdala and fusiform gyrus) were estimated by calculating the intraclass correlation coefficient (ICC). Significant repeatability of signal amplitude was only found within the right amygdala during the perception of 50% fearful faces, but disappeared when physiological noise correction was performed. Spatial repeatability was higher within the fusiform gyrus than within the amygdala, and better at the group level than at the participant level. Neither physiological noise correction, nor consideration of BOLD responsiveness, assessed through the breath-holding, increased repeatability. The findings lead to the conclusion that low repeatability of BOLD response amplitude to emotional faces is more likely to be explained by the lack of stability in the underlying neural signal than by physiological noise contamination. Furthermore, reported repeatability might be a result of repeatability of task-correlated physiological variation rather than neural activity. This means that the emotion paradigm used in this study might not be useful for studies that require the BOLD response to be a stable measure of emotional processing, for example in the context of biomarkers.

This study aims to map the acute effects of caffeine ingestion on grey matter oxygen metabolism and haemodynamics with a novel MRI method. Sixteen healthy caffeine consumers (8 males, age=24.7±5.1) were recruited to this randomised, double-blind, placebo-controlled study. Each participant was scanned on two days before and after the delivery of an oral caffeine (250 mg) or placebo capsule. Our measurements were obtained with a newly proposed estimation approach applied to data from a dual calibration fMRI experiment that uses hypercapnia and hyperoxia to modulate brain blood flow and oxygenation. Estimates were based on a forward model that describes analytically the contributions of cerebral blood flow (CBF) and of the measured end-tidal partial pressures of CO2 and O2 to the acquired dual-echo GRE signal. The method allows the estimation of grey matter maps of: oxygen extraction fraction (OEF), CBF, CBF-related cerebrovascular reactivity (CVR) and cerebral metabolic rate of oxygen consumption (CMRO2). Other estimates from a multi inversion time ASL acquisition (mTI-ASL), salivary samples of the caffeine concentration and behavioural measurements are also reported. We observed significant differences between caffeine and placebo on average across grey matter, with OEF showing an increase of 15.6% (SEM±4.9%, p<0.05) with caffeine, while CBF and CMRO2 showed differences of −30.4% (SEM±1.6%, p<0.01) and −18.6% (SEM±2.9%, p<0.01) respectively with caffeine administration. The reduction in oxygen metabolism found is somehow unexpected, but consistent with a hypothesis of decreased energetic demand, supported by previous electrophysiological studies reporting reductions in spectral power with EEG. Moreover the maps of the physiological parameters estimated illustrate the spatial distribution of changes across grey matter enabling us to localise the effects of caffeine with voxel-wise resolution. CBF changes were widespread as reported by previous findings, while changes in OEF were found to be more restricted, leading to unprecedented mapping of significant CMRO2 reductions mainly in frontal gyrus, parietal and occipital lobes. In conclusion, we propose the estimation framework based on our novel forward model with a dual calibrated fMRI experiment as a viable MRI method to map the effects of drugs on brain oxygen metabolism and haemodynamics with voxel-wise resolution.

It is well known that the blood oxygen level-dependent (BOLD) signal measured by functional magnetic resonance imaging (fMRI) is influenced—in addition to neuronal activity—by fluctuations in physiological signals, including arterial CO 2 , respiration and heart rate/heart rate variability (HR/HRV). Even spontaneous fluctuations of the aforementioned physiological signals have been shown to influence the BOLD fMRI signal in a regionally specific manner. Related to this, estimates of functional connectivity between different brain regions, performed when the subject is at rest, may be confounded by the effects of physiological signal fluctuations. Moreover, resting functional connectivity has been shown to vary with respect to time (dynamic functional connectivity), with the sources of this variation not fully elucidated. In this context, we examine the relation between dynamic functional connectivity patterns and the time-varying properties of simultaneously recorded physiological signals (end-tidal CO 2 and HR/HRV) using resting-state fMRI measurements from 12 healthy subjects. The results reveal a modulatory effect of the aforementioned physiological signals on the dynamic resting functional connectivity patterns for a number of resting-state networks (default mode network, somatosensory, visual). By using discrete wavelet decomposition, we also show that these modulation effects are more pronounced in specific frequency bands.

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI-based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel-wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue-states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2-weighted hyperintense lesional tissue without T1-weighted hypointensity (T2L), and T1-weighted hypointense lesional tissue with corresponding T2-weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue-states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions.

Increasing numbers of 7 T (7 T) magnetic resonance imaging (MRI) scanners are in research and clinical use. 7 T MRI can increase the scanning speed, spatial resolution and contrast-to-noise-ratio of many neuroimaging protocols, but technical challenges in implementation have been addressed in a variety of ways across sites. In order to facilitate multi-centre studies and ensure consistency of findings across sites, it is desirable that 7 T MRI sites implement common high-quality neuroimaging protocols that can accommodate different scanner models and software versions. With the installation of several new 7 T MRI scanners in the United Kingdom, the UK7T Network was established with an aim to create a set of harmonized structural and functional neuroimaging sequences and protocols. The Network currently includes five sites, which use three different scanner platforms, provided by two different vendors. Here we describe the harmonization of functional and anatomical imaging protocols across the three different scanner models, detailing the necessary changes to pulse sequences and reconstruction methods. The harmonized sequences are fully described, along with implementation details. Example datasets acquired from the same subject on all Network scanners are made available. Based on these data, an evaluation of the harmonization is provided. In addition, the implementation and validation of a common system calibration process is described.

Functional magnetic resonance imaging (fMRI) is an essential workhorse of modern neuroscience, providing valuable insight into the functional organisation of the brain. The physiological mechanisms underlying the blood oxygenation level dependent (BOLD) effect are complex and preclude a straightforward interpretation of the signal. However, by employing appropriate calibration of the BOLD signal, quantitative measurements can be made of important physiological parameters including the absolute rate of cerebral metabolic oxygen consumption or oxygen metabolism (CMRO2) and oxygen extraction (OEF). The ability to map such fundamental parameters has the potential to greatly expand the utility of fMRI and to broaden its scope of application in clinical research and clinical practice. In this review article we discuss some of the practical issues related to the calibrated-fMRI approach to the measurement of CMRO2. We give an overview of the necessary precautions to ensure high quality data acquisition, and explore some of the pitfalls and challenges that must be considered as it is applied and interpreted in a widening array of diseases and research questions.

There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.

Abstract A better understanding of the cortical processes underlying attentional modulation of visceral and somatic pain in health are essential for interpretation of future imaging studies of hypervigilance towards bodily sensations which is considered to be an aetiologically important factor in the heightened pain reported by patients with irritable bowel syndrome and fibromyalgia. Twelve healthy subjects were recruited for this study. Simultaneous trains of electrical pulses (delivered to either the rectum or lower abdomen) and auditory tones lasting 6 s were delivered to the subjects during a whole‐brain functional scan acquisition. Subjects were instructed to attend to the auditory tones (distracter task) or electrical pulses (pain task). Pain intensity ratings were significantly lower during the distraction task compared with the pain task ( P &lt; 0.01) in both sensory modalities. The left primary somatosensory cortex increased in activity with increasing pain report, during attention to visceral pain. Bilateral anterior insula (aIns) cortex activity increased with increasing somatic pain report independent of the direction of attention. Conversely, the primary and secondary auditory cortices significantly increased in activation with decreased pain report. These results suggest that pain intensity perception during attentional modulation is reflected in the primary somatosensory cortex (visceral pain) and aIns cortex activity (somatic pain).

Opioid binding to the cerebral blood vessels may affect vascular responsiveness and hence confound interpretation of blood oxygen level-dependent (BOLD) responses, which are usually interpreted as neuronal in origin. Opioid binding varies in different brain regions. It is unclear whether opioids alter neurovascular coupling, or whether their effects are purely neuronal. This study used BOLD functional magnetic resonance imaging (FMRI) to investigate the effect of a μ-opioid agonist remifentanil, on cerebrovascular CO 2 reactivity (being one component of neurovascular coupling). Hypercapnic challenges were delivered to human volunteers, while controlling potential opioid-induced respiratory depression. The BOLD signal increase to hypercapnia was compared before and during remifentanil administration. Remifentanil was shown not to have a generalised effect on CO 2 responsiveness in the cerebral vasculature. However, it caused a significant reduction in the positive BOLD response to hypercapnia in the bilateral primary sensorimotor cortices, bilateral extrastriate visual areas, left insula, left caudate nucleus, and left inferior temporal gyrus. We conclude that remifentanil does not modulate cerebrovascular CO 2 reactivity, as we saw no difference in BOLD response to hypercapnia in areas with high opioid receptor densities. We did however see a focal reduction in areas related to motor control and putative task activation, which we conclude to be related to changes in neuronal activity related to the sedative effects of remifentanil. Our method of controlling CO 2 levels effectively mitigated the potential confound of respiratory depression and allowed comparison over a similar range of CO 2 levels. We suggest that similar methodology should be used when investigating other potentially vasoactive compounds with FMRI.

Functional neuroimaging can distinguish components of the pain experience associated with anticipation to pain from those associated with the experience of pain itself. Anticipation to pain is thought to increase the suffering of chronic pain patients. Inappropriate anxiety, of which anticipation is a component, is also a cause of disability. We present a pharmacological functional magnetic resonance imaging (fMRI) study in which we investigate the selective modulation by midazolam of brain activity associated with anticipation to pain compared to pain itself. Eight right-handed male volunteers underwent fMRI combined with a thermal pain conditioning paradigm and midazolam (30 μg/kg) or saline administration on different occasions, with order randomized across volunteers. Volunteers learned to associate a colored light with either painful, hot stimulation or nonpainful, warm stimulation to the back of the left hand. Comparison of the period during thermal stimulation (pain−warm) revealed a network of brain activity commonly associated with noxious stimulation, including activities in the anterior cingulate cortex (ACC), the bilateral insular cortices (anterior and posterior), the thalamus, S1, the motor cortex, the brainstem, the prefrontal cortex and the cerebellum. Comparison of the periods preceding thermal stimulation (anticipation to pain−anticipation to warm) revealed activity principally in the ACC, the contralateral anterior insular cortex and the ipsilateral S2/posterior insula. Detected by a region-of-interest analysis, midazolam reduced the activity associated specifically with anticipation to pain while controlling for anticipation to warm. This was most significant in the contralateral anterior insula (P<.05). There were no significant drug effects on the activity associated with pain itself. In identifying a pharmacological effect on activity preceding but not during pain, we have successfully demonstrated an fMRI assay that can be used to study the action of anxiolytic agents in a relatively small cohort of humans.

Caffeine, an adenosine A1 and A2A receptor antagonist, is the most popular psychostimulant drug in the world, but it is also anxiogenic. The neural correlates of caffeine-induced anxiety are currently unknown. This study investigated the effects of caffeine on brain regions implicated in social threat processing and anxiety. Participants were 14 healthy male non/infrequent caffeine consumers. In a double-blind placebo-controlled crossover design, they underwent blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) while performing an emotional face processing task 1 h after receiving caffeine (250 mg) or placebo in two fMRI sessions (counterbalanced, 1-week washout). They rated anxiety and mental alertness, and their blood pressure was measured, before and 2 h after treatment. Results showed that caffeine induced threat-related (angry/fearful faces > happy faces) midbrain-periaqueductal gray activation and abolished threat-related medial prefrontal cortex wall activation. Effects of caffeine on extent of threat-related amygdala activation correlated negatively with level of dietary caffeine intake. In concurrence with these changes in threat-related brain activation, caffeine increased self-rated anxiety and diastolic blood pressure. Caffeine did not affect primary visual cortex activation. These results are the first to demonstrate potential neural correlates of the anxiogenic effect of caffeine, and they implicate the amygdala as a key site for caffeine tolerance.

Across-trial averaging is a widely used approach to enhance the signal-to-noise ratio (SNR) of event-related potentials (ERPs). However, across-trial variability of ERP latency and amplitude may contain physiologically relevant information that is lost by across-trial averaging. Hence, we aimed to develop a novel method that uses 1) wavelet filtering (WF) to enhance the SNR of ERPs and 2) a multiple linear regression with a dispersion term (MLR d ) that takes into account shape distortions to estimate the single-trial latency and amplitude of ERP peaks. Using simulated ERP data sets containing different levels of noise, we provide evidence that, compared with other approaches, the proposed WF+MLR d method yields the most accurate estimate of single-trial ERP features. When applied to a real laser-evoked potential data set, the WF+MLR d approach provides reliable estimation of single-trial latency, amplitude, and morphology of ERPs and thereby allows performing meaningful correlations at single-trial level. We obtained three main findings. First, WF significantly enhances the SNR of single-trial ERPs. Second, MLR d effectively captures and measures the variability in the morphology of single-trial ERPs, thus providing an accurate and unbiased estimate of their peak latency and amplitude. Third, intensity of pain perception significantly correlates with the single-trial estimates of N2 and P2 amplitude. These results indicate that WF+MLR d can be used to explore the dynamics between different ERP features, behavioral variables, and other neuroimaging measures of brain activity, thus providing new insights into the functional significance of the different brain processes underlying the brain responses to sensory stimuli.

The process of neurovascular coupling ensures that increases in neuronal activity are fed by increases in cerebral blood flow. Evidence suggests that neurovascular coupling may be impaired in Multiple Sclerosis (MS) due to a combination of brain hypoperfusion, altered cerebrovascular reactivity and oxygen metabolism, and altered levels of vasoactive compounds. Here, we tested the hypothesis that neurovascular coupling is impaired in MS. We characterized neurovascular coupling as the relationship between changes in neuronal oscillatory power within the gamma frequency band (30-80 Hz), as measured by magnetoencephalography (MEG), and associated hemodynamic changes (blood oxygenation level dependent, BOLD, and cerebral blood flow, CBF) as measured by functional MRI. We characterized these responses in the visual cortex in 13 MS patients and in 10 matched healthy controls using a reversing checkerboard stimulus at five visual contrasts. There were no significant group differences in visual acuity, P100 latencies, occipital gray matter (GM) volumes and baseline CBF. However, in the MS patients we found a significant reduction in peak gamma power, BOLD and CBF responses. There were no significant differences in neurovascular coupling between groups, in the visual cortex. Our results suggest that neuronal and vascular responses are altered in MS. Gamma power reduction could be an indicator of GM dysfunction, possibly mediated by GABAergic changes. Altered hemodynamic responses confirm previous reports of a vascular dysfunction in MS. Despite altered neuronal and vascular responses, neurovascular coupling appears to be preserved in MS, at least within the range of damage and disability studied here.

In this work, we investigate the regional characteristics of the dynamic interactions between arterial CO2 and BOLD (dynamic cerebrovascular reactivity - dCVR) during normal breathing and hypercapnic, externally induced step CO2 challenges. To obtain dCVR curves at each voxel, we use a custom set of basis functions based on the Laguerre and gamma basis sets. This allows us to obtain robust dCVR estimates both in larger regions of interest (ROIs), as well as in individual voxels. We also implement classification schemes to identify brain regions with similar dCVR characteristics. Our results reveal considerable variability of dCVR across different brain regions, as well as during different experimental conditions (normal breathing and hypercapnic challenges), suggesting a differential response of cerebral vasculature to spontaneous CO2 fluctuations and larger, externally induced CO2 changes that are possibly associated with the underlying differences in mean arterial CO2 levels. The clustering results suggest that anatomically distinct brain regions are characterized by different dCVR curves that in some cases do not exhibit the standard, positive valued curves that have been previously reported. They also reveal a consistent set of dCVR cluster shapes for resting and forcing conditions, which exhibit different distribution patterns across brain voxels.

Dual-calibrated fMRI is a multi-parametric technique that allows for the quantification of the resting oxygen extraction fraction (OEF), the absolute rate of cerebral metabolic oxygen consumption (CMRO2), cerebral vascular reactivity (CVR) and baseline perfusion (CBF). It combines measurements of arterial spin labelling (ASL) and blood oxygenation level dependent (BOLD) signal changes during hypercapnic and hyperoxic gas challenges. Here we propose an extension to this methodology that permits the simultaneous quantification of the effective oxygen diffusivity of the capillary network (DC). The effective oxygen diffusivity has the scope to be an informative biomarker and useful adjunct to CMRO2, potentially providing a non-invasive metric of microvascular health, which is known to be disturbed in a range of neurological diseases. We demonstrate the new method in a cohort of healthy volunteers (n = 19) both at rest and during visual stimulation. The effective oxygen diffusivity was found to be highly correlated with CMRO2 during rest and activation, consistent with previous PET observations of a strong correlation between metabolic oxygen demand and effective diffusivity. The increase in effective diffusivity during functional activation was found to be consistent with previously reported increases in capillary blood volume, supporting the notion that measured oxygen diffusivity is sensitive to microvascular physiology.

In preterm (PT) infants, regional cerebral blood flow (CBF) disturbances may predispose to abnormal brain maturation even without overt brain injury. Therefore, it would be informative to determine the spatial distribution of grey matter (GM) CBF in PT and full-term (FT) newborns at term-equivalent age (TEA) and to assess the relationship between the features of the CBF pattern and both prematurity and prematurity-related brain lesions. In this prospective study, we obtained measures of CBF in 66 PT (51 without and 15 with prematurity-related brain lesions) and 38 FT newborns through pseudo-continuous arterial spin labeling (pCASL) MRI acquired at TEA. The pattern of GM CBF was characterized by combining an atlas-based automated segmentation of structural MRI with spatial normalization and hierarchical clustering. The effects of gestational age (GA) at birth and brain injury on the CBF pattern were investigated. We identified 4 physiologically-derived clusters of brain regions that were labeled Fronto-Temporal, Parieto-Occipital, Insular-Deep GM (DGM) and Sensorimotor, from the least to the most perfused. We demonstrated that GM perfusion was associated with GA at birth in the Fronto-Temporal and Sensorimotor clusters, positively and negatively, respectively. Moreover, the presence of periventricular leukomalacia was associated with significantly increased Fronto-Temporal GM perfusion and decreased Insular-DGM perfusion, while the presence of germinal matrix hemorrhage appeared to mildly decrease the Insular-DGM perfusion. Prematurity and prematurity-related brain injury heterogeneously affect brain perfusion. ASL MRI may, therefore, have strong potential as a noninvasive tool for the accurate stratification of individuals at risk of domain-specific impairment.

Nociceptive processing within the human brain takes place within two distinct and parallel systems: the lateral and medial pain systems. Current knowledge indicates that the lateral system is involved in processing the sensory-discriminative aspects of pain, and that the medial system is involved in processing the affective-motivational aspects of pain. Hemispheric differences in brain activation (lateralisation) during nociceptive processing were studied to further clarify the division of function between the lateral and medial pain systems. Hemispheric lateralisation was studied by applying painful CO2 laser stimuli of 3-s duration sequentially to the left and right medial lower calves of five normal right-handed human subjects. The resultant brain activity was measured using 3-T functional magnetic resonance imaging, by determining significant changes in blood oxygen level dependent (BOLD) signal and applying a general linear modelling approach. Volumes of interest were defined for the primary and secondary somatosensory cortices (SI and SII), the insular cortex, and the thalamus, on individual subjects' high-resolution structural scans. Hemispheric lateralisation was quantified by comparing the level of activation between brain hemispheres within each volume of interest. In SII, no significant hemispheric difference in activation was detected. In the insula, activation was significantly greater in the left hemisphere than the right. In both SI and the thalamus, activation in response to painful stimulation was significantly greater in the hemisphere contralateral to the stimulus, which is consistent with these areas being involved in processing the sensory-discriminative aspects of pain.

Laser stimulation of Aδ-fibre nociceptors in the skin evokes nociceptive-specific brain responses (laser-evoked potentials, LEPs). The largest vertex complex (N2–P2) is widely used to assess nociceptive pathways in physiological and clinical studies. The aim of this study was to develop an automated method to measure amplitudes and latencies of the N2 and P2 peaks on a single-trial basis. LEPs were recorded after Nd:YAP laser stimulation of the left hand dorsum in 7 normal volunteers. For each subject, a basis set of 4 regressors (the N2 and P2 waveforms and their respective temporal derivatives) was derived from the time-averaged data and regressed against every single-trial LEP response. This provided a separate quantitative estimate of amplitude and latency for the N2 and P2 components of each trial. All estimates of LEP parameters correlated significantly with the corresponding measurements performed by a human expert (N2 amplitude: R2=0.70; P2 amplitude: R2=0.70; N2 latency: R2=0.81; P2 latency: R2=0.59. All P<0.0001). Furthermore, regression analysis was able to extract an LEP response from a subset of the trials that had been classified by the human expert as without response. This method provides a simple, fast and unbiased measurement of different components of single-trial LEP responses. This method is particularly desirable in several experimental conditions (e.g. drug studies, correlations with experimental variables, simultaneous EEG/fMRI and low signal-to-noise ratio data) and in clinical practice. The described multiple linear regression approach can be easily implemented for measuring evoked potentials in other sensory modalities.

Functional neuroimaging has the potential to improve the decision-making process in the development of new drugs. With the high cost of failure of compounds in later stages of development, there is a need to establish, early in man, reliable measures of drug activity and efficacy in the brain. Functional magnetic resonance imaging (FMRI) is a tool for serially examining normal and pathological brain function at the systems level. FMRI is helping us to understand therapeutic mechanisms and can provide clinically relevant markers of disease responses to drugs. An analysis of the value of FMRI to aid decision-making requires an appreciation of the techniques and their validation, a task that has begun and which necessitates an investment of its own.

Hypoxic hypoxia (inspiratory hypoxia) stimulates an increase in cerebral blood flow (CBF) maintaining oxygen delivery to the brain. However, this response, particularly at the tissue level, is not well characterised. This study quantifies the CBF response to acute hypoxic hypoxia in healthy subjects. A 20-min hypoxic (mean P(ETO2) = 52 mmHg) challenge was induced and controlled by dynamic end-tidal forcing whilst CBF was measured using pulsed arterial spin labelling perfusion MRI. The rate constant, temporal delay and magnitude of the CBF response were characterised using an exponential model for whole-brain and regional grey matter. Grey matter CBF increased from 76.1 mL/100 g/min (95% confidence interval (CI) of fitting: 75.5 mL/100 g/min, 76.7 mL/100 g/min) to 87.8 mL/100 g/min (95% CI: 86.7 mL/100 g/min, 89.6 mL/100 g/min) during hypoxia, and the temporal delay and rate constant for the response to hypoxia were 185 s (95% CI: 132 s, 230 s) and 0.0035 s(-1) (95% CI: 0.0019 s(-1), 0.0046 s(-1)), respectively. Recovery from hypoxia was faster with a delay of 20 s (95% CI: -38 s, 38 s) and a rate constant of 0.0069 s(-1) (95% CI: 0.0020 s(-1), 0.0103 s(-1)). R2*, an index of blood oxygenation obtained simultaneously with the CBF measurement, increased from 30.33 s(-1) (CI: 30.31 s(-1), 30.34 s(-1)) to 31.48 s(-1) (CI: 31.47 s(-1), 31.49 s(-1)) with hypoxia. The delay and rate constant for changes in R2 * were 24 s (95% CI: 21 s, 26 s) and 0.0392 s(-1) (95% CI: 0.0333 s(-1), 0.045 s(-1)), respectively, for the hypoxic response, and 12 s (95% CI: 10 s, 13 s) and 0.0921 s(-1) (95% CI: 0.0744 s(-1), 0.1098 s(-1)/) during the return to normoxia, confirming rapid changes in blood oxygenation with the end-tidal forcing system. CBF and R2* reactivity to hypoxia differed between subjects, but only R2* reactivity to hypoxia differed significantly between brain regions.

Cerebral autoregulation ensures constant cerebral blood flow during periods of increased blood pressure by increasing cerebrovascular resistance. However, whether this increase in resistance occurs at the level of major cerebral arteries as well as at the level of smaller pial arterioles is still unknown in humans. Here, we measure cerebral arterial compliance, a measure that is inversely related to cerebrovascular resistance, with our novel non-invasive magnetic resonance imaging-based measurement, which employs short inversion time pulsed arterial spin labelling to map arterial blood volume at different phases of the cardiac cycle. We investigate the differential response of the cerebrovasculature during post exercise ischemia (a stimulus which leads to increased cerebrovascular resistance because of increases in blood pressure and sympathetic outflow). During post exercise ischemia in eight normotensive men (30.4 ± 6.4 years), cerebral arterial compliance decreased in the major cerebral arteries at the level of and below the Circle of Willis, while no changes were measured in arteries above the Circle of Willis. The reduction in arterial compliance manifested as a reduction in the arterial blood volume during systole. This study provides the first evidence that in humans the major cerebral arteries may play an important role in increasing cerebrovascular resistance.

A noninvasive method of assessing cerebral arterial compliance (AC) is introduced in which arterial spin labeling (ASL) is used to measure changes in arterial blood volume (aBV) occurring within the cardiac cycle. Short inversion time pulsed ASL (PASL) was performed in healthy volunteers with inversion times ranging from 250 to 850 ms. A model of the arterial input function was used to obtain the cerebral aBV. Results indicate that aBV depends on the cardiac phase of the arteries in the imaging volume. Cerebral AC, estimated from aBV and brachial blood pressure measured noninvasively in systole and diastole, was assessed in the flow territories of the basal cerebral arteries originating from the circle of Willis: right and left middle cerebral arteries (RMCA and LMCA), right and left posterior cerebral arteries (RPCA and LPCA), and the anterior cerebral artery (ACA). Group average AC values calculated for the RMCA, LMCA, ACA, RPCA, and LPCA were 0.56%±0.2%, 0.50%±0.3%, 0.4%±0.2%, 1.1%±0.5%, and 1.1%±0.3% per mm Hg, respectively. The current experiment has shown the feasibility of measuring AC of cerebral arteries with short inversion time PASL.

The measurement of the absolute rate of cerebral metabolic oxygen consumption (CMRO2) is likely to offer a valuable biomarker in many brain diseases and could prove to be important in our understanding of neural function. As such there is significant interest in developing robust MRI techniques that can quantify CMRO2 non-invasively. One potential MRI method for the measurement of CMRO2 is via the combination of fMRI and cerebral blood flow (CBF) data acquired during periods of hypercapnic and hyperoxic challenges. This method is based on the combination of two, previously independent, signal calibration techniques. As such analysis of the data has been approached in a stepwise manner, feeding the results of one calibration experiment into the next. Analysing the data in this manner can result in unstable estimates of the output parameter (CMRO2), due to the propagation of errors along the analysis pipeline. Here we present a forward modelling approach that estimates all the model parameters in a one-step solution. The method is implemented using a regularized non-linear least squares approach to provide a robust and computationally efficient solution. The proposed framework is compared with previous analytical approaches using modelling studies and in vivo acquisitions in healthy volunteers (n = 10). The stability of parameter estimates is demonstrated to be superior to previous methods (both in vivo and in simulation). In vivo estimates made with the proposed framework also show better agreement with expected physiological variation, demonstrating a strong negative correlation between baseline CBF and oxygen extraction fraction. It is anticipated that the proposed analysis framework will increase the reliability of absolute CMRO2 measurements made with calibrated BOLD.

Brain plasticity is the basis for systems-level functional reorganization that promotes recovery in multiple sclerosis (MS). As inflammation interferes with plasticity, its pharmacological modulation may restore plasticity by promoting desired patterns of functional reorganization. Here, we tested the hypothesis that brain plasticity probed by a visuomotor adaptation task is impaired with MS inflammation and that pharmacological reduction of inflammation facilitates its restoration. MS patients were assessed twice before (sessions 1 and 2) and once after (session 3) the beginning of Interferon beta (IFN beta), using behavioural and structural MRI measures. During each session, 2 functional MRI runs of a visuomotor task, separated by 25-minutes of task practice, were performed. Within-session between-run change in task-related functional signal was our imaging marker of plasticity. During session 1, patients were compared with healthy controls. Comparison of patients' sessions 2 and 3 tested the effect of reduced inflammation on our imaging marker of plasticity. The proportion of patients with gadolinium-enhancing lesions reduced significantly during IFN beta. In session 1, patients demonstrated a greater between-run difference in functional MRI activity of secondary visual areas and cerebellum than controls. This abnormally large practice-induced signal change in visual areas, and in functionally connected posterior parietal and motor cortices, was reduced in patients in session 3 compared with 2. Our results suggest that MS inflammation alters short-term plasticity underlying motor practice. Reduction of inflammation with IFN beta is associated with a restoration of this plasticity, suggesting that modulation of inflammation may enhance recovery-oriented strategies that rely on patients' brain plasticity. Hum Brain Mapp 37:2431-2445, 2016. © 2016 Wiley Periodicals, Inc.

Several techniques have been proposed to estimate relative changes in cerebral metabolic rate of oxygen consumption (CMRO2) by exploiting combined BOLD fMRI and cerebral blood flow data in conjunction with hypercapnic or hyperoxic respiratory challenges. More recently, methods based on respiratory challenges that include both hypercapnia and hyperoxia have been developed to assess absolute CMRO2, an important parameter for understanding brain energetics. In this paper, we empirically optimize a previously presented "original calibration model" relating BOLD and blood flow signals specifically for the estimation of oxygen extraction fraction (OEF) and absolute CMRO2. To do so, we have created a set of synthetic BOLD signals using a detailed BOLD signal model to reproduce experiments incorporating hypercapnic and hyperoxic respiratory challenges at 3T. A wide range of physiological conditions was simulated by varying input parameter values (baseline cerebral blood volume (CBV0), baseline cerebral blood flow (CBF0), baseline oxygen extraction fraction (OEF0) and hematocrit (Hct)). From the optimization of the calibration model for estimation of OEF and practical considerations of hypercapnic and hyperoxic respiratory challenges, a new "simplified calibration model" is established which reduces the complexity of the original calibration model by substituting the standard parameters α and β with a single parameter θ. The optimal value of θ is determined (θ=0.06) across a range of experimental respiratory challenges. The simplified calibration model gives estimates of OEF0 and absolute CMRO2 closer to the true values used to simulate the experimental data compared to those estimated using the original model incorporating literature values of α and β. Finally, an error propagation analysis demonstrates the susceptibility of the original and simplified calibration models to measurement errors and potential violations in the underlying assumptions of isometabolism. We conclude that using the simplified calibration model results in a reduced bias in OEF0 estimates across a wide range of potential respiratory challenge experimental designs.

Pulsed arterial spin labeling (PASL) is an increasingly common technique for noninvasively measuring cerebral blood flow (CBF) and has previously been shown to have good repeatability. It is likely to find a place in clinical trials and in particular the investigation of pharmaceutical agents active in the central nervous system. We aimed to estimate the sample sizes necessary to detect regional changes in CBF in common types of clinical trial design including (a) between groups, (b) a two-period crossover and (3) within-session single dosing. Whole brain CBF data were acquired at 3 T in two independent groups of healthy volunteers at rest; one of the groups underwent a repeat scan. Using these data, we were able to estimate between-groups, between-session and within-session variability along with regional mean estimates of CBF. We assessed the number of PASL tag-control image pairs that was needed to provide stable regional estimates of CBF and variability of regional CBF across groups. Forty tag-control image pairs, which take approximately 3 min to acquire using a single inversion label delay time, were adequate for providing stable CBF estimates at the group level. Power calculations based on the variance estimates of regional CBF measurements suggest that comparatively small cohorts are adequate. For example, detecting a 15% change in CBF, depending on the region of interest, requires from 7-15 subjects per group in a crossover design, 6-10 subjects in a within-session design and 20-41 subjects in a between-groups design. Such sample sizes make feasible the use of such CBF measurements in clinical trials of drugs.

A wealth of research has investigated the ageing brain using blood oxygenation level dependent functional MRI (BOLD fMRI). However, many studies do not consider the ageing of the cerebrovascular system, which can influence the BOLD signal independently from neural activity, limiting what can be inferred when comparing age groups. Here, we discuss the ways in which the ageing neurovascular system can impact BOLD fMRI, the consequence for age-group comparisons and possible solutions. While BOLD fMRI is a valuable tool in this context, it is hoped that this review will highlight the importance of correction and consideration of vascular confounds.

Genome-wide association studies (GWAS) show that many common alleles confer risk for developing Alzheimer's disease (AD). These risk loci may contribute to MRI alterations in young individuals, preceding the clinical manifestations of AD. Prior evidence identifies vascular dysregulation as the earliest marker of disease progression. However, it remains unclear whether cerebrovascular function (measured via grey-matter cerebral blood flow (gmCBF)) is altered in young individuals with increased AD genetic risk. We establish relationships between gmCBF with APOE and AD polygenic risk score in a young cohort (N = 75; aged: 19-32). Genetic risk was assessed via a) possessing at least one copy of the APOE ɛ4 allele and b) a polygenic risk score (AD-PRS) estimated from AD-GWAS. We observed a reduction in gmCBF in APOE ɛ4 carriers and a negative relationship between AD-PRS and gmCBF. We further found regional reductions in gmCBF in individuals with higher AD-PRS across the frontal cortex (PFWE < 0.05). Our findings suggest that a larger burden of AD common genetic risk alleles is associated with attenuated cerebrovascular function, during young adulthood. These results suggest that cerebral vasculature is a mechanism by which AD risk alleles confer susceptibility.

Purpose This study investigates the implications of all degrees of freedom of within‐scan patient head motion on patient safety. Methods Electromagnetic simulations were performed by displacing and/or rotating a virtual body model inside an 8‐channel transmit array to simulate 6 degrees of freedom of motion. Rotations of up to 20° and displacements of up to 20 mm including off‐axis axial/coronal translations were investigated, yielding 104 head positions. Quadrature excitation, RF shimming, and multi‐spoke parallel‐transmit excitation pulses were designed for axial slice‐selection at 7T, for seven slices across the head. Variation of whole‐head specific absorption rate (SAR) and 10‐g averaged local SAR of the designed pulses, as well as the change in the maximum eigenvalue (worst‐case pulse) were investigated by comparing off‐center positions to the central position. Results In their respective worst‐cases, patient motion increased the eigenvalue‐based local SAR by 42%, whole‐head SAR by 60%, and the 10‐g averaged local SAR by 210%. Local SAR was observed to be more sensitive to displacements along right–left and anterior–posterior directions than displacement in the superior–inferior direction and rotation. Conclusion This is the first study to investigate the effect of all 6 degrees of freedom of motion on safety of practical pulses. Although the results agree with the literature for overlapping cases, the results demonstrate higher increases (up to 3.1‐fold) in local SAR for off‐axis displacement in the axial plane, which had received less attention in the literature. This increase in local SAR could potentially affect the local SAR compliance of subjects, unless realistic within‐scan patient motion is taken into account during pulse design.

We present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network's “Travelling Heads” study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5–3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies. Ten healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each “home” site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space. Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001–0.005 ppm (χ) and 0.0005–0.001 ms−1 (R2*). For χ this is 2.1–4.8 fold better than 3T reports, and 1.1–3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol. The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.

Ischemic stroke of the middle cerebral artery (MCA), a major brain vessel that supplies the primary motor and premotor cortex, is one of the most common causes for severe upper limb impairment. Currently available motor rehabilitation training largely lacks satisfying efficacy with over 70% of stroke survivors showing residual upper limb dysfunction. Motor imagery-based functional magnetic resonance imaging neurofeedback (fMRI-NF) has been suggested as a potential therapeutic technique to improve motor impairment in stroke survivors. In this preregistered proof-of-concept study (https://osf.io/y69jc/), we translated graded fMRI-NF training, a new paradigm that we have previously studied in healthy participants, to first-time MCA stroke survivors with residual mild to severe impairment of upper limb motor function. Neurofeedback was provided from the supplementary motor area (SMA) targeting two different neurofeedback target levels (low and high). We hypothesized that MCA stroke survivors will show (1) sustained SMA-region of interest (ROI) activation and (2) a difference in SMA-ROI activation between low and high neurofeedback conditions during graded fMRI-NF training. At the group level, we found only anecdotal evidence for these preregistered hypotheses. At the individual level, we found anecdotal to moderate evidence for the absence of the hypothesized graded effect for most subjects. These null findings are relevant for future attempts to employ fMRI-NF training in stroke survivors. The study introduces a Bayesian sequential sampling plan, which incorporates prior knowledge, yielding higher sensitivity. The sampling plan was preregistered together with a priori hypotheses and all planned analysis before data collection to address potential publication/researcher biases. Unforeseen difficulties in the translation of our paradigm to a clinical setting required some deviations from the preregistered protocol. We explicitly detail these changes, discuss the accompanied additional challenges that can arise in clinical neurofeedback studies, and formulate recommendations for how these can be addressed. Taken together, this work provides new insights about the feasibility of motor imagery-based graded fMRI-NF training in MCA stroke survivors and serves as a first example for comprehensive study preregistration of an (fMRI) neurofeedback experiment.

In-scanner head motion represents a major confounding factor in functional connectivity studies and it raises particular concerns when motion correlates with the effect of interest. One such instance regards research focused on functional connectivity modulations induced by sustained cognitively demanding tasks. Indeed, cognitive engagement is generally associated with substantially lower in-scanner movement compared with unconstrained, or minimally constrained, conditions. Consequently, the reliability of condition-dependent changes in functional connectivity relies on effective denoising strategies. In this study, we evaluated the ability of common denoising pipelines to minimize and balance residual motion-related artifacts between resting-state and task conditions. Denoising pipelines-including realignment/tissue-based regression, PCA/ICA-based methods (aCompCor and ICA-AROMA, respectively), global signal regression, and censoring of motion-contaminated volumes-were evaluated according to a set of benchmarks designed to assess either residual artifacts or network identifiability. We found a marked heterogeneity in pipeline performance, with many approaches showing a differential efficacy between rest and task conditions. The most effective approaches included aCompCor, optimized to increase the noise prediction power of the extracted confounding signals, and global signal regression, although both strategies performed poorly in mitigating the spurious distance-dependent association between motion and connectivity. Censoring was the only approach that substantially reduced distance-dependent artifacts, yet this came at the great cost of reduced network identifiability. The implications of these findings for best practice in denoising task-based functional connectivity data, and more generally for resting-state data, are discussed.

Abstract Purpose: To demonstrate the application of Mescher‐Garwood (MEGA) point‐resolved spectroscopy sequence (PRESS) editing to the detection of lactate in the brain at 3T and to investigate changes in lactate concentration associated with inspiratory gas challenges. Materials and Methods: Edited lactate measurements were made in six healthy volunteers while the subjects breathed normoxic (21% O 2 ), hypoxic (12% O 2 ), and hyperoxic (40% O 2 ) gas mixtures. Lactate concentration was quantified relative to the unsuppressed water signal from the same volume. Results: Lactate concentration was elevated in all subjects during hypoxia in a highly significant fashion (mean increase = 39%; P = 0.0003). There was no significant change seen in hyperoxia. Conclusion: MEGA‐PRESS editing at 3T is sufficiently sensitive to detect lactate in the healthy brain with good signal‐to‐noise ratio (SNR), and can be used to investigate changes in cerebral metabolism arising during inspiratory gas challenges. J. Magn. Reson. Imaging 2010;32:320–325. © 2010 Wiley‐Liss, Inc.

Although cerebral arterial stiffness may be an important marker for cerebrovascular health, there is not yet a measurement that accurately reflects the distensibility of major intracranial arteries. Herein, we aim to noninvasively measure distension of the human middle cerebral artery (MCA).Ten healthy volunteers (age: 30.3 ± 10.8 years) underwent ultra-high-field (7-tesla) MRI scanning. Time-of-flight angiography and phase-contrast flow imaging were used to locate the M1 segment of the MCA and to determine the occurrence of systole and diastole. High-resolution cross-sectional cardiac triggered T2-weighted images of the M1 segment of the MCA were acquired in systole and diastole.The average distension of the MCA area from diastole to systole was 2.58% (range: 0.08%-6.48%). There was no significant correlation between MCA distension and the pulsatility index, calculated from the phase-contrast flow velocity profiles.These results lead to the first noninvasive image-based estimation of distensibility of the MCA (approx. 5.8 × 10-4 mm Hg-1) and demonstrate that ultra-high-field MRI could be a promising tool for investigating distensibility of intracranial arteries in relation to cerebrovascular pathology.

Calibrated BOLD is a promising technique that overcomes the sensitivity of conventional fMRI to the cerebrovascular state; measuring either the basal level, or the task-induced response of cerebral metabolic rate of oxygen consumption (CMRO2). The calibrated BOLD method is susceptible to errors in the measurement of the calibration parameter M, the theoretical BOLD signal change that would occur if all deoxygenated hemoglobin were removed. The original and most popular method for measuring M uses hypercapnia (an increase in arterial CO2), making the assumption that it does not affect CMRO2. This assumption has since been challenged and recent studies have used a corrective term, based on literature values of a reduction in basal CMRO2 with hypercapnia. This is not ideal, as this value may vary across subjects and regions of the brain, and will depend on the level of hypercapnia achieved. Here we propose a new approach, using a graded hypercapnia design and the assumption that CMRO2 changes linearly with hypercapnia level, such that we can measure M without assuming prior knowledge of the scale of CMRO2 change. Through use of a graded hypercapnia gas challenge, we are able to remove the bias caused by a reduction in basal CMRO2 during hypercapnia, whilst simultaneously calculating the dose-wise CMRO2 change with hypercapnia. When compared with assuming no change in CMRO2, this approach resulted in significantly lower M values in both visual and motor cortices, arising from significant dose-dependent hypercapnia reductions in basal CMRO2 of 1.5±0.6%/mmHg (visual) and 1.8±0.7%/mmHg (motor), where mmHg is the unit change in end-tidal CO2 level. Variability in the basal CMRO2 response to hypercapnia, due to experimental differences and inter-subject variability, is accounted for in this approach, unlike previous correction approaches, which use literature values. By incorporating measurement of, and correction for, the reduction in basal CMRO2 during hypercapnia in the measurement of M values, application of our approach will correct for an overestimation in both CMRO2 task-response values and absolute CMRO2.

Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBV dHb ), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO 2 ) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (D C ) and the partial pressure of oxygen at the mitochondria (PmO 2 ). Significant between-group differences were observed as decreased CBF ( p = 0.010), CMRO 2 ( p &lt; 0.001) and D C ( p = 0.002), and increased PmO 2 ( p = 0.043) in patients compared to controls. No significant differences were observed for CBV dHb ( p = 0.389), OEF ( p = 0.358), or GM volume ( p = 0.302). Regional analysis showed widespread reductions in CMRO 2 and D C for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration.

Non‐invasive magnetic resonance imaging (MRI) was used to characterize changes in left and right ventricular cardiac cycles following induction of experimental, streptozotocin (STZ)‐induced, diabetes in male Wistar rats at different ages. The effects of the angiotensin‐converting enzyme (ACE) inhibitor captopril upon such chronic physiological changes were then evaluated, also for the first time. Diabetes was induced at the age of 7 weeks in two experimental groups, of which one group was subsequently maintained on captopril (2 g l −1 )‐containing drinking water, and at 10 and 13 weeks in two further groups. The fifth group provided age‐matched controls. All groups ( each n = 4 animals) were scanned consistently at 16 weeks, in parallel with timings used in earlier studies that employed this experimental model. Cine magnetic resonance (MR) image acquisition provided transverse sections through both ventricles at twelve time points covering systole and most of diastole. These yielded reconstructions of cardiac anatomy used to derive critical functional indices and their dependence upon time following the triggering electrocardiographic R waves. The left and right ventricular end‐diastolic (EDV), end‐systolic (ESV) and stroke volumes (SV), and ejection fractions (EF) calculated from each, control and experimental, group showed matching values. This confirmed a necessary condition requiring balanced right and left ventricular outputs and further suggested that STZ‐induced diabetes produced physiological changes in both ventricles. Absolute left and right ventricular SVs were significantly altered in all diabetic animals; EDVs and EFs significantly altered in animals diabetic from 7 and 10 but not 13 weeks. When normalized to body weight, left and right ventricular SVs had significantly altered in animals diabetic from 7 and 10 weeks but not 13 weeks. Normalized left ventricular EDVs were also significantly altered in animals diabetic from 7 and 10 weeks. However, normalized right ventricular EDVs were significantly altered only in animals made diabetic from 7 weeks. Diabetic hearts showed major kinetic changes in left and right ventricular contraction (ejection) and relaxation (filling). Both the initial rates of volume change (d V /d t ) in both ventricles and the plots of d V /d t values through the cardiac cycle demonstrated more gradual developments of tension during systole and relaxation during diastole. Estimates of the derived left ventricular performance parameters of cardiac output, cardiac power output and stroke work in control animals were comparable with human values when normalized to both body (or cardiac) weight and heart rate. All deteriorated with diabetes. Comparisons of experimental groups diabetic from 7 weeks demonstrated that captopril treatment relieved the alterations in critical volumes, dependence of SV upon EDV, kinetics of systolic contraction and diastolic relaxation and in the derived indicators of ventricular performance. This study represents the first demonstration using non‐invasive MRI of early, chronic changes in diastolic filling and systolic ejection in both the left and the right ventricles and of their amelioration by ACE inhibition following STZ‐induction of diabetes in intact experimental animals.

Forty-four studies of regional cerebral blood flow (rCBF), fractional oxygen extraction (rOER) and oxygen consumption (rCMRO2) were made on twenty-five patients with recent internal carotid artery territory infarcts. The purpose was to study flow-metabolism relationships in the contralateral hemispheres, and to investigate whether contralateral rCMRO2 was depressed as a result of the recent infarcts. Two groups of controls were included for comparison--seventeen normal volunteers, and ten patients with proven extracranial cerebrovascular disease but without evidence of cerebral infarction. The results demonstrated that: contralateral hemispheric rCMRO2 was less variable than regional oxygen availability (the product of rCBF and arterial oxygen content). This was due, in part, to the effect of individual variations in PaCO2 on rCBF, but other uncontrolled factors, such as intracranial pressure, may have had influences. As a result, rCMRO2 did not correlate with rCBF; mean rCMRO2 in the contralateral hemispheres was 12% lower than normal (a significant difference), but was not different from the value found in patients with extracranial vascular disease in whom there was no evidence of infarction or ischemia; contralateral rCMRO2 did not correlate with the size of the infarct in the opposite hemisphere. It is concluded that rCMRO2 cannot be inferred from rCBF measurements in uncontrolled human studies (as frequently done in the past), and that depression of contralateral rCMRO2 may have preceded infarction in the opposite hemisphere, a consequence of the previous influences of diseases that predispose to stroke.

Resting fluctuations in arterial CO2 (a cerebral vasodilator) are believed to be an important source of low-frequency blood oxygenation level dependent (BOLD) signal fluctuations. In this study we focus on the two commonly used resting-states in functional magnetic resonance imaging experiments, eyes open and eyes closed, and quantify the degree to which measured spontaneous fluctuations in the partial pressure of end-tidal CO2 (Petco2) relate to BOLD signal time series. A significantly longer latency of BOLD signal changes following Petco2 fluctuations was found in the eyes closed condition compared to with eyes open, which may reveal different intrinsic vascular response delays in CO2 reactivity or an alteration in the net BOLD signal arising from Petco2 fluctuations and altered neural activity with eyes closed. By allowing a spatially varying time delay for the compensation of this temporal difference, a more spatially consistent CO2 correlation map can be obtained. Finally, Granger-causality analysis demonstrated a “causal” relationship between Petco2 and BOLD. The identified dominant Petco2→BOLD directional coupling supports the notion that Petco2 fluctuations are indeed a cause of resting BOLD variance in the majority of subjects.

Investigating how intrathoracic pressure changes affect cerebral blood flow (CBF) is important for a clear interpretation of neuroimaging data in patients with abnormal respiratory physiology, intensive care patients receiving mechanical ventilation and in research paradigms that manipulate intrathoracic pressure. Here, we investigated the effect of experimentally increased and decreased intrathoracic pressures upon CBF and the stimulus-evoked CBF response to visual stimulation. Twenty healthy volunteers received intermittent inspiratory and expiratory loads (plus or minus 9cmH2O for 270s) and viewed an intermittent 2Hz flashing checkerboard, while maintaining stable end-tidal CO2. CBF was recorded with transcranial Doppler sonography (TCD) and whole-brain pseudo-continuous arterial spin labeling magnetic resonance imaging (PCASL MRI). Application of inspiratory loading (negative intrathoracic pressure) showed an increase in TCD-measured CBF of 4% and a PCASL-measured increase in grey matter CBF of 5%, but did not alter mean arterial pressure (MAP). Expiratory loading (positive intrathoracic pressure) did not alter CBF, while MAP increased by 3%. Neither loading condition altered the perfusion response to visual stimulation in the primary visual cortex. In both loading conditions localized CBF increases were observed in the somatosensory and motor cortices, and in the cerebellum. Altered intrathoracic pressures, whether induced experimentally, therapeutically or through a disease process, have possible significant effects on CBF and should be considered as a potential systematic confound in the interpretation of perfusion-based neuroimaging data.

Pain-related anxiety and fear are associated with increased difficulties in attention, increased awareness of pain, impaired disengagement from pain, and can moderate the effects of attentional coping attempts. Accurately assessing the direct impact of pain-related anxiety and fear on pain behavior has proved difficult. Studies have demonstrated no or limited influence of pain-related fear and anxiety on behavior but this may be due to inherent problems with the scales used. Neuroimaging has improved the understanding of neural processes underlying the factors that influence pain perception. This study aimed to establish if a Picture and Imagination Task (PIT), largely developed from the Photographs of Daily Activity (PHODA) assessment tool, could help explore how people living with chronic pain process information about daily activities. Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to compare brain responses in patients with chronic musculoskeletal pain (CMSKP) (n = 15) and healthy controls (n = 15). Subjects were asked to imagine how they would feel mentally and physically if asked to perform daily activities illustrated in PIT. The results found that a number of regions involved in pain processing saw increased BOLD activation in patients compared with controls when undertaking the task and included the insula, anterior cingulate cortex, thalamus and inferior and superior parietal cortices. Similarly, increased BOLD responses in patients compared to controls in the frontal pole, paracingulate and the supplementary motor cortex may be suggestive of a memory component to the responses The amygdala, orbitofrontal cortex, substantia nigra/ventral tegmentum, putamen, thalamus, pallidum, inferior parietal (supramarginal and angular gyrus) and cingulate cortex were also seen to have greater differences in BOLD signal changes in patients compared with controls and many of these regions are also associated with general phobic responses. Therefore, we suggest that PIT is a useful task to explore pain- and movement-related anxiety and fear in fMRI studies. Regions in the Default Mode Network remained active or were less deactivated during the PIT task in patients with CMSKP compared to healthy controls supporting the contention that the DMN is abnormal in patients with CMSKP.

As energy metabolism in the brain is largely oxidative, the measurement of cerebral metabolic rate of oxygen consumption (CMRO2) is a desirable biomarker for quantifying brain activity and tissue viability. Currently, PET techniques based on oxygen isotopes are the gold standard for obtaining whole brain CMRO2 maps. Among MRI techniques that have been developed as an alternative are dual calibrated fMRI (dcFMRI) methods, which exploit simultaneous measurements of BOLD and ASL signals during a hypercapnic-hyperoxic experiment to modulate brain blood flow and oxygenation. In this study we quantified the repeatability of a dcFMRI approach developed in our lab, evaluating its limits and informing its application in studies aimed at characterising the metabolic state of human brain tissue over time. Our analysis focussed on the estimates of oxygen extraction fraction (OEF), cerebral blood flow (CBF), CBF-related cerebrovascular reactivity (CVR) and CMRO2 based on a forward model that describes analytically the acquired dual echo GRE signal. Indices of within- and between-session repeatability are calculated from two different datasets both at a bulk grey matter and at a voxel-wise resolution and finally compared with similar indices obtained from previous MRI and PET measurements. Within- and between-session values of intra-subject coefficient of variation (CVintra) calculated from bulk grey matter estimates 6.7 ± 6.6% (mean ± std.) and 10.5 ± 9.7% for OEF, 6.9 ± 6% and 5.5 ± 4.7% for CBF, 12 ± 9.7% and 12.3 ± 10% for CMRO2. Coefficient of variation (CV) and intraclass correlation coefficient (ICC) maps showed the spatial distribution of the repeatability metrics, informing on the feasibility limits of the method. In conclusion, results show an overall consistency of the estimated physiological parameters with literature reports and a satisfactory level of repeatability considering the higher spatial sensitivity compared to other MRI methods, with varied performance depending on the specific parameter under analysis, on the spatial resolution considered and on the study design.

Cardiorespiratory fitness is thought to have beneficial effects on systemic vascular health, in part, by decreasing arterial stiffness. However, in the absence of non-invasive methods, it remains unknown whether this effect extends to the cerebrovasculature. The present study uses a novel pulsed arterial spin labelling (pASL) technique to explore the relationship between cardiorespiratory fitness and arterial compliance of the middle cerebral arteries (MCAC). Other markers of cerebrovascular health, including resting cerebral blood flow (CBF) and cerebrovascular reactivity to CO 2 (CVR CO2 ) were also investigated. Eleven healthy males aged 21 ± 2 years with varying levels of cardiorespiratory fitness (maximal oxygen uptake ([Formula: see text]O 2MAX ) 38–76 ml/min/kg) underwent MRI scanning at 3 Tesla. Higher [Formula: see text]O 2MAX was associated with greater MCAC (R 2 = 0.64, p &lt; 0.01) and lower resting grey matter CBF (R 2 = 0.75, p &lt; 0.01). However, [Formula: see text]O 2MAX was not predictive of global grey matter BOLD-based CVR (R 2 = 0.47, p = 0.17) or CBF-based CVR (R 2 = 0.19, p = 0.21). The current experiment builds upon the established benefits of exercise on arterial compliance in the systemic vasculature, by showing that increased cardiorespiratory fitness is associated with greater cerebral arterial compliance in early adulthood.