John Evans

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.

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.

The purpose of this study is to describe the Gannet toolkit for the quantitative batch analysis of gamma-aminobutyric acid (GABA) -edited MRS data.Using MEGA-PRESS editing and standard acquisition parameters, four MEGA-PRESS spectra were acquired in three brain regions in 10 healthy volunteers. These 120 datasets were processed without user intervention with Gannet, a Matlab-based tool that takes raw time-domain data input, processes it to generate the frequency-domain edited spectrum, and applies a simple modeling procedure to estimate GABA concentration relative to the creatine or, if provided, the unsuppressed water signal. A comparison of four modeling approaches is also presented.All data were successfully processed by Gannet. Coefficients of variation across subjects ranged from 11% for the occipital region to 17% for the dorsolateral prefrontal region. There was no clear difference in fitting performance between the simple Gaussian model used by Gannet and the other more complex models presented.Gannet, the GABA Analysis Toolkit, can be used to process and quantify GABA-edited MRS spectra without user intervention.

There is increasing interest in the use of edited proton magnetic resonance spectroscopy for the detection of GABA in the human brain. At a recent meeting held at Cardiff University, a number of spectroscopy groups met to discuss the acquisition, analysis and interpretation of GABA-edited MR spectra. This paper aims to set out the issues discussed at this meeting, reporting areas of consensus around parameters and procedures in the field and highlighting those areas where differences remain. It is hoped that this paper can fulfill two needs, providing a summary of the current ‘state-of-the-art’ in the field of GABA-edited MRS at 3 T using MEGA-PRESS and a basic guide to help researchers new to the field to avoid some of the pitfalls inherent in the acquisition and processing of edited MRS for GABA.

Studies using proton magnetic resonance spectroscopy (MRS) have indicated that unmedicated, acutely depressed patients have decreased levels of gamma-aminobutyric acid (GABA) in occipital cortex. Cortical levels of glutamate (Glu) may be increased, although these data are less consistent. The aim of this study was to use MRS to determine whether changes in GABA and Glu levels were present in patients with mood disorders who had recovered and were no longer taking medication.An [1H]-MRS was used to measure levels of GABA, of the combined concentration of Glu and glutamine (Gln), and of N-acetylaspartate (NAA) in occipital cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression (n = 15), bipolar disorder (n = 16), and a group of healthy controls (n = 18).Occipital levels of GABA and NAA were significantly lower in recovered depressed and bipolar subjects than in healthy controls, whereas Glu +Gln concentrations were higher.Our data suggest that recovered unmedicated subjects with a history of mood disorder have changes in cortical concentrations of GABA, NAA, and Glu +Gln. These biochemical abnormalities may be markers of a trait vulnerability to mood disorder, rather than neurochemical correlates of an abnormal mood state.

Abstract The observation of electromagnetic radiation from radio to γ-ray wavelengths has provided a wealth of information about the Universe. However, at PeV (10 15 eV) energies and above, most of the Universe is impenetrable to photons. New messengers, namely cosmic neutrinos, are needed to explore the most extreme environments of the Universe where black holes, neutron stars, and stellar explosions transform gravitational energy into non-thermal cosmic rays. These energetic particles have millions of times higher energies than those produced in the most powerful particle accelerators on Earth. As neutrinos can escape from regions otherwise opaque to radiation, they allow an unique view deep into exploding stars and the vicinity of the event horizons of black holes. The discovery of cosmic neutrinos with IceCube has opened this new window on the Universe. IceCube has been successful in finding first evidence for cosmic particle acceleration in the jet of an active galactic nucleus. Yet, ultimately, its sensitivity is too limited to detect even the brightest neutrino sources with high significance, or to detect populations of less luminous sources. In this white paper, we present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the Universe at the highest energies. IceCube-Gen2 is designed to: (a) Resolve the high-energy neutrino sky from TeV to EeV energies (b) Investigate cosmic particle acceleration through multi-messenger observations (c) Reveal the sources and propagation of the highest energy particles in the Universe (d) Probe fundamental physics with high-energy neutrinos IceCube-Gen2 will enhance the existing IceCube detector at the South Pole. It will increase the annual rate of observed cosmic neutrinos by a factor of ten compared to IceCube, and will be able to detect sources five times fainter than its predecessor. Furthermore, through the addition of a radio array, IceCube-Gen2 will extend the energy range by several orders of magnitude compared to IceCube. Construction will take 8 years and cost about $350M. The goal is to have IceCube-Gen2 fully operational by 2033. IceCube-Gen2 will play an essential role in shaping the new era of multi-messenger astronomy, fundamentally advancing our knowledge of the high-energy Universe. This challenging mission can be fully addressed only through the combination of the information from the neutrino, electromagnetic, and gravitational wave emission of high-energy sources, in concert with the new survey instruments across the electromagnetic spectrum and gravitational wave detectors which will be available in the coming years.

Purpose Frequency and phase drifts are a common problem in the acquisition of in vivo magnetic resonance spectroscopy (MRS) data. If not accounted for, frequency and phase drifts will result in artifactual broadening of spectral peaks, distortion of spectral lineshapes, and a reduction in signal‐to‐noise ratio (SNR). We present herein a new method for estimating and correcting frequency and phase drifts in in vivo MRS data. Methods We used a simple method of fitting each spectral average to a reference scan (often the first average in the series) in the time domain through adjustment of frequency and phase terms. Due to the similarity with image registration, this method is referred to as “spectral registration.” Using simulated data with known frequency and phase drifts, the performance of spectral registration was compared with two existing methods at various SNR levels. Results Spectral registration performed well in comparison with the other methods tested in terms of both frequency and phase drift estimation. Conclusions Spectral registration provides an effective method for frequency and phase drift correction. It does not involve the collection of navigator echoes, and does not rely on any specific resonances, such as residual water or creatine, making it highly versatile. Magn Reson Med 73:44–50, 2015. © 2014 Wiley Periodicals, Inc.

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.

The IceCube Neutrino Observatory has established the existence of a high-energy all-sky neutrino flux of astrophysical origin. This discovery was made using events interacting within a fiducial region of the detector surrounded by an active veto and with reconstructed energy above 60 TeV, commonly known as the high-energy starting event sample, or HESE. We revisit the analysis of the HESE sample with an additional 4.5 years of data, newer glacial ice models, and improved systematics treatment. This paper describes the sample in detail, reports on the latest astrophysical neutrino flux measurements, and presents a source search for astrophysical neutrinos. We give the compatibility of these observations with specific isotropic flux models proposed in the literature as well as generic power-law-like scenarios. Assuming $ν_e:ν_μ:ν_τ=1:1:1$, and an equal flux of neutrinos and antineutrinos, we find that the astrophysical neutrino spectrum is compatible with an unbroken power law, with a preferred spectral index of ${2.87}^{+0.20}_{-0.19}$ for the $68.3\%$ confidence interval.

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.

Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure.To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia.Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014.Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score.Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = -2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95% CI, 0.01-0.12]; P = .02) and those with light use (<5 occasions) (difference in cortical thickness, 0.11 [95% CI, 0.03-0.18]; P = .004).Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.

A supermassive black hole, obscured by cosmic dust, powers the nearby active galaxy NGC 1068. Neutrinos, which rarely interact with matter, could provide information on the galaxy's active core. We searched for neutrino emission from astrophysical objects using data recorded with the IceCube neutrino detector between 2011 and 2020. The positions of 110 known gamma-ray sources were individually searched for neutrino detections above atmospheric and cosmic backgrounds. We found that NGC 1068 has an excess of [Formula: see text] neutrinos at tera-electron volt energies, with a global significance of 4.2σ, which we interpret as associated with the active galaxy. The flux of high-energy neutrinos that we measured from NGC 1068 is more than an order of magnitude higher than the upper limit on emissions of tera-electron volt gamma rays from this source.

Functional magnetic resonance imaging neurofeedback (fMRI-NF) training of areas involved in emotion processing can reduce depressive symptoms by over 40% on the Hamilton Depression Rating Scale (HDRS). However, it remains unclear if this efficacy is specific to feedback from emotion-regulating regions. We tested in a single-blind, randomized, controlled trial if upregulation of emotion areas (NFE) yields superior efficacy compared to upregulation of a control region activated by visual scenes (NFS). Forty-three moderately to severely depressed medicated patients were randomly assigned to five sessions augmentation treatment of either NFE or NFS training. At primary outcome (week 12) no significant group mean HDRS difference was found (B = -0.415 [95% CI -4.847 to 4.016], p = 0.848) for the 32 completers (16 per group). However, across groups depressive symptoms decreased by 43%, and 38% of patients remitted. These improvements lasted until follow-up (week 18). Both groups upregulated target regions to a similar extent. Further, clinical improvement was correlated with an increase in self-efficacy scores. However, the interpretation of clinical improvements remains limited due to lack of a sham-control group. We thus surveyed effects reported for accepted augmentation therapies in depression. Data indicated that our findings exceed expected regression to the mean and placebo effects that have been reported for drug trials and other sham-controlled high-technology interventions. Taken together, we suggest that the experience of successful self-regulation during fMRI-NF training may be therapeutic. We conclude that if fMRI-NF is effective for depression, self-regulation training of higher visual areas may provide an effective alternative.

Abstract We present a measurement of the high-energy astrophysical muon–neutrino flux with the IceCube Neutrino Observatory. The measurement uses a high-purity selection of 650k neutrino-induced muon tracks from the northern celestial hemisphere, corresponding to 9.5 yr of experimental data. With respect to previous publications, the measurement is improved by the increased size of the event sample and the extended model testing beyond simple power-law hypotheses. An updated treatment of systematic uncertainties and atmospheric background fluxes has been implemented based on recent models. The best-fit single power-law parameterization for the astrophysical energy spectrum results in a normalization of <?CDATA ${\phi }_{@100\mathrm{TeV}}^{{\nu }_{\mu }+{\bar{\nu }}_{\mu }}={1.44}_{-0.26}^{+0.25}\times {10}^{-18}\,{\mathrm{GeV}}^{-1}{\mathrm{cm}}^{-2}{{\rm{s}}}^{-1}{\mathrm{sr}}^{-1}$?> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msubsup> <mml:mrow> <mml:mi>ϕ</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>@</mml:mo> <mml:mn>100</mml:mn> <mml:mi>TeV</mml:mi> </mml:mrow> <mml:mrow> <mml:msub> <mml:mrow> <mml:mi>ν</mml:mi> </mml:mrow> <mml:mrow> <mml:mi>μ</mml:mi> </mml:mrow> </mml:msub> <mml:mo>+</mml:mo> <mml:msub> <mml:mrow> <mml:mover accent="true"> <mml:mrow> <mml:mi>ν</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>¯</mml:mo> </mml:mrow> </mml:mover> </mml:mrow> <mml:mrow> <mml:mi>μ</mml:mi> </mml:mrow> </mml:msub> </mml:mrow> </mml:msubsup> <mml:mo>=</mml:mo> <mml:msubsup> <mml:mrow> <mml:mn>1.44</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>0.26</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>+</mml:mo> <mml:mn>0.25</mml:mn> </mml:mrow> </mml:msubsup> <mml:mo>×</mml:mo> <mml:msup> <mml:mrow> <mml:mn>10</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>18</mml:mn> </mml:mrow> </mml:msup> <mml:mspace width="0.25em" /> <mml:msup> <mml:mrow> <mml:mi>GeV</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> <mml:msup> <mml:mrow> <mml:mi>cm</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>2</mml:mn> </mml:mrow> </mml:msup> <mml:msup> <mml:mrow> <mml:mi mathvariant="normal">s</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> <mml:msup> <mml:mrow> <mml:mi>sr</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> </mml:math> and a spectral index <?CDATA ${\gamma }_{\mathrm{SPL}}={2.37}_{-0.09}^{+0.09}$?> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msub> <mml:mrow> <mml:mi>γ</mml:mi> </mml:mrow> <mml:mrow> <mml:mi>SPL</mml:mi> </mml:mrow> </mml:msub> <mml:mo>=</mml:mo> <mml:msubsup> <mml:mrow> <mml:mn>2.37</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>0.09</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>+</mml:mo> <mml:mn>0.09</mml:mn> </mml:mrow> </mml:msubsup> </mml:math> , constrained in the energy range from 15 TeV to 5 PeV. The model tests include a single power law with a spectral cutoff at high energies, a log-parabola model, several source-class-specific flux predictions from the literature, and a model-independent spectral unfolding. The data are consistent with a single power-law hypothesis, however, spectra with softening above one PeV are statistically more favorable at a two-sigma level.

The origin of high-energy cosmic rays, atomic nuclei that continuously impact Earth's atmosphere, has been a mystery for over a century. Due to deflection in interstellar magnetic fields, cosmic rays from the Milky Way arrive at Earth from random directions. However, near their sources and during propagation, cosmic rays interact with matter and produce high-energy neutrinos. We search for neutrino emission using machine learning techniques applied to ten years of data from the IceCube Neutrino Observatory. We identify neutrino emission from the Galactic plane at the 4.5$\sigma$ level of significance, by comparing diffuse emission models to a background-only hypothesis. The signal is consistent with modeled diffuse emission from the Galactic plane, but could also arise from a population of unresolved point sources.

Gamma-ray bursts (GRBs) have long been considered a possible source of high-energy neutrinos. While no correlations have yet been detected between high-energy neutrinos and GRBs, the recent observation of GRB 221009A - the brightest GRB observed by Fermi-GBM to date and the first one to be observed above an energy of 10 TeV - provides a unique opportunity to test for hadronic emission. In this paper, we leverage the wide energy range of the IceCube Neutrino Observatory to search for neutrinos from GRB 221009A. We find no significant deviation from background expectation across event samples ranging from MeV to PeV energies, placing stringent upper limits on the neutrino emission from this source.

Examining the unresolved relationship between the lower motor neuron disorder progressive muscular atrophy (PMA) and ALS is important in clinical practice because of emerging therapies.Spinal and brainstem tissues donated from patients with ALS/motor neuron disorder (n = 81) were examined. Using retrospective case note review, the authors assigned patients into three categories: PMA (12), PMA progressing to ALS (6), and ALS ab initio (63). Conventional stains for long tract degeneration and immunocytochemistry for ubiquitin and the macrophage marker CD68 were examined.Rapid progression and typical ubiquitinated inclusions in lower motor neurons were present in 77 (95%) of the cases. Immunocytochemistry for CD68 was a more sensitive marker of long tract pathology in comparison with conventional stains. Half of the cases with PMA showed corticospinal tract degeneration by CD68.Patients with PMA frequently have undetected long tract pathology and most have ubiquitinated inclusions typical of ALS. A patient presenting with PMA with rapid clinical evolution likely has the pathology and pathophysiology of ALS whether or not upper motor neuron signs evolve.

Studies using proton magnetic resonance spectroscopy (1H-MRS) indicate that unmedicated, acutely depressed patients have decreased levels of gamma-aminobutyric acid (GABA) in the occipital cortex. The aim of this study was to use 1H-MRS to determine if changes in occipital and frontal cortical GABA levels were present in patients with a history of depression who had recovered and were no longer taking medication. We used 1H-MRS to measure levels of GABA in both occipital cortex and anterior cingulate cortex/prefrontal cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression. Levels of GABA in both occipital and anterior cingulate cortex were significantly lower in recovered depressed subjects than healthy controls. Our data provide preliminary evidence that a history of recurrent depression is associated with decreased GABA levels in anterior cingulate cortex and occipital cortex. These changes could represent part of the neurobiological vulnerability to recurrent depressive episodes.

The neural mechanisms underlying variability in human sensory perception remain incompletely understood. In particular, few studies have attempted to investigate the relationship between in vivo measurements of neurochemistry and individuals' behavioral performance. Our previous work found a relationship between GABA concentration in the visual cortex and orientation discrimination thresholds (Edden et al., 2009). In the present study, we used magnetic resonance spectroscopy of GABA and psychophysical testing of vibrotactile frequency thresholds to investigate whether individual differences in tactile frequency discrimination performance are correlated with GABA concentration in sensorimotor cortex. Behaviorally, individuals showed a wide range of discrimination thresholds ranging from 3 to 7.6 Hz around the 25 Hz standard. These frequency discrimination thresholds were significantly correlated with GABA concentration (r = -0.58; p < 0.05) in individuals' sensorimotor cortex, but not with GABA concentration in an occipital control region (r = -0.04). These results demonstrate a link between GABA concentration and frequency discrimination in vivo, and support the hypothesis that GABAergic mechanisms have an important role to play in sensory discrimination.

People vary markedly in how quickly they can resolve competitive action decisions. Using magnetic resonance spectroscopy, the authors find that the speed with which an individual resolves such competition can be predicted by the concentration of GABA in a region of frontal cortex. People vary markedly in the efficiency with which they can resolve competitive action decisions, even simple ones such as shifting gaze to one stimulus rather than another. We found that an individual's ability to rapidly resolve such competition is predicted by the concentration of GABA, the main inhibitory neurotransmitter, in a region of frontal cortex that is relevant for eye movements, but not in a control region (occipital cortex).

Subliminal visual stimuli affect motor planning, but the size of such effects differs greatly between individuals. Here, we investigated whether such variation may be related to neurochemical differences between people. Cortical responsiveness is expected to be lower under the influence of more of the main inhibitory neurotransmitter, GABA. Thus, we hypothesized that, if an individual has more GABA in the supplementary motor area (SMA)--a region previously associated with automatic motor control--this would result in smaller subliminal effects. We measured the reversed masked prime--or negative compatibility--effect, and found that it correlated strongly with GABA concentration, measured with magnetic resonance spectroscopy. This occurred specifically in the SMA region, and not in other regions from which spectroscopy measurements were taken. We replicated these results in an independent cohort: more GABA in the SMA region is reliably associated with smaller effect size. These findings suggest that, across individuals, the responsiveness of subconscious motor mechanisms is related to GABA concentration in the SMA.

Impulsivity is a multifaceted personality construct associated with numerous psychiatric disorders. Recent research has characterized four facets of impulsivity: "urgency" (the tendency to act rashly especially in the context of distress or cravings); "lack of premeditation" (not envisaging the consequences of actions); "lack of perseverance" (not staying focused on a task); and "sensation seeking" (engaging in exciting activities). Urgency is particularly associated with clinical populations and problematic disinhibited behavior.We used magnetic resonance spectroscopy to measure concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the dorsolateral prefrontal cortex (DLPFC) in two cohorts of 12 and 13 participants.We find that variation in trait urgency in healthy men correlates with GABA concentration in the DLPFC. The result was replicated in an independent cohort. More GABA predicted lower urgency scores, consistent with a role in self-control for GABA-mediated inhibitory mechanisms in DLPFC.These findings help account for individual differences in self-control and thus clarify the relationship between GABA and a wide range of psychiatric disorders associated with impaired self-control.

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.

Background Altered white matter microstructure in tracts integral to mood regulation networks could underlie vulnerability to major depressive disorder (MDD). Guided by functional magnetic resonance studies, we explored whether a positive family history of MDD (FH+) and anhedonia (reduced capacity for pleasure) were associated with altered white matter microstructure in the cingulum bundles and uncinate fasciculi. Methods Diffusion tensor magnetic resonance imaging data were acquired on 34 healthy female student volunteers (mean age 22 years). Exclusion criteria included other current or previous psychiatric disorder, current depression, and current psychotropic medication. Family history was determined using established criteria. Fiber tractography was performed for each individual for a priori tracts of interest and a comparison tract. Mean fractional anisotropy (FA), an index of microstructure, was calculated for each tract. Results Tracts were reconstructed in 18 FH+ individuals and 15 FH– individuals, who did not differ by age or subclinical depressive symptoms. FH+ subjects had 3% to 5% lower FA in the right and left cingulum bundles than FH– individuals (p = .012, p = .059, respectively). Post hoc analysis demonstrated 8% lower FA in the left subgenual cingulate (p = .007). Hedonic tone correlated positively with FA in the right and left cingulum bundles (r = .342, p = .052; r = .477, p = .005, respectively), and the left subgenual cingulum (r = .500, p = .003). Conclusions Both family history of MDD and subclinical anhedonia are associated with reduced FA in the bilateral cingulum bundles, particularly in the left subgenual cingulum. Altered cingulum white matter architecture is implicated in the etiology of MDD. Altered white matter microstructure in tracts integral to mood regulation networks could underlie vulnerability to major depressive disorder (MDD). Guided by functional magnetic resonance studies, we explored whether a positive family history of MDD (FH+) and anhedonia (reduced capacity for pleasure) were associated with altered white matter microstructure in the cingulum bundles and uncinate fasciculi. Diffusion tensor magnetic resonance imaging data were acquired on 34 healthy female student volunteers (mean age 22 years). Exclusion criteria included other current or previous psychiatric disorder, current depression, and current psychotropic medication. Family history was determined using established criteria. Fiber tractography was performed for each individual for a priori tracts of interest and a comparison tract. Mean fractional anisotropy (FA), an index of microstructure, was calculated for each tract. Tracts were reconstructed in 18 FH+ individuals and 15 FH– individuals, who did not differ by age or subclinical depressive symptoms. FH+ subjects had 3% to 5% lower FA in the right and left cingulum bundles than FH– individuals (p = .012, p = .059, respectively). Post hoc analysis demonstrated 8% lower FA in the left subgenual cingulate (p = .007). Hedonic tone correlated positively with FA in the right and left cingulum bundles (r = .342, p = .052; r = .477, p = .005, respectively), and the left subgenual cingulum (r = .500, p = .003). Both family history of MDD and subclinical anhedonia are associated with reduced FA in the bilateral cingulum bundles, particularly in the left subgenual cingulum. Altered cingulum white matter architecture is implicated in the etiology of MDD.

Diffusion MRI is being used increasingly in studies of the brain and other parts of the body for its ability to provide quantitative measures that are sensitive to changes in tissue microstructure. However, inter-scanner and inter-protocol differences are known to induce significant measurement variability, which in turn jeopardises the ability to obtain ‘truly quantitative measures’ and challenges the reliable combination of different datasets. Combining datasets from different scanners and/or acquired at different time points could dramatically increase the statistical power of clinical studies, and facilitate multi-centre research. Even though careful harmonisation of acquisition parameters can reduce variability, inter-protocol differences become almost inevitable with improvements in hardware and sequence design over time, even within a site. In this work, we present a benchmark diffusion MRI database of the same subjects acquired on three distinct scanners with different maximum gradient strength (40, 80, and 300 mT/m), and with ‘standard’ and ‘state-of-the-art’ protocols, where the latter have higher spatial and angular resolution. The dataset serves as a useful testbed for method development in cross-scanner/cross-protocol diffusion MRI harmonisation and quality enhancement. Using the database, we compare the performance of five different methods for estimating mappings between the scanners and protocols. The results show that cross-scanner harmonisation of single-shell diffusion data sets can reduce the variability between scanners, and highlight the promises and shortcomings of today's data harmonisation techniques.

To investigate the quantitative impact of frequency drift on Gamma-Aminobutyric acid (GABA+)-edited MRS of the human brain at 3 Tesla (T).Three sequential GABA+-edited MEGA-PRESS acquisitions were acquired in fifteen sessions; in ten of these, MRS was preceded by functional MRI (fMRI) to induce frequency drift, which was estimated from the creatine resonance at 3.0 ppm. Simulations were performed to examine the effects of frequency drift on the editing efficiency of GABA and co-edited macromolecules (MM) and of subtraction artifacts on GABA+ quantification. The efficacy of postprocessing frequency correction was also investigated.Gradient-induced frequency drifts affect GABA+ quantification for at least 30 min after imaging. Average frequency drift was low in control sessions and as high as -2 Hz/min after fMRI. Uncorrected frequency drift has an approximately linear effect on GABA+ measurements with a -10 Hz drift resulting in a 16% decrease in GABA+, primarily due to subtraction artifacts.Imaging acquisitions with high gradient duty cycles can impact subsequent GABA+ measurements. Postprocessing can address subtraction artifacts, but not changes in editing efficiency or GABA:MM signal ratios; therefore, protocol design should avoid intensive gradient sequences before edited MRS Magn Reson Med 72:941-948, 2014. © 2013 Wiley Periodicals, Inc.

The conduction velocity (CV) of action potentials along axons is a key neurophysiological property central to neural communication. The ability to estimate CV in humans in vivo from non-invasive MRI methods would therefore represent a significant advance in neuroscience. However, there are two major challenges that this paper aims to address: (1) Much of the complexity of the neurophysiology of action potentials cannot be captured with currently available MRI techniques. Therefore, we seek to establish the variability in CV that can be captured when predicting CV purely from parameters that have been reported to be estimatable from MRI: inner axon diameter (AD) and g-ratio. (2) errors inherent in existing MRI-based biophysical models of tissue will propagate through to estimates of CV, the extent to which is currently unknown. Issue (1) is investigated by performing a sensitivity analysis on a comprehensive model of axon electrophysiology and determining the relative sensitivity to various morphological and electrical parameters. The investigations suggest that 85% of the variance in CV is accounted for by variation in AD and g-ratio. The observed dependency of CV on AD and g-ratio is well characterised by the previously reported model by Rushton. Issue (2) is investigated through simulation of diffusion and relaxometry MRI data for a range of axon morphologies, applying models of restricted diffusion and relaxation processes to derive estimates of axon volume fraction (AVF), AD and g-ratio and estimating CV from the derived parameters. The results show that errors in the AVF have the biggest detrimental impact on estimates of CV, particularly for sparse fibre populations (AVF<0.3). For our equipment set-up and acquisition protocol, CV estimates are most accurate (below 5% error) where AVF is above 0.3, g-ratio is between 0.6 and 0.85 and AD is high (above 4μm). CV estimates are robust to errors in g-ratio estimation but are highly sensitive to errors in AD estimation, particularly where ADs are small. We additionally show CV estimates in human corpus callosum in a small number of subjects. In conclusion, we demonstrate accurate CV estimates are possible in regions of the brain where AD is sufficiently large. Problems with estimating ADs for smaller axons presents a problem for estimating CV across the whole CNS and should be the focus of further study.

Abstract Gamma-ray bursts (GRBs) are considered as promising sources of ultra-high-energy cosmic rays (UHECRs) due to their large power output. Observing a neutrino flux from GRBs would offer evidence that GRBs are hadronic accelerators of UHECRs. Previous IceCube analyses, which primarily focused on neutrinos arriving in temporal coincidence with the prompt gamma-rays, found no significant neutrino excess. The four analyses presented in this paper extend the region of interest to 14 days before and after the prompt phase, including generic extended time windows and targeted precursor searches. GRBs were selected between 2011 May and 2018 October to align with the data set of candidate muon-neutrino events observed by IceCube. No evidence of correlation between neutrino events and GRBs was found in these analyses. Limits are set to constrain the contribution of the cosmic GRB population to the diffuse astrophysical neutrino flux observed by IceCube. Prompt neutrino emission from GRBs is limited to ≲1% of the observed diffuse neutrino flux, and emission on timescales up to 10 4 s is constrained to 24% of the total diffuse flux.

Abstract Using data from the IceCube Neutrino Observatory, we searched for high-energy neutrino emission from the gravitational-wave events detected by the advanced LIGO and Virgo detectors during their third observing run. We did a low-latency follow-up on the public candidate events released during the detectors’ third observing run and an archival search on the 80 confident events reported in the GWTC-2.1 and GWTC-3 catalogs. An extended search was also conducted for neutrino emission on longer timescales from neutron star containing mergers. Follow-up searches on the candidate optical counterpart of GW190521 were also conducted. We used two methods; an unbinned maximum likelihood analysis and a Bayesian analysis using astrophysical priors, both of which were previously used to search for high-energy neutrino emission from gravitational-wave events. No significant neutrino emission was observed by any analysis, and upper limits were placed on the time-integrated neutrino flux as well as the total isotropic equivalent energy emitted in high-energy neutrinos.

Abstract The IceCube Neutrino Observatory sends realtime neutrino alerts with a high probability of being astrophysical in origin. We present a new method to correlate these events and possible candidate sources using 2089 blazars from the Fermi-LAT 4LAC-DR2 catalog and with 3413 active galactic nuclei (AGNs) from the Radio Fundamental Catalog. No statistically significant neutrino emission was found in any of the catalog searches. The result suggests that a small fraction, &lt;1%, of the studied AGNs emit neutrinos that pass the alert criteria, and is compatible with prior evidence for neutrino emission presented by IceCube and other authors from sources such as TXS 0506 + 056 and PKS 1502 + 106. We also present cross-checks to other analyses that claim a significant correlation using similar data samples.

Abstract We present the results of a search for 10–1000 GeV neutrinos from 2268 gamma-ray bursts (GRBs) over 8 yr of IceCube-DeepCore data. This work probes burst physics below the photosphere where electromagnetic radiation cannot escape. Neutrinos of tens of giga electronvolts are predicted in sub-photospheric collision of free-streaming neutrons with bulk-jet protons. In a first analysis, we searched for the most significant neutrino-GRB coincidence using six overlapping time windows centered on the prompt phase of each GRB. In a second analysis, we conducted a search for a group of GRBs, each individually too weak to be detectable, but potentially significant when combined. No evidence of neutrino emission is found for either analysis. The most significant neutrino coincidence is for Fermi-GBM GRB bn 140807500, with a p -value of 0.097 corrected for all trials. The binomial test used to search for a group of GRBs had a p -value of 0.65 after all trial corrections. The binomial test found a group consisting only of GRB bn 140807500 and no additional GRBs. The neutrino limits of this work complement those obtained by IceCube at tera electronvolt to peta electronvolt energies. We compare our findings for the large set of GRBs as well as GRB 221009A to the sub-photospheric neutron-proton collision model and find that GRB 221009A provides the most constraining limit on baryon loading. For a jet Lorentz factor of 300 (800), the baryon loading on GRB 221009A is lower than 3.85 (2.13) at a 90% confidence level.

We report on a measurement of astrophysical tau neutrinos with 9.7 yr of IceCube data. Using convolutional neural networks trained on images derived from simulated events, seven candidate ν_{τ} events were found with visible energies ranging from roughly 20 TeV to 1 PeV and a median expected parent ν_{τ} energy of about 200 TeV. Considering backgrounds from astrophysical and atmospheric neutrinos, and muons from π^{±}/K^{±} decays in atmospheric air showers, we obtain a total estimated background of about 0.5 events, dominated by non-ν_{τ} astrophysical neutrinos. Thus, we rule out the absence of astrophysical ν_{τ} at the 5σ level. The measured astrophysical ν_{τ} flux is consistent with expectations based on previously published IceCube astrophysical neutrino flux measurements and neutrino oscillations.

<b><i>Background:</i></b> High angular resolution diffusion tensor imaging (HARD) is an MRI technique that exploits the mobility of water molecules to yield maps of structural order and directionality of white matter tracts with greater precision than six-direction diffusion tensor imaging (DTI) schemes. <b><i>Objective:</i></b> To assess whether HARD is more sensitive than conventional MRI or neurologic assessment in detecting the upper motor neuron (UMN) pathology of patients with ALS. <b><i>Methods:</i></b> Twenty-five patients with definite UMN clinical signs and 23 healthy volunteers underwent conventional MRI. HARD datasets were collected from a subset of these participants plus four patients with isolated lower motor neuron (LMN) signs. ALS symptom severity was assessed by a neurologist, the conventional MR images were reviewed by neuroradiologists, and the DTI maps were subject to quantitative region of interest analysis. <b><i>Results:</i></b> Motor cortex hypointensity on T2-weighted images and corona radiata hyperintensity on proton density-weighted images distinguished patients with UMN involvement from volunteers with 100% specificity, but only 20% sensitivity. Fractional anisotropy (FA) was reduced in the posterior limb of the internal capsule in patients with UMN involvement compared to volunteers. A FA threshold value with a sensitivity of 95% to detect patients with ALS (including those with isolated LMN signs) had a specificity of 71%. <b><i>Conclusions:</i></b> High angular resolution diffusion tensor imaging may be more sensitive than conventional MRI or neurologic assessment to the upper motor neuron (UMN) pathology of ALS, but it lacks the specificity required of a diagnostic marker. Instead, it is potentially useful as a quantitative tool for monitoring the progression of UMN pathology.

Abstract Purpose: To establish the diurnal stability of edited magnetic resonance spectroscopy measurements of gamma‐aminobutyric acid (GABA) in visual and sensorimotor regions of the brain. Materials and Methods: GABA measurements were made in two regions of the brain (an occipital, “visual” region and a “sensorimotor” region centered on the precentral gyrus) using the MEGA‐PRESS editing method, scanning eight healthy adults at five timepoints during a single day. GABA concentration was quantified from the ratio of the GABA integral to the unsuppressed water signal. Results: No significant effect of time on GABA concentration was seen ( P = 0.35). GABA was shown to be significantly more concentrated in visual regions than in sensorimotor regions (1.10 i.u. and 1.03 i.u., respectively; P = 0.050). Coefficients of variability (CVs) across all subjects of 9.1% and 12% (visual and sensorimotor) were significantly higher than mean within‐subjects CVs of 6.5% and 8.8. Conclusion: This study demonstrates the excellent reproducibility of MEGA‐PRESS detection of GABA, demonstrating that the method is sufficiently sensitive to detect inter‐subject variability, and suggests that (within the sensitivity limits of current measurements) time of day can be ignored in the design of MRS studies of visual and sensorimotor regions. J. Magn. Reson. Imaging 2010;31:204–209. © 2009 Wiley‐Liss, Inc.

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.

Schizophrenia is often regarded as a "dysconnectivity" disorder and recent work using graph theory has been used to better characterize dysconnectivity of the structural connectome in schizophrenia. However, there are still little data on the topology of connectomes in less severe forms of the condition. Such analysis will identify topological markers of less severe disease states and provide potential predictors of further disease development. Individuals with psychotic experiences (PEs) were identified from a population-based cohort without relying on participants presenting to clinical services. Such individuals have an increased risk of developing clinically significant psychosis. 123 individuals with PEs and 125 controls were scanned with diffusion-weighted MRI. Whole-brain structural connectomes were derived and a range of global and local GT-metrics were computed. Global efficiency and density were significantly reduced in individuals with PEs. Local efficiency was reduced in a number of regions, including critical network hubs. Further analysis of functional subnetworks showed differential impairment of the default mode network. An additional analysis of pair-wise connections showed no evidence of differences in individuals with PEs. These results are consistent with previous findings in schizophrenia. Reduced efficiency in critical core hubs suggests the brains of individuals with PEs may be particularly predisposed to dysfunction. The absence of any detectable effects in pair-wise connections illustrates that, at less severe stages of psychosis, white-matter alterations are subtle and only manifest when examining network topology. This study indicates that topology could be a sensitive biomarker for early stages of psychotic illness.

To compare the repeatability of γ-aminobutyric acid (GABA) measurements using J-difference editing, before and after spectral realignment-a technique which has previously been demonstrated to improve the quality of J-difference GABA spectra.We performed in vivo measurements in three brain regions (occipital, sensorimotor, and dorsolateral prefrontal cortex [DLPFC]), and analyzed these using alternative alignment approaches to evaluate the impact of alignment on repeatability: "Independent alignment" (aligning each subspectrum independently) and "Pairwise alignment" (aligning each on and off subspectrum as a pair) were compared.Pairwise alignment improved the group mean coefficient of variation in all regions; 0.4% in occipital, 1.1% in sensorimotor, and 1.1% in DLPFC. Independent alignment resulted in subtraction artifacts in the majority of cases, and increased the coefficient of variation in the DLPFC by 9.4%. Simulations demonstrate that the GABA quantification error in datasets with high B0 drift, is 4.5% without alignment, but <1% with optimal alignment.Pairwise alignment improves the repeatability of GABA spectroscopy data. However, independently aligning all on and off subspectra can lead to artifacts and worse repeatability when compared with nonaligned data.

The recent observation by the IceCube neutrino observatory of an astrophysical flux of neutrinos represents the "first light" in the nascent field of neutrino astronomy. The observed diffuse neutrino flux seems to suggest a much larger level of hadronic activity in the non-thermal universe than previously thought and suggests a rich discovery potential for a larger neutrino observatory. This document presents a vision for an substantial expansion of the current IceCube detector, IceCube-Gen2, including the aim of instrumenting a $10\,\mathrm{km}^3$ volume of clear glacial ice at the South Pole to deliver substantial increases in the astrophysical neutrino sample for all flavors. A detector of this size would have a rich physics program with the goal to resolve the sources of these astrophysical neutrinos, discover GZK neutrinos, and be a leading observatory in future multi-messenger astronomy programs.

IMPORTANCEEarly adversity is an important risk factor that relates to internalizing symptoms and altered brain structure.OBJECTIVE To assess the direct effects of early adversity and child internalizing symptoms (ie, depression, anxiety) on cortical gray matter (GM) volume, as well as the extent to which early adversity associates with variation in cortical GM volume indirectly via increased levels of internalizing symptoms. DESIGN, SETTING, AND PARTICIPANTSA prospective investigation of associations between adversity within the first 6 years of life, internalizing symptoms during childhood and early adolescence, and altered brain structure in late adolescence (age, 18-21 years) was conducted in a community-based birth cohort in England (Avon Longitudinal Study of Parents and Children).Participants from the cohort included 494 mother-son pairs monitored since the mothers were pregnant (estimated date of delivery between April 1, 1991, and December 31, 1992).Data collection for the present study was conducted between April 1, 1991, and November 30, 2010; the neuroimaging data were collected between September 1, 2010, and November 30, 2012, and data analyses for the present study occurred between January 25, 2013, and February 15, 2015.Risk factors were adversity within the first 6 years of the child's life (including prenatal exposure) and the child's internalizing symptoms between age 7 and 13 years.EXPOSURES Early childhood adversity. MAIN OUTCOMES AND MEASURESThe main outcome was GM volume of cortical regions previously associated with major depression measured through T1-weighted magnetic resonance images collected in late adolescence.RESULTS Among 494 young men included in this analysis, early adversity was directly associated with lower GM volumes in the anterior cingulate cortex (β = -.18;P = .01)and higher GM volume in the precuneus (β = .18;P = .009).Childhood internalizing symptoms were associated with lower GM volume in the right superior frontal gyrus (β = -.20;P = .002).Early adversity was also associated with higher levels of internalizing symptoms (β = .37;P < .001),which, in turn, were associated with lower superior frontal gyrus volume (ie, an indirect effect) (β = -.08;95% CI, -0.14 to -0.01; P = .02).CONCLUSIONS AND RELEVANCE Adversity early in life was associated with higher levels of internalizing symptoms as well as with altered brain structure.Early adversity was related to variation in brain structure both directly and via increased levels of internalizing symptoms.These findings may suggest that some of the structural variation often attributed to depression might be associated with early adversity in addition to the effect of depression.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38-71 years). Aging was associated with apparent glia but not neurite density damage in the fornix and the hippocampus. Mediation analysis supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlations between age and hippocampal damage disappear, but not vice versa. Fornix and hippocampal differences were both associated with reductions in episodic memory performance. These results suggest that fornix white matter glia damage may cause hippocampal gray matter damage during age-dependent limbic decline.

Neurobiology underlying inter-regional variations - across the human cerebral cortex - in measures derived with multi-modal magnetic resonance imaging (MRI) is poorly understood. Here, we characterize inter-regional variations in a large number of such measures, including T1 and T2 relaxation times, myelin water fraction (MWF), T1w/T2w ratio, mean diffusivity (MD), fractional anisotropy (FA), magnetization transfer ratio (MTR) and cortical thickness. We then employ a virtual-histology approach and relate these inter-regional profiles to those in cell-specific gene expression. Virtual histology revealed that most MRI-derived measures, including T1, T2 relaxation time, MWF, T1w/T2w ratio, MTR, FA and cortical thickness, are associated with expression profiles of genes specific to CA1 pyramidal cells; these genes are enriched in biological processes related to dendritic arborisation. In addition, T2 relaxation time, MWF and T1w/T2w ratio are associated with oligodendrocyte-specific gene-expression profiles, supporting their use as measures sensitive to intra-cortical myelin. MWF contributes more variance than T1w/T2w ratio to the mean oligodendrocyte expression profile, suggesting greater sensitivity to myelin. These cell-specific MRI associations may help provide a framework for determining which MRI sequences to acquire in studies with specific neurobiological hypotheses.

Continued improvements on existing reconstruction methods are vital to the success of high-energy physics experiments, such as the IceCube Neutrino Observatory. In IceCube, further challenges arise as the detector is situated at the geographic South Pole where computational resources are limited. However, to perform real-time analyses and to issue alerts to telescopes around the world, powerful and fast reconstruction methods are desired. Deep neural networks can be extremely powerful, and their usage is computationally inexpensive once the networks are trained. These characteristics make a deep learning-based approach an excellent candidate for the application in IceCube. A reconstruction method based on convolutional architectures and hexagonally shaped kernels is presented. The presented method is robust towards systematic uncertainties in the simulation and has been tested on experimental data. In comparison to standard reconstruction methods in IceCube, it can improve upon the reconstruction accuracy, while reducing the time necessary to run the reconstruction by two to three orders of magnitude.

We present a measurement of the density of GeV muons in near-vertical air showers using three years of data recorded by the IceTop array at the South Pole. Depending on the shower size, the muon densities have been measured at lateral distances between 200 m and 1000 m. From these lateral distributions, we derive the muon densities as functions of energy at reference distances of 600 m and 800 m for primary energies between 2.5 PeV and 40 PeV and between 9 PeV and 120 PeV, respectively. The muon densities are determined using, as a baseline, the hadronic interaction model Sibyll 2.1 together with various composition models. The measurements are consistent with the predicted muon densities within these baseline interaction and composition models. The measured muon densities have also been compared to simulations using the post-LHC models EPOS-LHC and QGSJet-II.04. The result of this comparison is that the post-LHC models together with any given composition model yield higher muon densities than observed. This is in contrast to the observations above 1 EeV where all model simulations yield for any mass composition lower muon densities than the measured ones. The post-LHC models in general feature higher muon densities so that the agreement with experimental data at the highest energies is improved but the muon densities are not correct in the energy range between 2.5 PeV and about 100 PeV.

Abstract Core-collapse supernovae are a promising potential high-energy neutrino source class. We test for correlation between seven years of IceCube neutrino data and a catalog containing more than 1000 core-collapse supernovae of types IIn and IIP and a sample of stripped-envelope supernovae. We search both for neutrino emission from individual supernovae as well as for combined emission from the whole supernova sample, through a stacking analysis. No significant spatial or temporal correlation of neutrinos with the cataloged supernovae was found. All scenarios were tested against the background expectation and together yield an overall p -value of 93%; therefore, they show consistency with the background only. The derived upper limits on the total energy emitted in neutrinos are 1.7 × 10 48 erg for stripped-envelope supernovae, 2.8 × 10 48 erg for type IIP, and 1.3 × 10 49 erg for type IIn SNe, the latter disfavoring models with optimistic assumptions for neutrino production in interacting supernovae. We conclude that stripped-envelope supernovae and supernovae of type IIn do not contribute more than 14.6% and 33.9%, respectively, to the diffuse neutrino flux in the energy range of about [ 10 3 –10 5 ] GeV, assuming that the neutrino energy spectrum follows a power-law with an index of −2.5. Under the same assumption, we can only constrain the contribution of type IIP SNe to no more than 59.9%. Thus, core-collapse supernovae of types IIn and stripped-envelope supernovae can both be ruled out as the dominant source of the diffuse neutrino flux under the given assumptions.

Abstract In this work, we present the results of searches for signatures of dark matter decay or annihilation into Standard Model particles, and secret neutrino interactions with dark matter. Neutrinos could be produced in the decay or annihilation of galactic or extragalactic dark matter. Additionally, if an interaction between dark matter and neutrinos exists then dark matter will interact with extragalactic neutrinos. In particular galactic dark matter will induce an anisotropy in the neutrino sky if this interaction is present. We use seven and a half years of the High-Energy Starting Event (HESE) sample data, which measures neutrinos in the energy range of approximately 60 TeV to 10 PeV, to study these phenomena. This all-sky event selection is dominated by extragalactic neutrinos. For dark matter of ∼ 1 PeV in mass, we constrain the velocity-averaged annihilation cross section to be smaller than 10 -23 cm 3 /s for the exclusive μ + μ - channel and 10 -22 cm 3 /s for the bb̅ channel. For the same mass, we constrain the lifetime of dark matter to be larger than 10 28 s for all channels studied, except for decaying exclusively to bb̅ where it is bounded to be larger than 10 27 s. Finally, we also search for evidence of astrophysical neutrinos scattering on galactic dark matter in two scenarios. For fermionic dark matter with a vector mediator, we constrain the dimensionless coupling associated with this interaction to be less than 0.1 for dark matter mass of 0.1 GeV and a mediator mass of 10 -4 GeV. In the case of scalar dark matter with a fermionic mediator, we constrain the coupling to be less than 0.1 for dark matter and mediator masses below 1 MeV.

Abstract We present a catalog of likely astrophysical neutrino track-like events from the IceCube Neutrino Observatory. IceCube began reporting likely astrophysical neutrinos in 2016, and this system was updated in 2019. The catalog presented here includes events that were reported in real time since 2019, as well as events identified in archival data samples starting from 2011. We report 275 neutrino events from two selection channels as the first entries in the catalog, the IceCube Event Catalog of Alert Tracks, which will see ongoing extensions with additional alerts. The Gold and Bronze alert channels respectively provide neutrino candidates with a 50% and 30% probability of being astrophysical, on average assuming an astrophysical neutrino power-law energy spectral index of 2.19. For each neutrino alert, we provide the reconstructed energy, direction, false-alarm rate, probability of being astrophysical in origin, and likelihood contours describing the spatial uncertainty in the alert's reconstructed location. We also investigate a directional correlation of these neutrino events with gamma-ray and X-ray catalogs, including 4FGL, 3HWC, TeVCat, and Swift-BAT.

Dark matter particles in the Galactic Center and halo can annihilate or decay into a pair of neutrinos producing a monochromatic flux of neutrinos. The spectral feature of this signal is unique and it is not expected from any astrophysical production mechanism. Its observation would constitute a dark matter smoking gun signal. We performed the first dedicated search with a neutrino telescope for such signal, by looking at both the angular and energy information of the neutrino events. To this end, a total of five years of IceCube’s DeepCore data has been used to test dark matter masses ranging from 10 GeV to 40 TeV. No significant neutrino excess was found and upper limits on the annihilation cross section, as well as lower limits on the dark matter lifetime, were set. The limits reached are of the order of 10−24 cm3/s for an annihilation and up to 1027 s for decaying dark matter. Using the same data sample we also derive limits for dark matter annihilation or decay into a pair of Standard Model charged particles.2 MoreReceived 27 March 2023Accepted 7 July 2023DOI:https://doi.org/10.1103/PhysRevD.108.102004© 2023 American Physical SocietyPhysics Subject Headings (PhySH)Research AreasParticle astrophysicsParticle dark matterWeakly interacting massive particlesTechniquesCosmic ray & astroparticle detectorsNeutrino detectionParticles & Fields

It is not sufficiently realised that sleep-walking is not an hysterical condition, nor in any way related to epilepsy, nor that it can be accompanied by violent injury to the self or others. Three case reports here include that of a 14-year-old boy who rose from his bed at 2 a.m. and severely stabbed his five-year-old girl cousin. The sleeping mind is not in touch with reality and amnesia for events during sleep is usual.

To quantify changes in crystalline lens curvature, thickness, equatorial diameter, surface area, and volume during accommodation using a novel two-dimensional magnetic resonance imaging (MRI) paradigm to generate a complete three-dimensional crystalline lens surface model.Nineteen volunteers, aged 19 to 30 years, were recruited. T(2)-weighted MRIs, optimized to show fluid-filled chambers of the eye, were acquired using an eight-channel radio frequency head coil. Twenty-four oblique-axial slices of 0.8 mm thickness, with no interslice gaps, were acquired to visualize the crystalline lens. Three Maltese cross-type accommodative stimuli (at 0.17, 4.0, and 8.0 D) were presented randomly to the subjects in the MRI to examine lenticular changes with accommodation. MRIs were analyzed to generate a three-dimensional surface model.During accommodation, mean crystalline lens thickness increased (F = 33.39, P < 0.001), whereas lens equatorial diameter (F = 24.00, P < 0.001) and surface radii both decreased (anterior surface, F = 21.78, P < 0.001; posterior surface, F = 13.81, P < 0.001). Over the same stimulus range, mean crystalline lens surface area decreased (F = 7.04, P < 0.005) with a corresponding increase in lens volume (F = 6.06, P = 0.005). These biometric changes represent a 1.82% decrease and 2.30% increase in crystalline lens surface area and volume, respectively. CONCLUSIONS; The results indicate that the capsular bag undergoes elastic deformation during accommodation, causing reduced surface area, and the observed volumetric changes oppose the theory that the lens is incompressible.

To investigate factors that influence the multiplet pattern observed in J-difference editing of gamma-aminobutyric acid (GABA).Density matrix simulations were applied to investigate the shape of the 3 ppm GABA multiplet as a function of the editing sequence's slice-selective refocusing pulse properties, in particular bandwidth, transition width, and flip angle. For comparison to the calculations, experimental measurements were also made at 3 T on a 10 mM GABA solution using the MEGA-PRESS sequence at various refocusing pulse flip angles.Good agreement was found between experiments and simulations. The edited multiplet consists of two outer lines of slightly unequal intensity due to strong coupling, and a smaller central line, the result of the unequal J-couplings between the C4 and C3 protons. The size of the center peak increases with increasing slice-selective refocusing pulse transition width, and deviation of the flip angle from 180°.The 3 ppm GABA multiplet pattern observed in the MEGA-PRESS experiment depends quite strongly on the properties of the slice-selective refocusing pulses used. Under some circumstance, the central peak can be quite large; this does not necessarily indicate inefficient editing, or a subtraction artifact, but should be recognized as a property of the pulse sequence itself.

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.

Juvenile myoclonic epilepsy (JME) is a common idiopathic (genetic) generalized epilepsy (IGE) syndrome characterized by impairments in executive and cognitive control, affecting independent living and psychosocial functioning. There is a growing consensus that JME is associated with abnormal function of diffuse brain networks, typically affecting frontal and fronto-thalamic areas. Using diffusion MRI and a graph theoretical analysis, we examined bivariate (network-based statistic) and multivariate (global and local) properties of structural brain networks in patients with JME (N = 34) and matched controls. Neuropsychological assessment was performed in a subgroup of 14 patients. Neuropsychometry revealed impaired visual memory and naming in JME patients despite a normal full scale IQ (mean = 98.6). Both JME patients and controls exhibited a small world topology in their white matter networks, with no significant differences in the global multivariate network properties between the groups. The network-based statistic approach identified one subnetwork of hyperconnectivity in the JME group, involving primary motor, parietal and subcortical regions. Finally, there was a significant positive correlation in structural connectivity with cognitive task performance. Our findings suggest that structural changes in JME patients are distributed at a network level, beyond the frontal lobes. The identified subnetwork includes key structures in spike wave generation, along with primary motor areas, which may contribute to myoclonic jerks. We conclude that analyzing the affected subnetworks may provide new insights into understanding seizure generation, as well as the cognitive deficits observed in JME patients.

The Sun provides an excellent target for studying spin-dependent dark matter-proton scattering due to its high matter density and abundant hydrogen content. Dark matter particles from the Galactic halo can elastically interact with Solar nuclei, resulting in their capture and thermalization in the Sun. The captured dark matter can annihilate into Standard Model particles including an observable flux of neutrinos. We present the results of a search for low-energy (<500 GeV) neutrinos correlated with the direction of the Sun using 7 years of IceCube data. This work utilizes, for the first time, new optimized cuts to extend IceCube’s sensitivity to dark matter mass down to 5 GeV. We find no significant detection of neutrinos from the Sun. Our observations exclude capture by spin-dependent dark matter-proton scattering with cross section down to a few times 10−41 cm2, assuming there is equilibrium with annihilation into neutrinos/antineutrinos for dark matter masses between 5 GeV and 100 GeV. These are the strongest constraints at GeV energies for dark matter annihilation directly to neutrinos.Received 18 November 2021Accepted 7 February 2022DOI:https://doi.org/10.1103/PhysRevD.105.062004© 2022 American Physical SocietyPhysics Subject Headings (PhySH)Particle dark matterResearch AreasParticle astrophysicsParticle dark matterResearch AreasCosmic rays & astroparticlesParticle dark matterResearch AreasCosmologyDark matterParticle dark matterResearch AreasParticle dark matterParticles & FieldsGravitation, Cosmology & Astrophysics

The sources of the majority of the high-energy astrophysical neutrinos observed with the IceCube neutrino telescope at the South Pole are unknown. So far, only a gamma-ray blazar was compellingly associated with the emission of high-energy neutrinos. In addition, several studies suggest that the neutrino emission from the gamma-ray blazar population only accounts for a small fraction of the total astrophysical neutrino flux. In this work we probe the production of high-energy neutrinos in the cores of Active Galactic Nuclei (AGN), induced by accelerated cosmic rays in the accretion disk region. We present a likelihood analysis based on eight years of IceCube data, searching for a cumulative neutrino signal from three AGN samples created for this work. The neutrino emission is assumed to be proportional to the accretion disk luminosity estimated from the soft X-ray flux. Next to the observed soft X-ray flux, the objects for the three samples have been selected based on their radio emission and infrared color properties. For the largest sample in this search, an excess of high-energy neutrino events with respect to an isotropic background of atmospheric and astrophysical neutrinos is found, corresponding to a post-trial significance of 2.60$\sigma$. Assuming a power-law spectrum, the best-fit spectral index is $2.03^{+0.14}_{-0.11}$, consistent with expectations from particle acceleration in astrophysical sources. If interpreted as a genuine signal with the assumptions of a proportionality of X-ray and neutrino fluxes and a model for the sub-threshold flux distribution, this observation implies that at 100 TeV, 27$\%$ - 100$\%$ of the observed neutrinos arise from particle acceleration in the core of AGN.

Abstract High-energy tau neutrinos are rarely produced in atmospheric cosmic-ray showers or at cosmic particle accelerators, but are expected to emerge during neutrino propagation over cosmic distances due to flavor mixing. When high energy tau neutrinos interact inside the IceCube detector, two spatially separated energy depositions may be resolved, the first from the charged current interaction and the second from the tau lepton decay. We report a novel analysis of 7.5 years of IceCube data that identifies two candidate tau neutrinos among the 60 “High-Energy Starting Events” (HESE) collected during that period. The HESE sample offers high purity, all-sky sensitivity, and distinct observational signatures for each neutrino flavor, enabling a new measurement of the flavor composition. The measured astrophysical neutrino flavor composition is consistent with expectations, and an astrophysical tau neutrino flux is indicated at 2.8 $$\sigma $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>σ</mml:mi> </mml:math> significance.

Abstract Beginning in 2016, the IceCube Neutrino Observatory has sent out alerts in real time containing the information of high-energy ( E ≳ 100 TeV) neutrino candidate events with moderate to high (≳30%) probability of astrophysical origin. In this work, we use a recent catalog of such alert events, which, in addition to events announced in real time, includes events that were identified retroactively and covers the time period of 2011–2020. We also search for additional, lower-energy neutrinos from the arrival directions of these IceCube alerts. We show how performing such an analysis can constrain the contribution of rare populations of cosmic neutrino sources to the diffuse astrophysical neutrino flux. After searching for neutrino emission coincident with these alert events on various timescales, we find no significant evidence of either minute-scale or day-scale transient neutrino emission or of steady neutrino emission in the direction of these alert events. This study also shows how numerous a population of neutrino sources has to be to account for the complete astrophysical neutrino flux. Assuming that sources have the same luminosity, an E −2.5 neutrino spectrum, and number densities that follow star formation rates, the population of sources has to be more numerous than 7 × 10 −9 Mpc −3 . This number changes to 3 × 10 −7 Mpc −3 if number densities instead have no cosmic evolution.

We describe a new data sample of IceCube DeepCore and report on the latest measurement of atmospheric neutrino oscillations obtained with data recorded between 2011-2019. The sample includes significant improvements in data calibration, detector simulation, and data processing, and the analysis benefits from a detailed treatment of systematic uncertainties, with significantly higher level of detail since our last study. By measuring the relative fluxes of neutrino flavors as a function of their reconstructed energies and arrival directions we constrain the atmospheric neutrino mixing parameters to be $\sin^2\theta_{23} = 0.51\pm 0.05$ and $\Delta m^2_{32} = 2.41\pm0.07\times 10^{-3}\mathrm{eV}^2$, assuming a normal mass ordering. The resulting 40\% reduction in the error of both parameters with respect to our previous result makes this the most precise measurement of oscillation parameters using atmospheric neutrinos. Our results are also compatible and complementary to those obtained using neutrino beams from accelerators, which are obtained at lower neutrino energies and are subject to different sources of uncertainties.

Abstract Galactic PeV cosmic-ray accelerators (PeVatrons) are Galactic sources theorized to accelerate cosmic rays up to PeV in energy. The accelerated cosmic rays are expected to interact hadronically with nearby ambient gas or the interstellar medium, resulting in γ -rays and neutrinos. Recently, the Large High Altitude Air Shower Observatory (LHAASO) identified 12 γ -ray sources with emissions above 100 TeV, making them candidates for PeVatrons. While at these high energies the Klein–Nishina effect exponentially suppresses leptonic emission from Galactic sources, evidence for neutrino emission would unequivocally confirm hadronic acceleration. Here, we present the results of a search for neutrinos from these γ -ray sources and stacking searches testing for excess neutrino emission from all 12 sources as well as their subcatalogs of supernova remnants and pulsar wind nebulae with 11 yr of track events from the IceCube Neutrino Observatory. No significant emissions were found. Based on the resulting limits, we place constraints on the fraction of γ -ray flux originating from the hadronic processes in the Crab Nebula and LHAASO J2226+6057.

Abstract. The IceCube Neutrino Observatory instruments about 1 km3 of deep, glacial ice at the geographic South Pole. It uses 5160 photomultipliers to detect Cherenkov light emitted by charged relativistic particles. An unexpected light propagation effect observed by the experiment is an anisotropic attenuation, which is aligned with the local flow direction of the ice. We examine birefringent light propagation through the polycrystalline ice microstructure as a possible explanation for this effect. The predictions of a first-principles model developed for this purpose, in particular curved light trajectories resulting from asymmetric diffusion, provide a qualitatively good match to the main features of the data. This in turn allows us to deduce ice crystal properties. Since the wavelength of the detected light is short compared to the crystal size, these crystal properties include not only the crystal orientation fabric, but also the average crystal size and shape, as a function of depth. By adding small empirical corrections to this first-principles model, a quantitatively accurate description of the optical properties of the IceCube glacial ice is obtained. In this paper, we present the experimental signature of ice optical anisotropy observed in IceCube light-emitting diode (LED) calibration data, the theory and parameterization of the birefringence effect, the fitting procedures of these parameterizations to experimental data, and the inferred crystal properties.

Abstract IceCube alert events are neutrinos with a moderate-to-high probability of having astrophysical origin. In this study, we analyze 11 yr of IceCube data and investigate 122 alert events and a selection of high-energy tracks detected between 2009 and the end of 2021. This high-energy event selection (alert events + high-energy tracks) has an average probability of ≥0.5 of being of astrophysical origin. We search for additional continuous and transient neutrino emission within the high-energy events’ error regions. We find no evidence for significant continuous neutrino emission from any of the alert event directions. The only locally significant neutrino emission is the transient emission associated with the blazar TXS 0506+056, with a local significance of 3 σ , which confirms previous IceCube studies. When correcting for 122 test positions, the global p -value is 0.156 and compatible with the background hypothesis. We constrain the total continuous flux emitted from all 122 test positions at 100 TeV to be below 1.2 × 10 −15 (TeV cm 2 s) −1 at 90% confidence assuming an E −2 spectrum. This corresponds to 4.5% of IceCube’s astrophysical diffuse flux. Overall, we find no indication that alert events in general are linked to lower-energetic continuous or transient neutrino emission.

A novel, five-term relational reasoning paradigm was employed during functional magnetic resonance imaging to investigate neural correlates of the symbolic distance effect (SDE). Prior to scanning, participants learned a series of more-than (E>D>C>B>A) or less-than (A<B<C<D<E) ordered premise pairs. During scanning, inferential tests presented the premise pairs, adjacent, mutually entailed tasks (e.g., D<E and B>A) and nonadjacent one-step (A<C, B<D, C<E, C>A, D>B and E>C) and two-step (A<D, B<E, D>A and E>B) combinatorial entailed tasks. In terms of brain activation, the SDE was identified in the inferior frontal cortex, dorsolateral prefrontal cortex, and bilateral parietal cortex with a graded activation pattern from adjacent to one-step and two-step relations. We suggest that this captures the behavioural SDE of increased accuracy and decreased reaction time from adjacent to two-step relations. One-step relations involving endpoints A or E resulted in greater parietal activation compared to one-step relations without endpoints. Novel contrasts found enhanced activation in right parietal and prefrontal cortices during mutually entailed tasks only for participants who had learned all less-than relations. Increased parietal activation was found for one-step tasks that were inconsistent with prior training. Overall, the findings demonstrate a crucial role for parietal cortex during relational reasoning with a spatially ordered array.

The Precision IceCube Next Generation Upgrade (PINGU) is a proposed low-energy in-fill array of the IceCube Neutrino Observatory. Leveraging technology proven with IceCube, PINGU will feature the world's largest effective volume for neutrinos at an energy threshold of a few GeV, improving the sensitivity to several aspects of neutrino oscillation physics at modest cost. With its unprecedented statistical sample of low-energy atmospheric neutrinos, PINGU will have highly competitive sensitivity to $\nu_{\mu}$ disappearance, the $\theta_{23}$ octant, and maximal mixing, will make the world's best $\nu_{\tau}$ appearance measurement, allowing a unique probe of the unitarity of the PMNS mixing matrix, and will be able to distinguish the neutrino mass ordering at $3\sigma$ significance with less than 4 years of data. PINGU can also extend the indirect search for solar WIMP dark matter complimentary to the on-going and planned direct dark matter experiments. At the lower end of the energy range, PINGU may use neutrino tomography to directly probe the composition of the Earth's core. With its increased module density, PINGU will improve IceCube's sensitivity to galactic supernova neutrino bursts and enable it to extract the neutrino energy spectral shape.

Individuals at clinical high risk (CHR) of developing psychosis present with widespread functional abnormalities in the brain. Cognitive deficits, including working memory (WM) problems, as commonly elicited by n-back tasks, are observed in CHR individuals. However, functional MRI (fMRI) studies, comprising a heterogeneous cluster of general and social cognition paradigms, have not necessarily demonstrated consistent and conclusive results in this population. Hence, a comprehensive review of fMRI studies, spanning almost one decade, was carried out to observe for general trends with respect to brain regions and cognitive systems most likely to be dysfunctional in CHR individuals. 32 studies were included for this review, out of which 22 met the criteria for quantitative analysis using activation likelihood estimation (ALE). Task related contrast activations were firstly analysed by comparing CHR and healthy control participants in the total pooled sample, followed by a comparison of general cognitive function studies (excluding social cognition paradigms), and finally by only looking at n-back working memory task based studies. Findings from the ALE implicated four key dysfunctional and distinct neural regions in the CHR group, namely the right inferior parietal lobule (rIPL), the left medial frontal gyrus (lmFG), the left superior temporal gyrus (lSTG) and the right fronto-polar cortex (rFPC) of the superior frontal gyrus (SFG). Narrowing down to relatively few significant dysfunctional neural regions is a step forward in reducing the apparent ambiguity of overall findings, which would help to target specific neural regions and pathways of interest for future research in CHR populations.

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) can be measured in vivo using edited magnetic resonance spectroscopy (MRS), but quantification suffers from contamination by macromolecules (MM). It is possible to suppress this contamination using symmetric editing, but this procedure potentially compromises reliability of the GABA measurement. The aim of this study was to compare the repeatability of GABA-edited MRS with and without MM suppression.GABA' (non-MM contaminated) and GABA'+MM (MM-contaminated) concentration was measured in the occipital lobe (OCC) and anterior cingulate (AC) using symmetric and standard editing (n = 15). Each method was performed twice in each region.Within-participant coefficients of variation for each technique were 4.0% (GABA'+MM) and 8.6% (GABA') in the OCC and 14.8% (GABA'+MM) and 12.6% (GABA') in the AC. Intraclass correlation coefficients were better for the suppression method than standard editing in both the OCC (0.72 versus 0.67) and AC (0.41 versus 0.16). These findings were replicated in the OCC of a second cohort (n = 15).Symmetric suppression is shown to be comparable in repeatability to standard GABA-editing. Measuring a purer quantification of GABA becomes increasingly important as more research is conducted on links between GABA concentration, pathology and healthy behavior.

The ordering of the neutrino mass eigenstates is one of the fundamental open questions in neutrino physics. While current-generation neutrino oscillation experiments are able to produce moderate indications on this ordering, upcoming experiments of the next generation aim to provide conclusive evidence. In this paper we study the combined performance of the two future multi-purpose neutrino oscillation experiments JUNO and the IceCube Upgrade, which employ two very distinct and complementary routes towards the neutrino mass ordering. The approach pursued by the $20\,\mathrm{kt}$ medium-baseline reactor neutrino experiment JUNO consists of a careful investigation of the energy spectrum of oscillated $\bar{\nu}_e$ produced by ten nuclear reactor cores. The IceCube Upgrade, on the other hand, which consists of seven additional densely instrumented strings deployed in the center of IceCube DeepCore, will observe large numbers of atmospheric neutrinos that have undergone oscillations affected by Earth matter. In a joint fit with both approaches, tension occurs between their preferred mass-squared differences $ \Delta m_{31}^{2}=m_{3}^{2}-m_{1}^{2} $ within the wrong mass ordering. In the case of JUNO and the IceCube Upgrade, this allows to exclude the wrong ordering at $>5\sigma$ on a timescale of 3--7 years --- even under circumstances that are unfavorable to the experiments' individual sensitivities. For PINGU, a 26-string detector array designed as a potential low-energy extension to IceCube, the inverted ordering could be excluded within 1.5 years (3 years for the normal ordering) in a joint analysis.

In multi-messenger astronomy, rapid investigation of interesting transients is imperative. As an observatory with a 4$\pi$ steradian field of view and $\sim$99\% uptime, the IceCube Neutrino Observatory is a unique facility to follow up transients, and to provide valuable insight for other observatories and inform their observing decisions. Since 2016, IceCube has been using low-latency data to rapidly respond to interesting astrophysical events reported by the multi-messenger observational community. Here, we describe the pipeline used to perform these follow up analyses and provide a summary of the 58 analyses performed as of July 2020. We find no significant signal in the first 58 analyses performed. The pipeline has helped inform various electromagnetic observing strategies, and has constrained neutrino emission from potential hadronic cosmic accelerators.

We provide a rich multi-contrast microstructural MRI dataset acquired on an ultra-strong gradient 3T Connectom MRI scanner comprising 5 repeated sets of MRI microstructural contrasts in 6 healthy human participants. The availability of data sets that support comprehensive simultaneous assessment of test-retest reliability of multiple microstructural contrasts (i.e., those derived from advanced diffusion, multi-component relaxometry and quantitative magnetisation transfer MRI) in the same population is extremely limited. This unique dataset is offered to the imaging community as a test-bed resource for conducting specialised analyses that may assist and inform their current and future research. The Microstructural Image Compilation with Repeated Acquisitions (MICRA) dataset includes raw data and computed microstructure maps derived from multi-shell and multi-direction encoded diffusion, multi-component relaxometry and quantitative magnetisation transfer acquisition protocols. Our data demonstrate high reproducibility of several microstructural MRI measures across scan sessions as shown by intra-class correlation coefficients and coefficients of variation. To illustrate a potential use of the MICRA dataset, we computed sample sizes required to provide sufficient statistical power a priori across different white matter pathways and microstructure measures for different statistical comparisons. We also demonstrate whole brain white matter voxel-wise repeatability in several microstructural maps. The MICRA dataset will be of benefit to researchers wishing to conduct similar reliability tests, power estimations or to evaluate the robustness of their own analysis pipelines.

We present an all-sky 90% confidence level upper limit on the cosmic flux of relativistic magnetic monopoles using 2886 days of IceCube data. The analysis was optimized for monopole speeds between 0.750c and 0.995c, without any explicit restriction on the monopole mass. We constrain the flux of relativistic cosmic magnetic monopoles to a level below 2.0×10^{-19} cm^{-2} s^{-1} sr^{-1} over the majority of the targeted speed range. This result constitutes the most strict upper limit to date for magnetic monopoles with β≳0.8 and up to β∼0.995 and fills the gap between existing limits on the cosmic flux of nonrelativistic and ultrarelativistic magnetic monopoles.

Along their long propagation from production to detection, neutrinos undergo flavour conversions that convert their types or flavours1,2. High-energy astrophysical neutrinos propagate unperturbed over a billion light years in vacuum3 and are sensitive to small effects caused by new physics. Effects of quantum gravity4 are expected to appear at the Planck energy scale. Such a high-energy universe would have existed only immediately after the Big Bang and is inaccessible by human technologies. On the other hand, quantum gravity effects may exist in our low-energy vacuum5–8, but are suppressed by inverse powers of the Planck energy. Measuring the coupling of particles to such small effects is difficult via kinematic observables, but could be observable through flavour conversions. Here we report a search with the IceCube Neutrino Observatory, using astrophysical neutrino flavours9,10 to search for new space–time structure. We did not find any evidence of anomalous flavour conversion in the IceCube astrophysical neutrino flavour data. We apply the most stringent limits of any known technologies, down to 10−42 GeV−2 with Bayes factor greater than 10 on the dimension-six operators that parameterize the space–time defects. We thus unambiguously reach the parameter space of quantum-gravity-motivated physics. The IceCube Collaboration reports a search for quantum gravity effects imprinted in flavour conversions of astrophysical neutrinos. No evidence for anomalous conversions between neutrino flavours is observed.

Abstract This paper presents the results of a search for neutrinos that are spatially and temporally coincident with 22 unique, nonrepeating fast radio bursts (FRBs) and one repeating FRB (FRB 121102). FRBs are a rapidly growing class of Galactic and extragalactic astrophysical objects that are considered a potential source of high-energy neutrinos. The IceCube Neutrino Observatory’s previous FRB analyses have solely used track events. This search utilizes seven years of IceCube cascade events which are statistically independent of track events. This event selection allows probing of a longer range of extended timescales due to the low background rate. No statistically significant clustering of neutrinos was observed. Upper limits are set on the time-integrated neutrino flux emitted by FRBs for a range of extended time windows.

Abstract The D-Egg, an acronym for “Dual optical sensors in an Ellipsoid Glass for Gen2,” is one of the optical modules designed for future extensions of the IceCube experiment at the South Pole. The D-Egg has an elongated-sphere shape to maximize the photon-sensitive effective area while maintaining a narrow diameter to reduce the cost and the time needed for drilling of the deployment holes in the glacial ice for the optical modules at depths up to 2700 m. The D-Egg design is utilized for the IceCube Upgrade, the next stage of the IceCube project also known as IceCube-Gen2 Phase 1, where nearly half of the optical sensors to be deployed are D-Eggs. With two 8-inch high-quantum efficiency photomultiplier tubes (PMTs) per module, D-Eggs offer an increased effective area while retaining the successful design of the IceCube digital optical module (DOM). The convolution of the wavelength-dependent effective area and the Cherenkov emission spectrum provides an effective photodetection sensitivity that is 2.8 times larger than that of IceCube DOMs. The signal of each of the two PMTs is digitized using ultra-low-power 14-bit analog-to-digital converters with a sampling frequency of 240 MSPS, enabling a flexible event triggering, as well as seamless and lossless event recording of single-photon signals to multi-photons exceeding 200 photoelectrons within 10 ns. Mass production of D-Eggs has been completed, with 277 out of the 310 D-Eggs produced to be used in the IceCube Upgrade. In this paper, we report the design of the D-Eggs, as well as the sensitivity and the single to multi-photon detection performance of mass-produced D-Eggs measured in a laboratory using the built-in data acquisition system in each D-Egg optical sensor module.

Abstract Atmospheric muon neutrinos are produced by meson decays in cosmic-ray-induced air showers. The flux depends on meteorological quantities such as the air temperature, which affects the density of air. Competition between decay and re-interaction of those mesons in the first particle production generations gives rise to a higher neutrino flux when the air density in the stratosphere is lower, corresponding to a higher temperature. A measurement of a temperature dependence of the atmospheric $$\nu _{\mu }$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>ν</mml:mi> <mml:mi>μ</mml:mi> </mml:msub> </mml:math> flux provides a novel method for constraining hadronic interaction models of air showers. It is particularly sensitive to the production of kaons. Studying this temperature dependence for the first time requires a large sample of high-energy neutrinos as well as a detailed understanding of atmospheric properties. We report the significant ( $$&gt; 10 \; \sigma $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mo>&gt;</mml:mo> <mml:mn>10</mml:mn> <mml:mspace /> <mml:mi>σ</mml:mi> </mml:mrow> </mml:math> ) observation of a correlation between the rate of more than 260,000 neutrinos, detected by IceCube between 2012 and 2018, and atmospheric temperatures of the stratosphere, measured by the Atmospheric Infrared Sounder (AIRS) instrument aboard NASA’s AQUA satellite. For the observed 10 $$\%$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mo>%</mml:mo> </mml:math> seasonal change of effective atmospheric temperature we measure a 3.5(3) $$\%$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mo>%</mml:mo> </mml:math> change in the muon neutrino flux. This observed correlation deviates by about 2-3 standard deviations from the expected correlation of 4.3 $$\%$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mo>%</mml:mo> </mml:math> as obtained from theoretical predictions under the assumption of various hadronic interaction models.

The pharmacological effects of monoamine potentiating antidepressants are likely to be expressed ultimately on cortical pyramidal neurones that use glutamate as a neurotransmitter. However, there are few data on the effects of antidepressant treatment on cortical glutamate levels in humans. The aim of the present study was to use proton magnetic resonance spectroscopy (MRS) to assess the effects of short-term administration of the selective serotonin re-uptake inhibitor, citalopram and the selective noradrenaline re-uptake inhibitor, reboxetine, on a composite measure of glutamate and glutamine (Glx) in occipital cortex in healthy volunteers using a parallel group, placebo-controlled design. We found that relative both to placebo and reboxetine, seven days treatment with citalopram significantly increased cortical Glx. Our data suggest that short-term treatment with citalopram, but not reboxetine, increases occipital Glx in healthy subjects. Further studies are needed to find out if similar effects occur in anterior brain regions and whether they reflect changes in glutamate or glutamine or both.

ABSTRACT Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by 1 H‐MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J ‐difference edited 1 H‐MRS to changes in extracellular GABA concentrations. MEGA‐PRESS was used to obtain GABA‐edited spectra in 10 male individuals, before and after a 15‐mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self‐reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)‐derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission. Synapse 68:355–362, 2014 . © 2014 Wiley Periodicals, Inc.

The quantification of γ-aminobutyric acid (GABA) concentration using localised MRS suffers from partial volume effects related to differences in the intrinsic concentration of GABA in grey (GM) and white (WM) matter. These differences can be represented as a ratio between intrinsic GABA in GM and WM: rM . Individual differences in GM tissue volume can therefore potentially drive apparent concentration differences. Here, a quantification method that corrects for these effects is formulated and empirically validated. Quantification using tissue water as an internal concentration reference has been described previously. Partial volume effects attributed to rM can be accounted for by incorporating into this established method an additional multiplicative correction factor based on measured or literature values of rM weighted by the proportion of GM and WM within tissue-segmented MRS volumes. Simulations were performed to test the sensitivity of this correction using different assumptions of rM taken from previous studies. The tissue correction method was then validated by applying it to an independent dataset of in vivo GABA measurements using an empirically measured value of rM . It was shown that incorrect assumptions of rM can lead to overcorrection and inflation of GABA concentration measurements quantified in volumes composed predominantly of WM. For the independent dataset, GABA concentration was linearly related to GM tissue volume when only the water signal was corrected for partial volume effects. Performing a full correction that additionally accounts for partial volume effects ascribed to rM successfully removed this dependence. With an appropriate assumption of the ratio of intrinsic GABA concentration in GM and WM, GABA measurements can be corrected for partial volume effects, potentially leading to a reduction in between-participant variance, increased power in statistical tests and better discriminability of true effects.

Precuneus/posterior cingulate cortex (PCu/PCC) are key components of a midline network, activated during rest but also in tasks that involve construction of scene or situation models. Despite growing interest in PCu/PCC functional alterations in disease and disease risk, the underlying neurochemical modulators of PCu/PCC's task-evoked activity are largely unstudied. Here, a multimodal imaging approach was applied to investigate whether interindividual differences in PCu/PCC fMRI activity, elicited during perceptual discrimination of scene stimuli, were correlated with local brain metabolite levels, measured during resting-state 1 H-MRS. Forty healthy young adult participants completed an fMRI perceptual odd-one-out task for scenes, objects and faces. 1 H-MRS metabolites N-acetyl-aspartate (tNAA), glutamate (Glx) and γ-amino-butyric acid (GABA+) were quantified via PRESS and MEGA-PRESS scans in a PCu/PCC voxel and an occipital (OCC) control voxel. Whole brain fMRI revealed a cluster in right dorsal PCu/PCC that showed a greater BOLD response to scenes versus faces and objects. When extracted from an independently defined PCu/PCC region of interest, scene activity (vs. faces and objects and also vs. baseline) was positively correlated with PCu/PCC, but not OCC, tNAA. A voxel-wise regression analysis restricted to the PCu/PCC 1 H-MRS voxel area identified a significant PCu/PCC cluster, confirming the positive correlation between scene-related BOLD activity and PCu/PCC tNAA. There were no correlations between PCu/PCC activity and Glx or GABA+ levels. These results demonstrate, for the first time, that scene activity in PCu/PCC is linked to local tNAA levels, identifying a neurochemical influence on interindividual differences in the task-driven activity of a key brain hub.

The flux of high-energy neutrinos passing through the Earth is attenuated due to their interactions with matter. The interaction rate is modulated by the neutrino interaction cross section and affects the flux arriving at the IceCube Neutrino Observatory, a cubic-kilometer neutrino detector embedded in the Antarctic ice sheet. We present a measurement of the neutrino cross section between 60 TeV and 10 PeV using the high-energy starting events (HESE) sample from IceCube with 7.5 years of data. The result is binned in neutrino energy and obtained using both Bayesian and frequentist statistics. We find it compatible with predictions from the Standard Model. Flavor information is explicitly included through updated morphology classifiers, proxies for the the three neutrino flavors. This is the first such measurement to use the three morphologies as observables and the first to account for neutrinos from tau decay.

We report constraints on nonstandard neutrino interactions (NSI) from the observation of atmospheric neutrinos with IceCube, limiting all individual coupling strengths from a single dataset. Furthermore, IceCube is the first experiment to constrain flavor-violating and nonuniversal couplings simultaneously. Hypothetical NSI are generically expected to arise due to the exchange of a new heavy mediator particle. Neutrinos propagating in matter scatter off fermions in the forward direction with negligible momentum transfer. Hence the study of the matter effect on neutrinos propagating in the Earth is sensitive to NSI independently of the energy scale of new physics. We present constraints on NSI obtained with an all-flavor event sample of atmospheric neutrinos based on three years of IceCube DeepCore data. The analysis uses neutrinos arriving from all directions, with reconstructed energies between 5.6 GeV and 100 GeV. We report constraints on the individual NSI coupling strengths considered singly, allowing for complex phases in the case of flavor-violating couplings. This demonstrates that IceCube is sensitive to the full NSI flavor structure at a level competitive with limits from the global analysis of all other experiments. In addition, we investigate a generalized matter potential, whose overall scale and flavor structure are also constrained.5 MoreReceived 14 June 2021Accepted 6 August 2021DOI:https://doi.org/10.1103/PhysRevD.104.072006Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI. Funded by SCOAP3.Published by the American Physical SocietyPhysics Subject Headings (PhySH)Research AreasFlavor changing neutral currentsNeutrino interactionsNeutrino oscillationsPhysical SystemsNeutrinosParticles & Fields

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.

Magnetic resonance spectroscopy (MRS) studies have consistently demonstrated reduced cortical γ-aminobutyric acid (GABA) concentrations in individuals with major depression. However, evidence for a persistent deficit during remission, which would suggest that GABA dysfunction is a possible trait marker of depression, is equivocal. Although MRS measures total concentration of GABA, magneto-encephalography provides direct measures of neural activity, with cortical γ oscillations shaped by the activity of GABAergic inhibitory interneurons. In this study we investigated whether γ oscillations and GABA concentrations would differ in individuals with remitted depression (RD) compared with never depressed control subjects (ND).Thirty-seven healthy, unmedicated female volunteers (n = 19 RD, and n = 18 ND) were recruited. The γ oscillation frequencies and amplitudes in the visual cortex, induced by simple grating stimuli, were quantified with time-frequency analyses. Distinct GABA/glutamate + glutamine MRS peaks were resolved from MEGA-PRESS difference spectra in prefrontal, occipital, and subcortical volumes.The RD and ND individuals did not differ in the frequency of subclinical depressive symptoms. The ND were slightly older (mean = 23 years vs. 21 years), but age did not correlate with dependent measures. There were no group differences in GABA levels or induced cortical γ measures, but RD individuals had markedly reduced M80 (C1) components of the pattern-onset evoked response (46% reduction, Cohen's d = 1.01, p = .006).Both MRS and magneto-encephalography measures of the GABA system are normal in RD. However, the early visual evoked response is a potential trait marker of the disorder.

This series of experiments investigated the neural basis of conscious vision in humans using a form of transcranial magnetic stimulation (TMS) known as continuous theta burst stimulation (cTBS). Previous studies have shown that occipital TMS, when time-locked to the onset of visual stimuli, can induce a phenomenon analogous to blindsight in which conscious detection is impaired while the ability to discriminate 'unseen' stimuli is preserved above chance. Here we sought to reproduce this phenomenon using offline occipital cTBS, which has been shown to induce an inhibitory cortical aftereffect lasting 45-60 minutes. Contrary to expectations, our first experiment revealed the opposite effect: cTBS enhanced conscious vision relative to a sham control. We then sought to replicate this cTBS-induced potentiation of consciousness in conjunction with magnetoencephalography (MEG) and undertook additional experiments to assess its relationship to visual cortical excitability and levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA; via magnetic resonance spectroscopy, MRS). Occipital cTBS decreased cortical excitability and increased regional GABA concentration. No significant effects of cTBS on MEG measures were observed, although the results provided weak evidence for potentiation of event related desynchronisation in the β band. Collectively these experiments suggest that, through the suppression of noise, cTBS can increase the signal-to-noise ratio of neural activity underlying conscious vision. We speculate that gating-by-inhibition in the visual cortex may provide a key foundation of consciousness.

APOE-ε4 is a major genetic risk factor for late-onset Alzheimer's disease that interacts with other risk factors, but the nature of such combined effects remains poorly understood. We quantified the impact of APOE-ε4, family history (FH) of dementia, and obesity on white matter (WM) microstructure in 165 asymptomatic adults (38-71 years old) using quantitative magnetization transfer and neurite orientation dispersion and density imaging. Microstructural properties of the fornix, parahippocampal cingulum, and uncinate fasciculus were compared with those in motor and whole-brain WM regions. Widespread interaction effects between APOE, FH, and waist-hip ratio were found in the myelin-sensitive macromolecular proton fraction from quantitative magnetization transfer. Among individuals with the highest genetic risk (FH+ and APOE-ε4), obesity was associated with reduced macromolecular proton fraction in the right parahippocampal cingulum, whereas no effects were present for those without FH. Risk effects on apparent myelin were moderated by hypertension and inflammation-related markers. These findings suggest that genetic risk modifies the impact of obesity on WM myelin consistent with neuroglia models of aging and late-onset Alzheimer's disease.

IceCube is a cubic-kilometer Cherenkov telescope operating at the South Pole. The main goal of IceCube is the detection of astrophysical neutrinos and the identification of their sources. High-energy muon neutrinos are observed via the secondary muons produced in charge current interactions with nuclei in the ice. Currently, the best performing muon track directional reconstruction is based on a maximum likelihood method using the arrival time distribution of Cherenkov photons registered by the experiment's photomultipliers. A known systematic shortcoming of the prevailing method is to assume a continuous energy loss along the muon track. However at energies $>1$ TeV the light yield from muons is dominated by stochastic showers. This paper discusses a generalized ansatz where the expected arrival time distribution is parametrized by a stochastic muon energy loss pattern. This more realistic parametrization of the loss profile leads to an improvement of the muon angular resolution of up to $20\%$ for through-going tracks and up to a factor 2 for starting tracks over existing algorithms. Additionally, the procedure to estimate the directional reconstruction uncertainty has been improved to be more robust against numerical errors.

Abstract A recent time-integrated analysis of a catalog of 110 candidate neutrino sources revealed a cumulative neutrino excess in the data collected by IceCube between 2008 April 6 and 2018 July 10. This excess, inconsistent with the background hypothesis in the Northern Hemisphere at the 3.3 σ level, is associated with four sources: NGC 1068, TXS 0506+056, PKS 1424+240, and GB6 J1542+6129. This Letter presents two time-dependent neutrino emission searches on the same data sample and catalog: a point-source search that looks for the most significant time-dependent source of the catalog by combining space, energy, and time information of the events, and a population test based on binomial statistics that looks for a cumulative time-dependent neutrino excess from a subset of sources. Compared to previous time-dependent searches, these analyses enable a feature to possibly find multiple flares from a single direction with an unbinned maximum-likelihood method. M87 is found to be the most significant time-dependent source of this catalog at the level of 1.7 σ post-trial, and TXS 0506+056 is the only source for which two flares are reconstructed. The binomial test reports a cumulative time-dependent neutrino excess in the Northern Hemisphere at the level of 3.0 σ associated with four sources: M87, TXS 0506+056, GB6 J1542+6129, and NGC 1068.

We present a high-energy neutrino event generator, called LeptonInjector, alongside an event weighter, called LeptonWeighter. Both are designed for large-volume Cherenkov neutrino telescopes such as IceCube. The neutrino event generator allows for quick and flexible simulation of neutrino events within and around the detector volume, and implements the leading Standard Model neutrino interaction processes relevant for neutrino observatories: neutrino-nucleon deep-inelastic scattering and neutrino-electron annihilation. In this paper, we discuss the event generation algorithm, the weighting algorithm, and the main functions of the publicly available code, with examples. Program Titles: LeptonInjector and LeptonWeighter CPC Library link to program files: https://doi.org/10.17632/662gkpjfd9.1 Developer's repository links: https://github.com/icecube/LeptonInjector and https://github.com/icecube/LeptonWeighter Licensing provisions: GNU Lesser General Public License, version 3. Programming Language: C++11 External Routines: Boost HDF5 nuflux (https://github.com/icecube/nuflux) nuSQuIDS (https://github.com/arguelles/nuSQuIDS) Photospline (https://github.com/icecube/photospline) SuiteSparse (https://github.com/DrTimothyAldenDavis/SuiteSparse) Nature of problem: LeptonInjector: Generate neutrino interaction events of all possible topologies and energies throughout and around a detector volume. LeptonWeighter: Reweight Monte Carlo events, generated by a set of LeptonInjector Generators, to any desired physical neutrino flux or cross section. Solution method: LeptonInjector: Projected ranges of generated leptons and the extent of the detector, in terms of column depth, are used to inject events in and around the detector volume. Event kinematics follow distributions provided in cross section files. LeptonWeighter: Event generation probabilities are calculated for each Generator, which are then combined into a generation weight and used to calculate an overall event weight.

We report a search for nonstandard neutrino interactions (NSI) using eight years of TeV-scale atmospheric muon neutrino data from the IceCube Neutrino Observatory. By reconstructing incident energies and zenith angles for atmospheric neutrino events, this analysis presents unified confidence intervals for the NSI parameter ε_{μτ}. The best-fit value is consistent with no NSI at a p value of 25.2%. With a 90% confidence interval of -0.0041≤ε_{μτ}≤0.0031 along the real axis and similar strength in the complex plane, this result is the strongest constraint on any NSI parameter from any oscillation channel to date.

The surface array of IceCube, IceTop, operates primarily as a cosmic-ray detector, as well as a veto for astrophysical neutrino searches for the IceCube in-ice instrumentation.However, the snow accumulation on top of the IceTop detectors increases the detection threshold and attenuates the measured IceTop signals.Enhancing IceTop by a hybrid array of scintillation detectors and radio antennas will lower the energy threshold for air-shower measurements, provide more efficient veto capabilities, enable more accurate cosmic-ray measurements, and improve the detector calibration by compensating for snow accumulation.After the initial commissioning period, a prototype station at the South Pole has been recording air-shower data and has successfully observed coincident events of both the scintillation detectors and the radio antennas with the IceTop array.The production and calibration of the detectors for the full planned array has been ongoing.Additionally, one station each has been installed at the Pierre Auger Observatory and the Telescope Array for further R&D of these detectors in different environmental conditions.This contribution will present the status and future plans of the hybrid detector stations for the IceCube Surface Array Enhancement.

Abstract The understanding of novae, the thermonuclear eruptions on the surfaces of white dwarf stars in binaries, has recently undergone a major paradigm shift. Though the bolometric luminosity of novae was long thought to arise directly from photons supplied by the thermonuclear runaway, recent gigaelectronvolt (GeV) gamma-ray observations have supported the notion that a significant portion of the luminosity could come from radiative shocks. More recently, observations of novae have lent evidence that these shocks are acceleration sites for hadrons for at least some types of novae. In this scenario, a flux of neutrinos may accompany the observed gamma rays. As the gamma rays from most novae have only been observed up to a few GeV, novae have previously not been considered as targets for neutrino telescopes, which are most sensitive at and above teraelectronvolt (TeV) energies. Here, we present the first search for neutrinos from novae with energies between a few GeV and 10 TeV using IceCube-DeepCore, a densely instrumented region of the IceCube Neutrino Observatory with a reduced energy threshold. We search both for a correlation between gamma-ray and neutrino emission as well as between optical and neutrino emission from novae. We find no evidence for neutrino emission from the novae considered in this analysis and set upper limits for all gamma-ray detected novae.

Abstract The Galactic plane, harboring a diffuse neutrino flux, is a particularly interesting target in which to study potential cosmic-ray acceleration sites. Recent gamma-ray observations by HAWC and LHAASO have presented evidence for multiple Galactic sources that exhibit a spatially extended morphology and have energy spectra continuing beyond 100 TeV. A fraction of such emission could be produced by interactions of accelerated hadronic cosmic rays, resulting in an excess of high-energy neutrinos clustered near these regions. Using 10 years of IceCube data comprising track-like events that originate from charged-current muon neutrino interactions, we perform a dedicated search for extended neutrino sources in the Galaxy. We find no evidence for time-integrated neutrino emission from the potential extended sources studied in the Galactic plane. The most significant location, at 2.6 σ post-trials, is a 1.°7 sized region coincident with the unidentified TeV gamma-ray source 3HWC J1951+266. We provide strong constraints on hadronic emission from several regions in the galaxy.

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.

A significant problem in the concurrent application of transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) is the image artefact caused by the effect of the TMS-coil on the homogeneity of the static magnetic field (B0). The resulting field inhomogeneity can lead to spatial distortions and local signal loss in echo-planar (EP) images. Here we demonstrate that passive shimming using thin patches of austenitic stainless steel can reduce the effect of the TMS-coil on B0 by ~ 80%, thus essentially eliminating the associated artefact. Initially the effect of the TMS-coil on B0 was measured using the phase of gradient echo images. Consequently the ideal distribution for the steel was simulated using the magnetic properties of the steel and the effects of the TMS-coil. Finally we demonstrate the effect of two different implementations of the passive shim on a spherical phantom and in vivo.

Is motor response inhibition supported by a specialised neuronal inhibitory control mechanism, or by a more general system of action updating? This pre-registered study employed a context-cueing paradigm requiring both inhibitory and non-inhibitory action updating in combination with functional magnetic resonance imaging to test the specificity of responses under different updating conditions, including the cancellation of actions. Cortical regions of activity were found to be common to multiple forms of action updating. However, functional specificity during response inhibition was observed in the anterior right inferior frontal gyrus. In addition, fronto-subcortical activity was explored using a novel contrast method. These exploratory results indicate that the specificity for response inhibition observed in right prefrontal cortex continued downstream and was observed in right hemisphere subcortical activity, while left hemisphere activity was associated with right-hand response execution. Overall, our findings reveal both common and distinct correlates of response inhibition in prefrontal cortex, with exploratory analyses supporting putative models of subcortical pathways and extending them through the demonstration of lateralisation.

Abstract Ultraluminous infrared galaxies (ULIRGs) have infrared luminosities L IR ≥ 10 12 L ⊙ , making them the most luminous objects in the infrared sky. These dusty objects are generally powered by starbursts with star formation rates that exceed 100 M ⊙ yr −1 , possibly combined with a contribution from an active galactic nucleus. Such environments make ULIRGs plausible sources of astrophysical high-energy neutrinos, which can be observed by the IceCube Neutrino Observatory at the South Pole. We present a stacking search for high-energy neutrinos from a representative sample of 75 ULIRGs with redshift z ≤ 0.13 using 7.5 yr of IceCube data. The results are consistent with a background-only observation, yielding upper limits on the neutrino flux from these 75 ULIRGs. For an unbroken E −2.5 power-law spectrum, we report an upper limit on the stacked flux <?CDATA ${{\rm{\Phi }}}_{{\nu }_{\mu }+{\bar{\nu }}_{\mu }}^{90 \% }=3.24\times {10}^{-14}\,{\mathrm{TeV}}^{-1}\,{\mathrm{cm}}^{-2}\,{{\rm{s}}}^{-1}\,{(E/10\,\mathrm{TeV})}^{-2.5}$?> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msubsup> <mml:mrow> <mml:mi mathvariant="normal">Φ</mml:mi> </mml:mrow> <mml:mrow> <mml:msub> <mml:mrow> <mml:mi>ν</mml:mi> </mml:mrow> <mml:mrow> <mml:mi>μ</mml:mi> </mml:mrow> </mml:msub> <mml:mo>+</mml:mo> <mml:msub> <mml:mrow> <mml:mover accent="true"> <mml:mrow> <mml:mi>ν</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>¯</mml:mo> </mml:mrow> </mml:mover> </mml:mrow> <mml:mrow> <mml:mi>μ</mml:mi> </mml:mrow> </mml:msub> </mml:mrow> <mml:mrow> <mml:mn>90</mml:mn> <mml:mo>%</mml:mo> </mml:mrow> </mml:msubsup> <mml:mo>=</mml:mo> <mml:mn>3.24</mml:mn> <mml:mo>×</mml:mo> <mml:msup> <mml:mrow> <mml:mn>10</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>14</mml:mn> </mml:mrow> </mml:msup> <mml:mspace width="0.25em" /> <mml:msup> <mml:mrow> <mml:mi>TeV</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> <mml:mspace width="0.25em" /> <mml:msup> <mml:mrow> <mml:mi>cm</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>2</mml:mn> </mml:mrow> </mml:msup> <mml:mspace width="0.25em" /> <mml:msup> <mml:mrow> <mml:mi mathvariant="normal">s</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> <mml:mspace width="0.25em" /> <mml:msup> <mml:mrow> <mml:mo stretchy="false">(</mml:mo> <mml:mi>E</mml:mi> <mml:mrow> <mml:mo stretchy="true">/</mml:mo> </mml:mrow> <mml:mn>10</mml:mn> <mml:mspace width="0.25em" /> <mml:mi>TeV</mml:mi> <mml:mo stretchy="false">)</mml:mo> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>2.5</mml:mn> </mml:mrow> </mml:msup> </mml:math> at 90% confidence level. In addition, we constrain the contribution of the ULIRG source population to the observed diffuse astrophysical neutrino flux as well as model predictions.

The nuSTORM facility has been designed to deliver beams of $\vec{v}$e and $\vec{v}$μ from the decay of a stored μ± beam with a central momentum of 3.8 GeV/c and a momentum acceptance of 10%. In his paper, Neu er studied muon decay rings with Eμ of 8, 4.5 and 1.5 GeV. With his 4.5 GeV ring design, he achieved a figure of merit of ≃6 x 109 useful neutrinos per 3 x 1013 protons on target.

Functional magnetic resonance imaging (fMRI) was employed to investigate the contributions of medial temporal lobe (MTL) regions to encoding operations underpinning recollection and familiarity. Participants first studied word pairs. Words in pairs were either weakly or strongly semantically related. In a subsequent retrieval task, participants distinguished between studied pairs, unstudied pairs, and recombined pairs formed from words taken from different studied pairs. Greater activity at encoding for correct judgments to studied pairs with strong, rather than weak, semantic relationships was assumed to index processes supporting subsequent familiarity-based responding. Greater activity for correct judgments to studied pairs than for recombined pairs identified incorrectly as studied pairs was assumed to index processes contributing to recollection-based responding. Evidence that these assumptions were reasonable was obtained in independent behavioural studies, while the outcomes of these fMRI contrasts indicated links between perirhinal cortex and familiarity, and anterior hippocampus and recollection. This functional separation is consistent with models in which the hippocampus and perirhinal cortex support two separable processes that contribute to memories for verbal associations.

Abstract We present the first comprehensive search for high-energy neutrino emission from high- and low-mass X-ray binaries conducted by IceCube. Galactic X-ray binaries are long-standing candidates for the source of Galactic hadronic cosmic rays and neutrinos. The compact object in these systems can be the site of cosmic-ray acceleration, and neutrinos can be produced by interactions of cosmic rays with radiation or gas, in the jet of a microquasar, in the stellar wind, or in the atmosphere of the companion star. We study X-ray binaries using 7.5 yr of IceCube data with three separate analyses. In the first, we search for periodic neutrino emission from 55 binaries in the Northern Sky with known orbital periods. In the second, the X-ray light curves of 102 binaries across the entire sky are used as templates to search for time-dependent neutrino emission. Finally, we search for time-integrated emission of neutrinos for a list of 4 notable binaries identified as microquasars. In the absence of a significant excess, we place upper limits on the neutrino flux for each hypothesis and compare our results with theoretical predictions for several binaries. In addition, we evaluate the sensitivity of the next generation neutrino telescope at the South Pole, IceCube-Gen2, and demonstrate its power to identify potential neutrino emission from these binary sources in the Galaxy.

The majority of astrophysical neutrinos have undetermined origins. The IceCube Neutrino Observatory has observed astrophysical neutrinos but has not yet identified their sources. Blazars are promising source candidates, but previous searches for neutrino emission from populations of blazars detected in $\gtrsim$ GeV gamma-rays have not observed any significant neutrino excess. Recent findings in multi-messenger astronomy indicate that high-energy photons, co-produced with high-energy neutrinos, are likely to be absorbed and reemitted at lower energies. Thus, lower-energy photons may be better indicators of TeV-PeV neutrino production. This paper presents the first time-integrated stacking search for astrophysical neutrino emission from MeV-detected blazars in the first Fermi-LAT low energy catalog (1FLE) using ten years of IceCube muon-neutrino data. The results of this analysis are found to be consistent with a background-only hypothesis. Assuming an E$^{-2}$ neutrino spectrum and proportionality between the blazars' MeV gamma-ray fluxes and TeV-PeV neutrino flux, the upper limit on the 1FLE blazar energy-scaled neutrino flux is determined to be $1.64 \times 10^{-12}$ TeV cm$^{-2}$ s$^{-1}$ at 90% confidence level. This upper limit is approximately 1% of IceCube's diffuse muon-neutrino flux measurement.

Abstract Galaxy clusters have the potential to accelerate cosmic rays (CRs) to ultrahigh energies via accretion shocks or embedded CR acceleration sites. The CRs with energies below the Hillas condition will be confined within the cluster and eventually interact with the intracluster medium gas to produce secondary neutrinos and gamma rays. Using 9.5 yr of muon neutrino track events from the IceCube Neutrino Observatory, we report the results of a stacking analysis of 1094 galaxy clusters with masses ≳10 14 M ⊙ and redshifts between 0.01 and ∼1 detected by the Planck mission via the Sunyaev–Zel’dovich effect. We find no evidence for significant neutrino emission and report upper limits on the cumulative unresolved neutrino flux from massive galaxy clusters after accounting for the completeness of the catalog up to a redshift of 2, assuming three different weighting scenarios for the stacking and three different power-law spectra. Weighting the sources according to mass and distance, we set upper limits at a 90% confidence level that constrain the flux of neutrinos from massive galaxy clusters (≳10 14 M ⊙ ) to be no more than 4.6% of the diffuse IceCube observations at 100 TeV, assuming an unbroken E −2.5 power-law spectrum.

The Ice Cube Neutrino Observatory has been measuring an isotropic astrophysical neutrino flux in multiple detection channels for almost a decade.Galactic diffuse emission, which arises from the interactions between cosmic rays and the interstellar medium, is an expected signal in IceCube.The superposition of an extragalactic flux and a galactic flux results in directional structure and variations in the spectrum.In this work, we use 12.3 years of high-purity muon-neutrino induced muon track data to perform a dedicated search for this galactic emission, combined with a spectral measurement of the isotropic astrophysical neutrino flux.To distinguish a galactic component from the dominant atmospheric and isotropic astrophysical components, the precise directional information available for muon tracks is fully utilized in a three-dimensional forward folding likelihood fit.We test a state-of-the-art model prediction of galactic diffuse emission based on recent cosmic ray data (CRINGE).We fit this prediction as a template scaled by a factor Ψ CRINGE , and find 2.9 ± 1.1 × Ψ CRINGE with a significance of 2.7 in an energy range between 400 GeV and 60 TeV in the Northern Sky.

Searching for the sources of high-energy cosmic particles requires sophisticated analysis techniques, frequently involving hypothesis tests with unbinned log-likelihood (LLH) functions.SkyLLH is an open-source, Python-based software tool to build these LLH functions and perform likelihood-ratio tests.We present a new easy-to-use and modular extension of SkyLLH that allows the user to perform neutrino point source searches in the entire sky using ten years of IceCube public data.To guide the user, SkyLLH provides tutorials showing how to analyze the experimental data and calculate useful statistical quantities.Here we describe the details of the analysis workflow and illustrate some of the possible methods to work with the IceCube public dataset.Additionally, we show that SkyLLH can reproduce the results from a previous IceCube publication that used the public data release.We obtain a similar local significance for the neutrino emission from a list of candidate sources within a maximum shift of 0.5.Finally, the measured neutrino flux from the most significant source candidate, NGC 1068, shows substantial agreement with the previously published result.