Considerations for event-related gamma-aminobutyric acid functional magnetic resonance spectroscopy.

The use of sequential proton magnetic resonance spectroscopy (MRS) to follow glutamate and gamma-aminobutyric acid (GABA) changes during functional task-based paradigms, functional MRS (fMRS), has increased. This technique has been used to investigate GABA dynamics during both sensory and behavioural tasks, usually with long 'block design' paradigms. Recently, there has been an increase in interest in the use of short stimuli and 'event-related' tasks. While changes in glutamate can be readily followed by collecting multiple individual transients (or shots), measurement of GABA, especially at 3 T, is usually performed using editing techniques like Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS), which by its nature is a dual shot approach. This poses problems when considering an event-related experiment, where it is unclear when GABA may change, or how this may affect the individual subspectra of the MEGA-PRESS acquisition. To address this issue, MEGA-PRESS data were simulated to reflect the effect of a transient change in GABA concentration due to a short event-related stimulus. The change in GABA was simulated for both the ON and OFF subspectra, and the effect of three different conditions (increase only during ON acquisition, increase during OFF acquisition and increase across both) on the corresponding edited GABA spectrum was modelled. Results show that a transient increase in GABA that only occurs during the ON subspectral acquisition, while not changing the results much from when GABA is changed across both conditions, will give a much larger change in the edited GABA spectrum than a transient increase that occurs only during the OFF subspectral acquisition. These results suggest that researchers should think carefully about the design of any event-related fMRS studies using MEGA-PRESS, as well as the analysis of other functional paradigms where transient changes in GABA may be expected. Experimental design considerations are therefore discussed, and suggestions are made.

Hypoxia alters posterior cingulate cortex metabolism during a memory task: A 1H fMRS study.

Environmental hypoxia (fraction of inspired oxygen (FIO2) ∼ 0.120) is known to trigger a global increase in cerebral blood flow (CBF). However, regionally, a heterogeneous response is reported, particularly within the posterior cingulate cortex (PCC) where decreased CBF is found after two hours of hypoxic exposure. Furthermore, hypoxia reverses task-evoked BOLD signals within the PCC, and other regions of the default mode network, suggesting a reversal of neurovascular coupling. An alternative explanation is that the neural architecture supporting cognitive tasks is reorganised. Therefore, to confirm if this previous result is neural or vascular in origin, a measure of neural activity that is not haemodynamic-dependant is required. To achieve this, we utilised functional magnetic resonance spectroscopy to probe the glutamate response to memory recall in the PCC during normoxia (FIO2 = 0.209) and after two hours of poikilocapnic hypoxia (FIO2 = 0.120). We also acquired ASL-based measures of CBF to confirm previous findings of reduced CBF within the PCC in hypoxia. Consistent with previous findings, hypoxia induced a reduction in CBF within the PCC and other regions of the default mode network. Under normoxic conditions, memory recall was associated with an 8% increase in PCC glutamate compared to rest (P = 0.019); a change which was not observed during hypoxia. However, exploratory analysis of other neurometabolites showed that PCC glucose was reduced during hypoxia compared to normoxia both at rest (P = 0.039) and during the task (P = 0.046). We conclude that hypoxia alters the activity-induced increase in glutamate, which may reflect a reduction in oxidative metabolism within the PCC. The reduction in glucose in hypoxia reflects continued metabolism, presumably by non-oxidative means, without replacement of glucose due to reduced CBF.

Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS): Experts' consensus recommendations.

The translation of MRS to clinical practice has been impeded by the lack of technical standardization. There are multiple methods of acquisition, post-processing, and analysis whose details greatly impact the interpretation of the results. These details are often not fully reported, making it difficult to assess MRS studies on a standardized basis. This hampers the reviewing of manuscripts, limits the reproducibility of study results, and complicates meta-analysis of the literature. In this paper a consensus group of MRS experts provides minimum guidelines for the reporting of MRS methods and results, including the standardized description of MRS hardware, data acquisition, analysis, and quality assessment. This consensus statement describes each of these requirements in detail and includes a checklist to assist authors and journal reviewers and to provide a practical way for journal editors to ensure that MRS studies are reported in full.

Bilateral regional extracranial blood flow regulation to hypoxia and unilateral duplex ultrasound measurement error.

NEW FINDINGS: What is the central question of this study? Is blood flow regulation to hypoxia different between the internal carotid arteries (ICAs) and vertebral arteries (VAs), and what is the measurement error in unilateral extracranial artery assessments compared to bilateral? What is the main finding and its importance? ICA and VA blood flow regulation to hypoxia is comparable when factoring for vessel type and vessel side. Compared to bilateral assessment, vessels assessed unilaterally had individual measurement errors of up to 37%. Assessing the vessel with the larger resting blood flow, not the left or right vessel, reduces unilateral measurement error. ABSTRACT: Whether blood flow regulation to hypoxia is similar between left and right internal carotid arteries (ICAs) and vertebral arteries (VAs) is unclear. Extracranial blood flow is regularly calculated by doubling a unilateral assessment; however, lateral artery differences may lead to measurement error. This study aimed to determine extracranial blood flow regulation to hypoxia when factoring for vessel type (ICAs or VAs) and vessel side (left or right) effects, and to investigate unilateral assessment measurement error compared to bilateral assessment. In a repeated-measures crossover design, extracranial arteries of 44 participants were assessed bilaterally by duplex ultrasound during 90 min of normoxic and poikilocapnic hypoxic (12.0% fraction of inspired oxygen) conditions. Linear mixed model analyses revealed no Condition × Vessel Type × Vessel Side interaction for blood flow, vessel diameter and flow velocity (all P > 0.05) indicating left and right ICA and VA blood flow regulation to hypoxia was similar. Bilateral hypoxic reactivity was comparable (ICAs, 1.4 (1.0) vs. VAs, 1.7 (1.1) Δ%·Δ SpO2-1 ; P = 0.12). Compared to bilateral assessment, unilateral mean measurement error of the relative blood flow response to hypoxia was up to 5%, but individual errors reached 37% and were greatest in ICAs and VAs with the smaller resting blood flow due to a ratio-scaling problem. In conclusion, left and right ICA and VA regulation to hypoxia is comparable when factoring for vessel type and vessel side. Assessing the ICA and VA vessels with the larger resting blood flow, not the left or right vessel, reduces unilateral measurement error.

Neurochemistry of response inhibition and interference in gambling disorder: a preliminary study of γ-aminobutyric acid (GABA+) and glutamate-glutamine (Glx).

BACKGROUND: Neurobehavioral research on the role of impulsivity in gambling disorder (GD) has produced heterogeneous findings. Impulsivity is multifaceted with different experimental tasks measuring different subprocesses, such as response inhibition and distractor interference. Little is known about the neurochemistry of inhibition and interference in GD. METHODS: We investigated inhibition with the stop signal task (SST) and interference with the Eriksen Flanker task, and related performance to metabolite levels in individuals with and without GD. We employed magnetic resonance spectroscopy (MRS) to record glutamate-glutamine (Glx/Cr) and inhibitory, γ-aminobutyric acid (GABA+/Cr) levels in the dorsal ACC (dACC), right dorsolateral prefrontal cortex (dlPFC), and an occipital control voxel. RESULTS: We found slower processing of complex stimuli in the Flanker task in GD (P < .001, η2p = 0.78), and no group differences in SST performance. Levels of dACC Glx/Cr and frequency of incongruent errors were correlated positively in GD only (r = 0.92, P = .001). Larger positive correlations were found for those with GD between dACC GABA+/Cr and SST Go error response times (z = 2.83, P = .004), as well as between dACC Glx/Cr and frequency of Go errors (z = 2.23, P = .03), indicating general Glx-related error processing deficits. Both groups expressed equivalent positive correlations between posterror slowing and Glx/Cr in the right dlPFC (GD: r = 0.74, P = .02; non-GD: r = .71, P = .01). CONCLUSION: Inhibition and interference impairments are reflected in dACC baseline metabolite levels and error processing deficits in GD.

Methodological consensus on clinical proton MRS of the brain: Review and recommendations.

Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

Errors in 1 H-MRS estimates of brain metabolite concentrations caused by failing to take into account tissue-specific signal relaxation.

Accurate measurement of brain metabolite concentrations with proton magnetic resonance spectroscopy (1 H-MRS) can be problematic because of large voxels with mixed tissue composition, requiring adjustment for differing relaxation rates in each tissue if absolute concentration estimates are desired. Adjusting for tissue-specific metabolite signal relaxation, however, also requires a knowledge of the relative concentrations of the metabolite in gray (GM) and white (WM) matter, which are not known a priori. Expressions for the estimation of the molality and molarity of brain metabolites with 1 H-MRS are extended to account for tissue-specific relaxation of the metabolite signals and examined under different assumptions with simulated and real data. Although the modified equations have two unknowns, and hence are unsolvable explicitly, they are nonetheless useful for the estimation of the effect of tissue-specific metabolite relaxation rates on concentration estimates under a range of assumptions and experimental parameters using simulated and real data. In simulated data using reported GM and WM T1 and T2 times for N-acetylaspartate (NAA) at 3 T and a hypothetical GM/WM NAA ratio, errors of 6.5-7.8% in concentrations resulted when TR = 1.5 s and TE = 0.144 s, but were reduced to less than 0.5% when TR = 6 s and TE = 0.006 s. In real data obtained at TR/TE = 1.5 s/0.04 s, the difference in the results (4%) was similar to that obtained with simulated data when assuming tissue-specific relaxation times rather than GM-WM-averaged times. Using the expressions introduced in this article, these results can be extrapolated to any metabolite or set of assumptions regarding tissue-specific relaxation. Furthermore, although serving to bound the problem, this work underscores the challenge of correcting for relaxation effects, given that relaxation times are generally not known and impractical to measure in most studies. To minimize such effects, the data should be acquired with pulse sequence parameters that minimize the effect of signal relaxation.

Towards a theory of functional magnetic resonance spectroscopy (fMRS): A meta-analysis and discussion of using MRS to measure changes in neurotransmitters in real time.

Proton magnetic resonance spectroscopy is a powerful tool to investigate neurochemistry and physiology in vivo. Recently researchers have started to use MRS to measure neurotransmitter changes related to neural activity, so called functional MRS (fMRS). Particular interest has been placed on measuring glutamate changes associated with neural function, but differences are reported in the size of changes seen. This review discusses fMRS, and includes meta-analyses of the relative size of glutamate changes seen in fMRS, and the impact experimental design and stimulus paradigm may have. On average glutamate was found to increase by 6.97% (±1.739%) in response to neural activation. However, factors of experimental design may have a large impact on the size of these changes. For example an increase of 4.749% (±1.45%) is seen in block studies compared to an increase of 13.429% (±3.59) in studies using event related paradigms. The stimulus being investigated also seems to play a role with prolonged visual stimuli showing a small mean increase in glutamate of 2.318% (±1.227%) while at the other extreme, pain stimuli show a mean stimulation effect of 14.458% (±3.736%). These differences are discussed with regards to possible physiologic interpretations, as well experimental design implications.

Unexpected reductions in regional cerebral perfusion during prolonged hypoxia.

KEY POINTS: Cognitive performance is impaired by hypoxia despite global cerebral oxygen delivery and metabolism being maintained. Using arterial spin labelled (ASL) magnetic resonance imaging, this is the first study to show regional reductions in cerebral blood flow (CBF) in response to decreased oxygen supply (hypoxia) at 2 h that increased in area and became more pronounced at 10 h. Reductions in CBF were seen in brain regions typically associated with the 'default mode' or 'task negative' network. Regional reductions in CBF, and associated vasoconstriction, within the default mode network in hypoxia is supported by increased vasodilatation in these regions to a subsequent hypercapnic (5% CO2 ) challenge. These results suggest an anatomical mechanism through which hypoxia may cause previously reported deficits in cognitive performance. ABSTRACT: Hypoxia causes an increase in global cerebral blood flow, which maintains global cerebral oxygen delivery and metabolism. However, neurological deficits are abundant under hypoxic conditions. We investigated regional cerebral microvascular responses to acute (2 h) and prolonged (10 h) poikilocapnic normobaric hypoxia. We found that 2 h of hypoxia caused an expected increase in frontal cortical grey matter perfusion but unexpected perfusion decreases in regions of the brain normally associated with the 'default mode' or 'task negative' network. After 10 h in hypoxia, decreased blood flow to the major nodes of the default mode network became more pronounced and widespread. The use of a hypercapnic challenge (5% CO2 ) confirmed that these reductions in cerebral blood flow from hypoxia were related to vasoconstriction. Our findings demonstrate steady-state deactivation of the default network under acute hypoxia, which become more pronounced over time. Moreover, these data provide a unique insight into the nuanced localized cerebrovascular response to hypoxia that is not attainable through traditional methods. The observation of reduced perfusion in the posterior cingulate and cuneal cortex, which are regions assumed to play a role in declarative and procedural memory, provides an anatomical mechanism through which hypoxia may cause deficits in working memory.

Event-related dynamics of glutamate and BOLD effects measured using functional magnetic resonance spectroscopy (fMRS) at 3T in a repetition suppression paradigm.

Proton MR spectroscopy ((1)H-MRS) complements other brain research methods by providing measures of neurometabolites noninvasively in a localized brain area. Improvements in MR scanner technologies, and data acquisition and analysis methods should allow functional (1)H-MRS (fMRS) to measure neurometabolite concentration changes during task-induced brain activation. The aim of the current study was to further develop event-related fMRS at 3T to investigate glutamate dynamics in response to repetition suppression. A secondary aim was to investigate the relationship between blood-oxygen-level-dependent (BOLD) responses and glutamate dynamics in the same paradigm at the same time. A novel approach of interleaved water-suppressed (metabolite) and unsuppressed (water) fMRS was used to simultaneously detect the event-related dynamics of glutamate and BOLD signal to repetition suppression in the lateral occipital cortex of thirteen (N=13) volunteers. On average, (1)H-MRS-visible glutamate increased after novel visual stimuli presentations by 12% and decreased by 11-13% on repeated compared to novel presentations. The BOLD signal, as measured by water peak amplitude changes, showed significant difference between Task and Rest trials, and, on a GLM based analysis of the time series, demonstrated a significant difference between the novel and repeated trials, however appeared to be decoupled from the glutamate response as no correlation was found between the two. These results are the first demonstration that reductions in neuronal activity typical of repetition suppression effects are reflected by reduced glutamatergic and BOLD measures, that glutamate and BOLD responses may not be coupled as previously thought, and that these changes and relationships can be measured simultaneously using event-related fMRS at 3T.

Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension.

OBJECTIVE: The study was undertaken to determine whether normobaric hypoxia causes elevated brain volume and intracranial pressure in individuals with symptoms consistent with acute mountain sickness (AMS). METHODS: Thirteen males age = (26 (sd 6)) years were exposed to normobaric hypoxia (12% O2 ) and normoxia (21% O2 ). After 2 and 10 hours, AMS symptoms were assessed alongside ventricular and venous vessel volumes, cerebral blood flow, regional brain volumes, and intracranial pressure, using high-resolution magnetic resonance imaging. RESULTS: In normoxia, neither lateral ventricular volume (R(2) = 0.07, p = 0.40) nor predominance of unilateral transverse venous sinus drainage (R(2) = 0.07, p = 0.45) was related to AMS symptoms. Furthermore, despite an increase in cerebral blood flow after 2 hours of hypoxia (hypoxia vs normoxia: Δ148ml/min(-1) , 95% confidence interval [CI] = 58 to 238), by 10 hours, when AMS symptoms had developed, cerebral blood flow was normal (Δ-51ml/min(-1) , 95% CI = -141 to 39). Conversely, at 10 hours brain volume was increased (Δ59ml, 95% CI = 8 to 110), predominantly due to an increase in gray matter volume (Δ73ml, 95% CI = 25 to 120). Therefore, cerebral spinal fluid volume was decreased (Δ-40ml, 95% CI = -67 to -14). The intracranial pressure response to hypoxia varied between individuals, and as hypothesized, the most AMS-symptomatic participants had the largest increases in intracranial pressure (AMS present, Δ7mmHg, 95% CI = -2.5 to 17.3; AMS not present, Δ-1mmHg, 95% CI = -3.3 to 0.5). Consequently, there was a significant relationship between the change in intracranial pressure and AMS symptom severity (R(2) = 0.71, p = 0.002). INTERPRETATION: The data provide the strongest evidence to date to support the hypothesis that the "random" nature of AMS symptomology is explained by a variable intracranial pressure response to hypoxia.

The Subjective Experience of Pain: An FMRI Study of Percept-Related Models and Functional Connectivity.

OBJECTIVE: Previous work suggests that the perception of pain is subjective and dependent on individual differences in physiological, emotional, and cognitive states. Functional magnetic resonance imaging (FMRI) studies have used both stimulus-related (nociceptive properties) and percept-related (subjective experience of pain) models to identify the brain networks associated with pain. Our objective was to identify the network involved in processing subjective pain during cold stimuli. METHODS: The current FMRI study directly contrasted a stimulus-related model with a percept-related model during blocks of cold pain stimuli in healthy adults. Specifically, neuronal activation was modelled as a function of changes in stimulus intensity vs as a function of increasing/decreasing levels of subjective pain corresponding to changes in pain ratings. In addition, functional connectivity analyses were conducted to examine intrinsic correlations between three proposed subnetworks (sensory/discriminative, affective/motivational, and cognitive/evaluative) involved in pain processing. RESULTS: The percept-related model captured more extensive activation than the stimulus-related model and demonstrated an association between higher subjective pain and activation in expected cortical (dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, insula, dorsal anterior cingulate cortex [dACC] extending into pre-supplementary motor area) and subcortical (thalamus, striatum) areas. Moreover, connectivity results supported the posited roles of dACC and insula as key relay sites during neural processing of subjective pain. In particular, anterior insula appeared to link sensory/discriminative regions with regions in the other subnetworks, and dACC appeared to serve as a hub for affective/motivational, cognitive/evaluative, and motor subnetworks. CONCLUSIONS: Using a percept-related model, brain regions involved in the processing of subjective pain during the application of cold stimuli were identified. Connectivity analyses identified linkages between key subnetworks involved in processing subjective pain.

Glutamatergic correlates of gamma-band oscillatory activity during cognition: a concurrent ER-MRS and EEG study.

Frequency specific synchronisation of neuronal firing within the gamma-band (30-70 Hz) appears to be a fundamental correlate of both basic sensory and higher cognitive processing. In-vitro studies suggest that the neurochemical basis of gamma-band oscillatory activity is based on interactions between excitatory (i.e. glutamate) and inhibitory (i.e. GABA) neurotransmitter concentrations. However, the nature of the relationship between excitatory neurotransmitter concentration and changes in gamma band activity in humans remains undetermined. Here, we examine the links between dynamic glutamate concentration and the formation of functional gamma-band oscillatory networks. Using concurrently acquired event-related magnetic resonance spectroscopy and electroencephalography, during a repetition-priming paradigm, we demonstrate an interaction between stimulus type (object vs. abstract pictures) and repetition in evoked gamma-band oscillatory activity, and find that glutamate levels within the lateral occipital cortex, differ in response to these distinct stimulus categories. Importantly, we show that dynamic glutamate levels are related to the amplitude of stimulus evoked gamma-band (but not to beta, alpha or theta or ERP) activity. These results highlight the specific connection between excitatory neurotransmitter concentration and amplitude of oscillatory response, providing a novel insight into the relationship between the neurochemical and neurophysiological processes underlying cognition.

Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA.

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 3T 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.

The salience network is responsible for switching between the default mode network and the central executive network: replication from DCM.

With the advent of new analysis methods in neuroimaging that involve independent component analysis (ICA) and dynamic causal modelling (DCM), investigations have focused on measuring both the activity and connectivity of specific brain networks. In this study we combined DCM with spatial ICA to investigate network switching in the brain. Using time courses determined by ICA in our dynamic causal models, we focused on the dynamics of switching between the default mode network (DMN), the network which is active when the brain is not engaging in a specific task, and the central executive network (CEN), which is active when the brain is engaging in a task requiring attention. Previous work using Granger causality methods has shown that regions of the brain which respond to the degree of subjective salience of a stimulus, the salience network, are responsible for switching between the DMN and the CEN (Sridharan et al., 2008). In this work we apply DCM to ICA time courses representing these networks in resting state data. In order to test the repeatability of our work we applied this to two independent datasets. This work confirms that the salience network drives the switching between default mode and central executive networks and that our novel technique is repeatable.

Prolonged (9 h) poikilocapnic hypoxia (12% O2) augments cutaneous thermal hyperaemia in healthy humans.

The primary aim of this study was to investigate the effect of systemic poikilocapnic hypoxia on forearm cutaneous thermal hyperaemia. A secondary aim was to examine the relationship between the individual susceptibility to oxygen desaturation and cutaneous vasodilator capacity. Twelve healthy participants (seven male) were exposed to 9 h of normoxia and 12% poikilocapnic hypoxia in a temperature- and humidity-controlled environmental chamber. Skin blood flow was assessed at the ventral forearm using laser Doppler flowmetry combined with rapid local heating. After 6 min at baseline (skin temperature clamped at 33°C), local skin temperature was elevated at a rate of 0.5°C every 5 s up to 42°C to elicit a sensory axon response and then held constant for 30 min to cause a plateau. Skin blood flow was calculated as cutaneous vascular conductance [CVC; in perfusion units/mean arterial blood pressure (APU mmHg(-1))] and expressed in raw format and relative to heating at 44°C in normoxia (%CVC44). During hypoxaemia, vasodilatation was greater during the initial peak (raw, Δ0.35 APU mmHg(-1), P = 0.09; %CVC44, Δ18%, P = 0.05) and the plateau phase (raw, Δ0.55 APU mmHg(-1), P = 0.03; %CVC44, Δ26%, P = 0.02). The rate of rise in cutaneous blood flow during the initial peak was significantly greater during poikilocapnic hypoxia (P < 0.01). We observed a negative relationship between oxygen saturation in poikilocapnic hypoxia and the change in baseline (P = 0.06), initial peak (P = 0.01) and plateau phase of thermal hyperaemia (P = 0.01). Prolonged poikilocapnic hypoxia causes robust increases in CVC during both phases of thermal hyperaemia that are dependent on the oxygen saturation of the individual.

Functional Magnetic Resonance Spectroscopy of Prolonged Motor Activation using Conventional and Spectral GLM Analyses.

Background: Functional MRS (fMRS) is a technique used to measure metabolic changes in response to increased neuronal activity, providing unique insights into neurotransmitter dynamics and neuroenergetics. In this study we investigate the response of lactate and glutamate levels in the motor cortex during a sustained motor task using conventional spectral fitting and explore the use of a novel analysis approach based on the application of linear modelling directly to the spectro-temporal fMRS data. Methods: fMRS data were acquired at a field strength of 3 Tesla from 23 healthy participants using a short echo-time (28ms) semi-LASER sequence. The functional task involved rhythmic hand clenching over a duration of 8 minutes and standard MRS preprocessing steps, including frequency and phase alignment, were employed. Both conventional spectral fitting and direct linear modelling were applied, and results from participant-averaged spectra and metabolite-averaged individual analyses were compared. Results: We observed a 20% increase in lactate in response to the motor task, consistent with findings at higher magnetic field strengths. However, statistical testing showed some variability between the two averaging schemes and fitting algorithms. While lactate changes were supported by the direct spectral modelling approach, smaller increases in glutamate (2%) were inconsistent. Exploratory spectral modelling identified a 4% decrease in aspartate, aligning with conventional fitting and observations from prolonged visual stimulation. Conclusion: We demonstrate that lactate dynamics in response to a prolonged motor task are observed using short-echo time semi-LASER at 3 Tesla, and that direct linear modelling of fMRS data is a useful complement to conventional analysis. Future work includes mitigating spectral confounds, such as scalp lipid contamination and lineshape drift, and further validation of our novel direct linear modelling approach through experimental and simulated datasets.

Reversal of neurovascular coupling in the default mode network: Evidence from hypoxia.

Local changes in cerebral blood flow are thought to match changes in neuronal activity, a phenomenon termed neurovascular coupling. Hypoxia increases global resting cerebral blood flow, but regional cerebral blood flow (rCBF) changes are non-uniform. Hypoxia decreases baseline rCBF to the default mode network (DMN), which could reflect either decreased neuronal activity or altered neurovascular coupling. To distinguish between these hypotheses, we characterized the effects of hypoxia on baseline rCBF, task performance, and the hemodynamic (BOLD) response to task activity. During hypoxia, baseline CBF increased across most of the brain, but decreased in DMN regions. Performance on memory recall and motion detection tasks was not diminished, suggesting task-relevant neuronal activity was unaffected. Hypoxia reversed both positive and negative task-evoked BOLD responses in the DMN, suggesting hypoxia reverses neurovascular coupling in the DMN of healthy adults. The reversal of the BOLD response was specific to the DMN. Hypoxia produced modest increases in activations in the visual attention network (VAN) during the motion detection task, and had no effect on activations in the visual cortex during visual stimulation. This regional specificity may be particularly pertinent to clinical populations characterized by hypoxemia and may enhance understanding of regional specificity in neurodegenerative disease pathology.

Circadian circuits in humans: White matter microstructure predicts daytime sleepiness.

The suprachiasmatic nucleus of the hypothalamus is the chief circadian pacemaker in the brain, and is entrained to day-night cycles by visual afferents from melanopsin containing retinal ganglion cells via the inferior accessory optic tract. Tracer studies have demonstrated efferents from the suprachiasmatic nucleus projecting to the paraventricular nucleus of the hypothalamus, which in turn project to first-order sympathetic neurons in the intermedio-lateral grey of the spinal cord. Sympathetic projections to the pineal gland trigger the secretion of the sleep inducing hormone melatonin. The current study reports the first demonstration of potential sympathopetal hypothalamic projections involved in circadian regulation in humans with in vivo virtual white matter dissections using probabilistic diffusion tensor imaging (DTI) tractography. Additionally, our data shows a correlation between individual differences in white matter microstructure (measured with fractional anisotropy) and increased daytime sleepiness [measured with the Epworth Sleepiness Scale (ESS, Johns, 1991)]. Sympathopetal connections with the hypothalamus were virtually dissected using designated masks on the optic chiasm, which served as an anatomical landmark for retinal fibres projecting to the suprachiasmatic nucleus, and a waypoint mask on the lateral medulla, where hypothalamic projections to the sympathetic nervous system traverse in humans. Sympathopetal projections were demonstrated in each hemisphere in twenty-six subjects. The tract passed through the suprachiasmatic nucleus of the hypothalamus and its trajectory corresponds to the dorsal longitudinal fasciculus traversing the periaqueductal region and the lateral medulla. White matter microstructure (FA) in the left hemisphere correlated with high scores on the ESS, suggesting an association between circadian pathway white matter microstructure, and increased daytime sleepiness.

Impulsive decision-making and gambling severity: The influence of γ-amino-butyric acid (GABA) and glutamate-glutamine (Glx).

Discounting larger, delayed rewards for smaller, immediate rewards is a stable psychological trait known to be impaired in gambling disorder (GD). Neuroimaging with non-GD populations indicates involvement of anterior cingulate (ACC) and dorsolateral prefrontal cortex (dlPFC) in delay discounting. However, little is known about the role of intrinsic properties of brain functioning, such as neurotransmitter action, in impaired discounting in GD. Here, we used magnetic resonance spectroscopy to assess glutamate-glutamine (Glx) and γ-amino-butyric acid (GABA+) concentrations in the dorsal ACC (dACC), dlPFC and occipital cortex of human males with and without GD. Gambling symptom severity correlated negatively with Glx levels in the dACC and occipital voxels. Discounting of small and medium delayed rewards was negatively associated with GABA+ in the dACC, while the discounting of large delayed rewards was negatively associated with GABA+/Glx ratios in the dlPFC. Additionally, in GD, discounting of large delayed rewards was negatively correlated with occipital GABA+ levels. Overall, these findings show that high gambling symptom severity is associated with low levels of Glx and that dACC (GABA+), right dlPFC (GABA+/Glx), and occipital areas (GABA+) track the magnitude of delayed rewards during discounting.