Design and methodology for a proof of mechanism study of individualized neuronavigated continuous Theta burst stimulation for auditory processing in adolescents with autism spectrum disorder.

It has been suggested that aberrant excitation/inhibition (E/I) balance and dysfunctional structure and function of relevant brain networks may underlie the symptoms of autism spectrum disorder (ASD). However, the nomological network linking these constructs to quantifiable measures and mechanistically relating these constructs to behavioral symptoms of ASD is lacking. Herein we describe a within-subject, controlled, proof-of-mechanism study investigating the pathophysiology of auditory/language processing in adolescents with ASD. We utilize neurophysiological and neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) metrics of language network structure and function. Additionally, we apply a single, individually targeted session of continuous theta burst stimulation (cTBS) as an experimental probe of the impact of perturbation of the system on these neurophysiological and neuroimaging outcomes. MRS, fMRI, and MEG measures are evaluated at baseline and immediately prior to and following cTBS over the posterior superior temporal cortex (pSTC), a region involved in auditory and language processing deficits in ASD. Also, behavioral measures of ASD and language processing and DWI measures of auditory/language network structures are obtained at baseline to characterize the relationship between the neuroimaging and neurophysiological measures and baseline symptom presentation. We hypothesize that local gamma-aminobutyric acid (GABA) and glutamate concentrations (measured with MRS), and structural and functional activity and network connectivity (measured with DWI and fMRI), will significantly predict MEG indices of auditory/language processing and behavioral deficits in ASD. Furthermore, a single session of cTBS over left pSTC is hypothesized to lead to significant, acute changes in local glutamate and GABA concentration, functional activity and network connectivity, and MEG indices of auditory/language processing. We have completed the pilot phase of the study (n=20 Healthy Volunteer adults) and have begun enrollment for the main phase with adolescents with ASD (n=86; age 14-17). If successful, this study will establish a nomological network linking local E/I balance measures to functional and structural connectivity within relevant brain networks, ultimately connecting them to ASD symptoms. Furthermore, this study will inform future therapeutic trials using cTBS to treat the symptoms of ASD.

Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder - a pilot study.

Introduction: Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. Individuals with alcohol use disorder (AUD) show elevated brain acetate metabolism at the expense of glucose, a shift in energy utilization that persists beyond acute intoxication. We recently reported that nutritional ketosis and administration of ketone bodies as an alternative energy source to glucose reduce alcohol withdrawal severity and alcohol craving in AUD. However, the regional effects of nutritional ketosis on brain ketone (beta-hydroxybutyrate [BHB]) and glucose metabolism have not been studied in AUD. Methods: Five participants with AUD underwent two magnetic resonance imaging (MRI) sessions and 4 participants with AUD underwent two positron emission tomography (PET) sessions with 18 F-fluorodeoxyglucose. All participants completed one session without KE intervention and one session during which they consumed 395 mg/kg (R) -3-hydroxybutyl (R) -3-hydroxybutyrate Ketone Ester (KE) intervention (TdeltaS Global Inc.) before the scan. The order of the sessions was randomized. For the PET cohort, blood glucose and ketone levels were assessed and voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) were computed at each session. For the MRI cohort, brain anterior cingulate BHB levels were assessed using magnetic resonance spectroscopy. Results: A single dose of KE elevated blood BHB and anterior cingulate BHB levels compared to baseline. Moreover, blood glucose levels were lower with KE than baseline, and whole-brain CMRglc decreased by 17%. The largest KE-induced CMRglc reductions were in the frontal, occipital, cortex, and anterior cingulate cortices. Conclusion: These findings provide preliminary evidence that KE administration elevates ketone and reduces brain glucose metabolism in humans, consistent with a shift from glucose to ketones as a brain energy source. Average reductions in CMRglc of 17% are similar to global average reductions documented with administration of 0.25-0.5 g/kg of alcohol. Documenting the clinical and neurometabolic effects of nutritional ketosis will yield fundamental knowledge as to its potential beneficial effects as a treatment for AUD and its underlying neural mechanisms.

Brain glutamate and sleep efficiency associations following a ketogenic diet intervention in individuals with Alcohol Use Disorder.

Background: We previously showed that ketogenic diet (KD) was effective in curbing alcohol withdrawal and craving in individuals with alcohol use disorder (AUD). We hypothesized that the clinical benefits were due to improvements in sleep. To test this, we performed a secondary analysis on the KD trial data to (1) examine the effects of KD on total sleep time (TST) and sleep quality and (2) investigate the association between KD-induced alterations in cingulate glutamate concentration and changes in TST and sleep quality. Methods: AUD individuals undergoing alcohol detoxification were randomized to receive KD (n=19) or standard American diet (SA; n=14) for three weeks. TST was measured weekly by self-report, GENEActive sleep accelerometer, and X4 Sleep Profiler ambulatory device. Sleep quality was assessed using subjectively ratings of sleep depth and restedness and Sleep Profiler (Sleep Efficiency [%]). Weekly 1H magnetic resonance spectroscopy scans measured cingulate glutamate levels. Results: TST was lower in KD than SA and increased with effect of time. Sleep depth, restedness, and Sleep Efficiency improved with time, but exhibited no effect of diet. In KD and SA combined, week 1 cingulate glutamate levels correlated positively with Sleep Efficiency, but not with TST. Conclusions: Although cingulate glutamate levels correlated positively with Sleep Efficiency in week 1, KD-induced glutamate elevation did not produce significant sleep improvements. Rather, KD was associated with lower TST than SA. Given the well-established associations between sleep and alcohol relapse, longer follow up assessment of KD's impact on sleep in AUD is warranted.

Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents.

Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.

Cerebral phosphoester signals measured by 31P magnetic resonance spectroscopy at 3 and 7 Tesla.

Abnormal cell membrane metabolism is associated with many neuropsychiatric disorders. Free phosphomonoesters and phosphodiesters, which can be detected by in vivo 31P magnetic resonance spectroscopy (MRS), are important cell membrane building blocks. However, the quantification of phosphoesters has been highly controversial even in healthy individuals due to overlapping signals from macromolecule membrane phospholipids (MP). In this study, high signal-to-noise ratio (SNR) cerebral 31P MRS spectra were acquired from healthy volunteers at both 3 and 7 Tesla. Our results indicated that, with minimal spectral interference from MP, the [phosphocreatine (PCr)]/[phosphocholine (PC) + glycerophosphocholine (GPC)] ratio measured at 7 Tesla agreed with its value expected from biochemical constraints. In contrast, the 3 Tesla [PCr]/[PC+GPC] ratio obtained using standard spectral fitting procedures was markedly smaller than the 7 Tesla ratio and than the expected value. The analysis suggests that the commonly used spectral model for MP may fail to capture its complex spectral features at 3 Tesla, and that additional prior knowledge is necessary to reliably quantify the phosphoester signals at low magnetic field strengths when spectral overlapping is significant.

Oxidative phosphorylation in creatine transporter deficiency.

X-linked creatine transporter deficiency (CTD) is one of the three types of cerebral creatine deficiency disorders. CTD arises from pathogenic variants in the X-linked gene SLC6A8. We report the first phosphorus (31 P) MRS study of patients with CTD, where both phosphocreatine and total creatine concentrations were found to be markedly reduced. Despite the diminished role of creatine and phosphocreatine in oxidative phosphorylation in CTD, we found no elevation of lactate or lowered pH, indicating that the brain energy supply still largely relied on oxidative metabolism. Our results suggest that mitochondrial function is a potential therapeutic target for CTD.

Parameterization of metabolite and macromolecule contributions in interrelated MR spectra of human brain using multidimensional modeling.

Macromolecular signals are crucial constituents of short echo-time 1 H MR spectra with potential clinical implications in themselves as well as essential ramifications for the quantification of the usually targeted metabolites. Their parameterization, needed for general fitting models, is difficult because of their unknown composition. Here, a macromolecular signal parameterization together with metabolite signal quantification including relaxation properties is investigated by multidimensional modeling of interrelated 2DJ inversion-recovery (2DJ-IR) datasets. Simultaneous and iterative procedures for defining the macromolecular background (MMBG) as mono-exponentially or generally decaying signals over TE are evaluated. Varying prior knowledge and restrictions in the metabolite evaluation are tested to examine their impact on results and fitting stability for two sets of three-dimensional spectra acquired with metabolite-cycled PRESS from cerebral gray and white matter locations. One dataset was used for model optimization, and also examining the influence of prior knowledge on estimated parameters. The most promising model was applied to a second dataset. It turned out that the mono-exponential decay model appears to be inadequate to represent TE-dependent signal features of the MMBG. TE-adapted MMBG spectra were therefore determined. For a reliable overall quantification of implicated metabolite concentrations and relaxation times, a general fitting model had to be constrained in terms of the number of fitting variables and the allowed parameter space. With such a model in place, fitting precision for metabolite contents and relaxation times was excellent, while fitting accuracy is difficult to judge and bias was likely influenced by the type of fitting constraints enforced. In summary, the parameterization of metabolite and macromolecule contributions in interrelated MR spectra has been examined by using multidimensional modeling on complex 2DJ-IR datasets. A tightly restricted model allows fitting of individual subject data with high fitting precision documented in small Cramér-Rao lower bounds, good repeatability values and a relatively small spread of estimated concentration and relaxation values for a healthy subject cohort.

Role of gamma-amino-butyric acid in the dorsal anterior cingulate in age-associated changes in cognition.

GABAergic mechanisms have been shown to contribute to cognitive aging in animal models, but there is currently limited in vivo evidence to support this relationship in humans. It is also unclear whether aging is associated with changes in GABA levels measured with proton magnetic resonance spectroscopy (MRS). Spectral-editing MRS at 3 T was used to measure GABA in the dorsal anterior cingulate cortex (dACC) for a large sample of healthy volunteers (N = 229) aged 18-55. In a subset of 171 participants, age effects on several cognitive tasks were studied. We formally tested whether the MRS measures mediated the relationship between age and cognition. Robust associations of age with performance were found for the Wisconsin Card Sorting Test ([WCST], p < 0.0001). Age was also significantly associated with declining levels of GABA in the dACC (p < 0.001), and GABA levels significantly predicted WCST performance (p < 0.0004). Mediation analysis revealed that GABA in the dACC mediated the effect of age on WCST performance (p < 0.01). Other metabolites were similarly associated with age, but only GABA and creatine levels were significantly associated with WCST performance. No association with age or cognitive performance was found in a frontal white matter control region in a subset of participants. The association of GABA with WCST performance was not related to the amount of brain atrophy associated with aging as measured by the proportion of CSF, gray, and white matter in the MRS voxel. These results implicate GABAergic and possibly energetic metabolism in the dACC as mechanisms of age effects in executive function.

Retrospective correction of frequency drift in spectral editing: The GABA editing example.

GABA levels can be measured using proton MRS with a two-step editing sequence. However due to the low concentration of GABA, long acquisition time is usually needed to achieve sufficient SNR to detect small differences in many psychiatric disorders. During this long scan time the frequency offset of the measured voxel can change because of magnetic field drift and patient movement. This drift will change the frequency of the editing pulse relative to that of metabolites, leading to errors in quantification. In this article we describe a retrospective method to correct for frequency drift in spectral editing. A series of reference signals for each metabolite was generated for a range of frequency offsets and then averaged together based on the history of frequency changes over the scan. These customized basis sets were used to fit the in vivo data. Our results demonstrate the effectiveness of the correction method and the remarkable robustness of a GABA editing technique with a top hat editing profile in the presence of frequency drift.

Brain γ-aminobutyric acid (GABA) detection in vivo with the J-editing (1) H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement, macromolecule contamination and test-retest reliability.

Abnormalities in brain γ-aminobutyric acid (GABA) have been implicated in various neuropsychiatric and neurological disorders. However, in vivo GABA detection by (1) H MRS presents significant challenges arising from the low brain concentration, overlap by much stronger resonances and contamination by mobile macromolecule (MM) signals. This study addresses these impediments to reliable brain GABA detection with the J-editing difference technique on a 3-T MR system in healthy human subjects by: (i) assessing the sensitivity gains attainable with an eight-channel phased-array head coil; (ii) determining the magnitude and anatomic variation of the contamination of GABA by MM; and (iii) estimating the test-retest reliability of the measurement of GABA with this method. Sensitivity gains and test-retest reliability were examined in the dorsolateral prefrontal cortex (DLPFC), whereas MM levels were compared across three cortical regions: DLPFC, the medial prefrontal cortex (MPFC) and the occipital cortex (OCC). A three-fold higher GABA detection sensitivity was attained with the eight-channel head coil compared with the standard single-channel head coil in DLPFC. Despite significant anatomical variation in GABA + MM and MM across the three brain regions (p < 0.05), the contribution of MM to GABA + MM was relatively stable across the three voxels, ranging from 41% to 49%, a non-significant regional variation (p = 0.58). The test-retest reliability of GABA measurement, expressed as either the ratio to voxel tissue water (W) or to total creatine, was found to be very high for both the single-channel coil and the eight-channel phased-array coil. For the eight-channel coil, for example, Pearson's correlation coefficient of test vs. retest for GABA/W was 0.98 (R(2) = 0.96, p = 0.0007), the percentage coefficient of variation (CV) was 1.25% and the intraclass correlation coefficient (ICC) was 0.98. Similar reliability was also found for the co-edited resonance of combined glutamate and glutamine (Glx) for both coils. Copyright © 2016 John Wiley & Sons, Ltd.

Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings.

OBJECTIVE: The authors sought to compare GABA levels in treated and untreated patients with psychosis with levels in their unaffected siblings and healthy control subjects, and to assess the effects of antipsychotic medications on GABA levels. METHOD: GABA+ levels (i.e., including signal from unrelated proteins or macromolecules) referenced to creatine or water were studied with J-edited proton spectroscopy in the dorsal anterior cingulate cortex of 289 individuals: 184 healthy control subjects, 83 treated patients with psychosis, 25 untreated patients, 31 unaffected siblings, and 17 patients studied both while off all medications and while on a single antipsychotic. RESULTS: GABA+ levels in the dorsal anterior cingulate did not differ between untreated patients and healthy controls. For treated patients, levels were modestly lower for GABA+/creatine but did not differ for GABA+/water compared with healthy controls. For both GABA+ measures, unaffected siblings had significantly lower levels compared with controls. GABA+/creatine showed a modest degree of familiality (intraclass correlation=0.36). Antipsychotic dosage was negatively correlated with GABA+ levels, but the on-off medication studies indicated no difference in GABA+ levels on antipsychotics compared with off antipsychotics. CONCLUSIONS: GABA+/creatine in the dorsal anterior cingulate may constitute an intermediate phenotype with low effect size for psychosis, but GABA+/water measures do not fully support this conclusion. Low GABA+ levels in unaffected siblings could suggest a genetic association, but the failure to find consistent evidence of this phenotype in the patients themselves weakens genetic inference on risk for psychosis. Replication in independent samples of siblings is warranted to confirm the potential genetic risk association.

Role of the sensorimotor cortex in Tourette syndrome using multimodal imaging.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Most patients describe uncomfortable premonitory sensations preceding the tics and a subjective experience of increased sensitivity to tactile stimuli. These reports indicate that a sensory processing disturbance is an important component of TS together with motor phenomena. Thus, we focused our investigation on the role of the sensorimotor cortex (SMC) in TS using multimodal neuroimaging techniques. We measured the gamma-aminobutyric acid (GABA)+/Creatine (Cre) ratio in the SMC using GABA (1) H magnetic resonance spectroscopy. We recorded the baseline beta activity in the SMC using magnetoencephalography and correlated GABA+/Cre ratio with baseline beta band power. Finally, we examined the resting state functional connectivity (FC) pattern of the SMC using functional magnetic resonance imaging (fMRI). GABA+/Cre ratio in the SMC did not differ between patients and controls. Correlation between the baseline beta band power and GABA+/Cre ratio was abnormal in patients. The anterior insula showed increased FC with the SMC in patients. These findings suggest that altered limbic input to the SMC and abnormal GABA-mediated beta oscillations in the SMC may underpin some of the sensorimotor processing disturbances in TS and contribute to tic generation.

Low single dose gabapentin does not affect prefrontal and occipital gamma-aminobutyric acid concentrations.

The γ-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0mg, 150mg and 300mg GBP. Subjects were scanned on a 3T scanner using a transmit-receive head coil that provided a relatively homogenous radiofrequency field to obtain spectroscopy measurement in the medial prefrontal (MPFC) and occipital cortex (OCC). There was no dose-dependent effect of GBP on GABA levels in the OCC or MPFC. There was also no effect on Glx, choline or N-acetyl-aspartate concentrations. The previously reported finding of increased GABA levels after GBP treatment is not evident for healthy subjects at the dose of 150 and 300mg. As a result, if subjects are scanned on a 3T scanner, low dose GPB is not useful as an experimental challenge agent on the GABA system.

Associations between prefrontal γ-aminobutyric acid concentration and the tryptophan hydroxylase isoform 2 gene, a panic disorder risk allele in women.

Associations between the central serotonergic and γ-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (-703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder. Our results revealed a significant association between increased GABA concentration in the PFC and the T-allele frequencies of two TPH2 SNPs, namely rs4570625 (-703 G/T) and rs2129575 (p⩽0.0004) and the C-allele frequency of one TPH2 SNP, namely rs1386491 (p = 0.0003) in female subjects. We concluded that rs4570625 (-703 G/T), rs2129575 and rs1386491 play a significant role in GABAergic neurotransmission and may contribute to the sex-specific dysfunction of the GABAergic system in the PFC.

Regional difference in GABA levels between medial prefrontal and occipital cortices.

PURPOSE: To avoid the confounding effects of variations in tissue composition this study measured regional GABA differences using two voxels with the same tissue composition. MATERIALS AND METHODS: Eighteen healthy adult volunteers were scanned using a 3 Tesla GE clinical scanner with a J-coupling based editing sequence. Spectroscopy voxels were placed in the medial prefrontal (MPFC) and occipital cortex (OCC) with essentially the same gray and white matter fractions. RESULTS: A 16% (P = 0.0001) significantly higher GABA to creatine ratio was found in the OCC (0.1103 ± 0.0050) compared with the MPFC (0.0953 ± 0.0041). When normalized to tissue water, GABA concentrations in the OCC were 14% higher than in the MPFC. CONCLUSION: A difference in GABA concentration was found between the OCC and MPFC voxels in healthy subjects which is attributable to differences other than tissue composition.

Age-modulated association between prefrontal NAA and the BDNF gene.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p = 0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 × age interaction on NAA level (p = 0.031). Specifically, the effect of rs1519480 on NAA level became significant at age ⩾34.17 yr. NAA level decreased with advancing age for genotype TT (p = 0.001) but not for genotype CT (p = 0.82) or CC (p = 0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions.

An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression.

Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine.

Genetic association of ErbB4 and human cortical GABA levels in vivo.

NRG1-ErbB4 signaling controls inhibitory circuit development in the mammalian cortex through ErbB4-dependent regulation of GABAergic interneuron connectivity. Common genetic variation in ErbB4 (rs7598440) has been associated with ErbB4 messenger RNA levels in the human cortex and risk for schizophrenia. Recent work demonstrates that Erbb4 is expressed exclusively on inhibitory interneurons, where its presence on parvalbumin-positive cells mediates the effects of NRG1 on inhibitory circuit formation in the cortex. We therefore hypothesized that genetic variation in ErbB4 at rs7598440 would impact indices of GABA concentration in the human cortex. We tested this hypothesis in 116 healthy volunteers by measuring GABA and GLX (glutamate + glutamine) with proton magnetic resonance spectroscopy in the dorsal anterior cingulate gyrus. ErbB4 rs7598440 genotype significantly predicted cortical GABA concentration (p = 0.014), but not GLX (p = 0.51), with A allele carriers having higher GABA as predicted by the allelic impact on ErbB4 expression. These data establish an association of ErbB4 and GABA in human brain and have implications for understanding the pathogenesis of schizophrenia and other psychiatric disorders.

Reproducibility of prefrontal γ-aminobutyric acid measurements with J-edited spectroscopy.

γ-Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the human brain, and GABA-ergic dysfunction has been implicated in a variety of neuropsychiatric disorders. Recent MRS techniques have allowed the quantification of GABA concentrations in vivo, and could therefore provide biologically relevant information. Few reports have formally characterized the reproducibility of these techniques, and differences in field strength, acquisition and processing parameters may result in large differences in measured GABA values. Here, we used a J-edited, single-voxel spectroscopy method of measurement of GABA + macromolecules (GABA + ) in the anterior cingulate cortex (ACC) and right frontal white matter (rFWM) at 3 T. We measured the coefficient of variation within subjects (CVw) and intra-class correlation coefficients on two repeated scans obtained from 10 healthy volunteers with processing procedures developed in-house for the quantification of GABA + and other major metabolites. In addition, by segmenting the spectroscopic voxel into cerebrospinal fluid, gray matter and white matter, and employing a linear regression technique to extrapolate metabolite values to pure gray and white matter, we determined metabolite differences between gray and white matter in ACC and rFWM. CVw values for GABA + /creatine, GABA + /H(2) O, GABA + , creatine, partially co-edited glutamate + glutamine (Glx)/creatine, partially co-edited Glx and N-acetylaspartic acid (NAA)/creatine were all below 12% in both ACC and rFWM. After extrapolation to pure gray and pure white matter, CVw values for all metabolites were below 16%. We found metabolite ratios between gray and white matter for GABA + /creatine, GABA + , creatine, partially co-edited Glx and NAA/creatine to be 0.88 ± 0.21 (standard deviation), 1.52 ± 0.32, 1.77 ± 0.4, 2.69 ± 0.74 and 0.70 ± 0.05, respectively. This study validates a reproducible method for the quantification of brain metabolites, and provides information on gray/white matter differences that may be important in the interpretation of results in clinical populations.

In vivo neurochemistry of primary focal hand dystonia: a magnetic resonance spectroscopic neurometabolite profiling study at 3T.

The neurochemical basis of dystonia is unknown. The purpose of this study was to assess the differences of the inhibitory neurotransmitter, gamma amino butyric acid (GABA), in the sensorimotor cortex and the basal ganglia using magnetic resonance spectroscopy with optimized GABA sensitivity. Twenty-two patients with focal hand dystonia and 22 healthy controls were studied. No significant differences in GABA were observed between the groups in either the sensorimotor cortex or in the basal ganglia.