Jan Willem van der Veen

Normal Prefrontal Gamma-Aminobutyric Acid Levels in Remitted Depressed Subjects Determined by Proton Magnetic Resonance Spectroscopy

BACKGROUND There is growing evidence that the brain gamma-aminobutyric acid (GABA) system is involved in depression. Lowered plasma GABA levels were identified as a traitlike abnormality found in patients with remitted unipolar depression and in healthy first-degree relatives of patients with unipolar depression. Major depressive disorder has been associated with neuroimaging and neuropathological abnormalities in the prefrontal cortex by various types of evidence. As a result, the current study investigates whether GABA levels in the prefrontal cortex differ between unmedicated subjects with remitted major depressive disorder (rMDD) and healthy control subjects. METHODS Sixteen rMDD subjects and 15 healthy control subjects underwent magnetic resonance spectroscopy. We used a 3 Tesla GE whole body scanner with a homogeneous resonator coil providing a homogenous radiofrequency field and capability of obtaining measurement from the prefrontal cortex. Gamma-aminobutyric acid levels were measured in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. RESULTS There was no difference in GABA concentrations between rMDD subjects and healthy control subjects in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. Secondary analyses provided preliminary evidence for a negative relationship between the glutamate/glutamine (Glx)/GABA ratio and age of onset of major depression in the ventromedial prefrontal cortex. CONCLUSIONS This result suggests that GABA levels in the prefrontal cortex, if found to be reduced in symptomatic depression, do not represent a persistent characteristic of major depression. Further research is needed to determine brain GABA levels in different brain regions, in different stages of depressive illness, and in different depressive subtypes.

Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation.

OBJECTIVE The diagnosis and treatment of youth with severe nonepisodic irritability and hyperarousal, a syndrome defined as severe mood dysregulation (SMD) by Leibenluft, has been the focus of increasing concern. We conducted the first randomized double-blind, placebo-controlled trial in SMD youth, choosing lithium on the basis of its potential in treating irritability and aggression and neuro-metabolic effects. METHODS SMD youths 7-17 years were tapered off their medications. Those who continued to meet SMD criteria after a 2-week, single-blind, placebo run-in were randomized to a 6-week double-blind trial of either lithium (n = 14) or placebo (n = 11). Clinical outcome measures were: (1) Clinical Global Impressions-Improvement (CGI-I) score less than 4 at trials end and (2) the Positive and Negative Syndrome Scale (PANSS) factor 4 score. Magnetic resonance spectroscopy (MRS) outcome measures were myoinositol (mI), N-acetyl-aspartate (NAA), and combined glutamate/glutamine (GLX), all referenced to creatine (Cr). RESULTS In all, 45% (n = 20/45) of SMD youths were not randomized due to significant clinical improvement during the placebo run-in. Among randomized patients, there were no significant between-group differences in either clinical or MRS outcome measures. CONCLUSION Our study suggests that although lithium may not result in significant clinical or neurometabolic alterations in SMD youths, further SMD treatment trials are warranted given its prevalence.

Effect of Acute Psychological Stress on Prefrontal GABA Concentration Determined by Proton Magnetic Resonance Spectroscopy

OBJECTIVE Impaired function of the central gamma-aminobutyric acid (GABA) system, which provides the brains major inhibitory pathways, is thought to play an important role in the pathophysiology of anxiety disorders. The effect of acute psychological stress on the human GABA-ergic system is still unknown, however. The purpose of this study was to determine the effect of acute stress on prefrontal GABA levels. METHOD A recently developed noninvasive magnetic resonance spectroscopy method was used to measure changes in the GABA concentration of the prefrontal cortex in 10 healthy human subjects during a threat-of-shock condition and during a safe condition (two sessions on different days). The main outcome measure was the mean GABA concentration within a 3×3×2-cm(3) voxel selected from the medial prefrontal cortex. RESULTS Prefrontal GABA decreased by approximately 18% in the threat-of-shock condition relative to the safe condition. This reduction was specific to GABA, since the concentrations of N-acetyl-aspartate, choline-containing compounds, and glutamate/glutamine levels obtained in the same spectra did not change significantly. CONCLUSIONS This result appeared compatible with evidence from preclinical studies in rodents, which showed rapid presynaptic down-regulation of GABA-ergic neurotransmission in response to acute psychological stress. The molecular mechanism and functional significance of this reduced inhibitory effect of acute psychological stress in relation to impaired GABA-ergic function in anxiety disorders merit further investigation.

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.

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 + /H2O, 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. Published in 2011 by John Wiley & Sons, Ltd.

Genetic Modulation of GABA Levels in the Anterior Cingulate Cortex by GAD1 and COMT

γ-Aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 (p=0.005) and rs769390 (p=0.004)) showed effects on GABA levels as did COMT val158met (p=0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p=0.001 and 0.003, respectively) and a trend toward a significant interaction (p=0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N=6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.

Prefrontal cortical gamma-aminobutyric Acid levels in panic disorder determined by proton magnetic resonance spectroscopy.

BACKGROUND Panic disorder (PD) is hypothesized to be associated with altered function of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Previous proton magnetic resonance spectroscopy (MRS) studies found lower GABA concentrations in the occipital cortex of subjects with PD relative to healthy control subjects. The current study is the first MRS study to compare GABA concentrations between unmedicated PD subjects and control subjects in the prefrontal cortex (PFC). METHODS Unmedicated subjects with PD (n = 17) and age- and sex-matched healthy control subjects (n = 17) were scanned on a 3 Tesla scanner using a transmit-receive head coil that provided a sufficiently homogenous radiofrequency field to obtain spectroscopic measurements in the dorsomedial/dorsal anterolateral and ventromedial areas of the PFC. RESULTS The prefrontal cortical GABA concentrations did not differ significantly between PD subjects and control subjects. There also was no statistically significant difference in glutamate/glutamine (Glx), choline, or N-acetyl aspartate concentrations. CONCLUSIONS The previously reported finding of reduced GABA concentrations in the occipital cortex of PD subjects does not appear to extend to the PFC.

Impact of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism on Levels of Hippocampal N-Acetyl-Aspartate Assessed by Magnetic Resonance Spectroscopic Imaging at 3 Tesla

BACKGROUND This study was conducted to corroborate prior evidence of an effect of the brain-derived neurotrophic factor (BDNF) valine (val) to methionine (met) amino acid substitution at codon 66 (val66met) polymorphism on measures of N-acetyl-aspartate (NAA) containing compounds in healthy subjects. METHODS The NAA to creatine (Cre) ratio (NAA/Cre), NAA to choline (Cho) ratio (NAA/Cho), and Cho to Cre ratio (Cho/Cre) were measured in the left and right hippocampi, left and right dorsolateral prefrontal cortices, occipital lobe, anterior cingulate, and white matter of the centrum semiovale of 69 carefully screened healthy volunteers utilizing proton magnetic resonance spectroscopic imaging (MRSI) at 3 Tesla (T). RESULTS Val/met subjects exhibited significantly reduced levels of left hippocampal NAA/Cre and NAA/Cho compared with val/val subjects. This effect was independent of age, IQ, number of voxels, hippocampal volume, or gray matter content in the voxels of interest. Analysis of other brain regions showed no effect of BDNF genotype on NAA measures. CONCLUSIONS We confirmed the association between the met-BDNF variant and reduced levels of hippocampal NAA found with a similar technique at 1.5T. The consonance of our results with prior findings adds to the evidence that the BDNF val/met genotype affects hippocampal biology with implications for a variety of neuropsychiatric disorders.

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 1H 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. Hum Brain Mapp 35:5834–5846, 2014. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

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.