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Background: In schizophrenia (SZ), disturbances in integration of activity among brain regions seem to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging has provided compelling evidence for WM abnormalities in SZ. However, diffusion tensor imaging alone cannot currently pinpoint the biological basis of these abnormalities. Methods: In this study, we combined a myelin-specific and an axon-specific magnetic resonance imaging approach to examine potentially distinct abnormalities of WM components in SZ. Magnetization transfer ratio (MTR) provides information on myelin content, whereas diffusion tensor spectroscopy provides information on metabolite diffusion within axons. We collected data from a 1×3×3 cm voxel within the right prefrontal cortex WM at 4 Tesla and studied 23 patients with SZ and 22 age- and sex-matched healthy control participants. Results: The MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-acetylaspartate (NAA) was significantly elevated, suggesting intra-axonal abnormalities. Greater abnormality of both MTR and the apparent diffusion coefficient of NAA correlated with more adverse outcomes in the patient group. Conclusions: The results suggest that WM abnormalities in SZ include both abnormal myelination and abnormal NAA diffusion within axons. These processes might be associated with abnormal signal transduction and abnormal information processing in SZ. [ABSTRACT FROM AUTHOR]

Functional neuroimaging studies have converged to suggest that cortico-striatal-thalamo-cortical (CSTC) circuit dysfunction is a core pathophysiologic feature of obsessive-compulsive disorder (OCD). Now, complementary approaches examining regional neurochemistry are beginning to yield additional insights with regard to the neurobiology of aberrant CSTC circuitry in OCD. In particular, proton magnetic resonance spectroscopy, which allows for the in vivo quantification of various neurochemicals in the CSTC circuit and other brain regions, has recently been used extensively in studies of OCD patients. In this review, we summarize the diverse and often seemingly inconsistent findings of these studies, consider methodological factors that might help to explain these inconsistencies, and discuss several convergent findings that tentatively seem to be emerging. We conclude with suggestions for possible future proton magnetic resonance spectroscopy studies in OCD. [ABSTRACT FROM AUTHOR]

Background: Chromosome 22q11.2 deletion syndrome (22q11DS), the most common microdeletion in humans, is associated with multiple medical features, almost universal cognitive deficits, and a high risk of schizophrenia. The metabolic basis of the psychological/psychiatric features is not well understood. Volumetric brain imaging studies have shown that gray matter abnormalities in the dorsolateral prefrontal cortex (DLPFC), an area that is believed to be integral for higher neurocognition, as well as being involved in schizophrenia, are associated with the psychological manifestations. However, studies have not characterized any possible metabolite alterations within the DLPFC of children with 22q11DS and their correlations with the psychological findings. Methods: We conducted a short echo time, single-voxel, in vivo proton spectroscopy study involving children with 22q11DS (n = 26) and matched control subjects (n = 23). Results: Absolute N-acetylaspartate (NAA) levels from the DLPFC were significantly elevated in children with 22q11DS compared with control subjects and the elevations were associated with poor global functioning and higher rates of comorbid attention-deficit/hyperactivity disorder. Children with 22q11DS had a lack of an age-associated decrease in NAA levels, a trend seen in the control subjects. However, the results did not remain statistically significant after corrections for multiple comparisons were made. Conclusions: These findings represent the first report of proton spectroscopy in children with 22q11DS. The elevated DLPFC NAA levels and the lack of decreasing trends in NAA with age in the 22q11DS group relative to control subjects suggest an alteration in cortical development. Also, such neuronal dysmaturation is associated with psychopathology in children with 22q11DS. [Copyright &y& Elsevier]

Background: Cognitive deficits in schizophrenia may be related to glutamatergic dysfunction, but in vivo measurement of glutamate metabolism has been challenging. We examined the relationship between glutamate metabolism and cognitive function in schizophrenia. Methods: Thirty subjects with DSM-IV schizophrenia and 28 healthy volunteers were studied using 4 Tesla proton echo planar spectroscopic imaging. Glutamate plus glutamine (Glx), N-acetylaspartate compounds, and Inositol concentrations in gray and white matter and broad neuropsychological function were assessed in all subjects. Results: Glutamate plus glutamine was positively correlated with overall cognitive performance in the schizophrenia group (p = .0006), accounting for about 36% of the variance. No correlation was found in control subjects. Group-averaged Glx levels were similar in schizophrenia and control subjects. N-acetylaspartate compounds were reduced in cortical gray matter in the younger schizophrenia subjects (age < 30; p = .04) compared with age-matched control subjects. Inositol was increased in cortical gray (p = .002) and white matter (p = .02) in the older schizophrenia subjects (age > 30) compared with age-matched control subjects. Conclusions: Although not reduced in schizophrenia as a group, lower Glx levels correlates with impaired cognition in the illness. This suggests heterogeneity in mechanisms that regulate glutamate function in schizophrenia. Patients with reduced glutamatergic reserves may be rendered into a more severe hypoglutamatergic state with cognitive consequences. Reduced cortical gray matter N-acetylaspartate compound concentration early in the illness with normalization in older subjects is consistent with a process of early dendritic retraction with subsequent increased neuronal packing. Later in the illness, Inositol elevation suggests glial involvement. [ABSTRACT FROM AUTHOR]

Background: Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T. Methods: We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects. Results: In schizophrenia subjects, we found decreased blood oxygen level–dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms. Conclusions: Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level–dependent response. [ABSTRACT FROM AUTHOR]

Background: The disconnectivity hypothesis as part of the neurodevelopmental model of schizophrenia states that an abnormality in brain development causing impaired corticocortical or interhemispheric connectivity leads to cognitive deficits and symptoms of the illness. Previous studies showed the altered morphology of corpus callosum in patients with schizophrenia. We investigated the metabolic integrity of corpus callosum of individuals at ultra high risk (UHR) of developing schizophrenia and first-episode patients. Methods: We studied 17 individuals at UHR of developing schizophrenia, 14 first-episode schizophrenia patients, and 30 healthy control subjects. We measured the absolute concentrations of neurometabolites and T2 relaxation time of tissue water (T2B) in the genu region of corpus callosum by using proton magnetic resonance spectroscopy. Results: N-acetylaspartate (NAA) concentrations were decreased and T2B values were prolonged in the UHR cases as well as in the first-episode patients, compared with the control subjects. The difference between the NAA concentrations of the UHR cases and first-episode patients was also significant. The NAA concentrations of the UHR cases and first-episode patients were correlated with the severity of negative symptoms. Conclusions: We demonstrated the disrupted metabolic integrity of corpus callosum among individuals at UHR of schizophrenia and the first-episode patients. [Copyright &y& Elsevier]

Background: Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially resulting from enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging (1H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N-acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD) and examined the relationship between changes in NAA and clinical outcome. Methods: Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by 1H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders (n = 9) or nonresponders (n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to the patients, received scans at the same time intervals. Molar NAA concentrations in bilateral hippocampus, and change in anxiety ratings were the primary outcome measures. Results: A group-by-time interaction was found, with riluzole responders showing mean increases in hippocampal NAA across the three time points, whereas nonresponders had decreases over time. In GAD patients at Week 8, hippocampal NAA concentration and proportional increase in NAA from baseline both were positively associated with improvements in worry and clinician-rated anxiety. Conclusions: These preliminary data support a specific association between hippocampal NAA and symptom alleviation following riluzole treatment in GAD. Placebo-controlled investigations that examine hippocampal NAA as a viable surrogate endpoint for clinical trials of neuroprotective and plasticity-enhancing agents are warranted. [Copyright &y& Elsevier]

Background: Studies using proton magnetic resonance spectroscopy (MRS) have indicated that unmedicated, acutely depressed patients have decreased levels of γ-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. Methods: 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). Results: 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. Conclusions: 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. [Copyright &y& Elsevier]

Background: Although brain imaging studies have reported neurobiological abnormalities in autism, the nature and distribution of the underlying neurochemical irregularities are unknown. The purpose of this study was to examine cerebral gray and white matter cellular neurochemistry in autism with proton magnetic resonance spectroscopic imaging (MRSI). Methods: Proton MRSI examinations were conducted in 26 males with autism (age 9.8 ± 3.2 years) and 29 male comparison subjects (age 11.1 ± 2.4 years). Estimates of cerebral gray and white matter concentrations of N-acetylaspartate (NAA), creatine + phosphocreatine, choline-containing compounds, myo-inositol, and glutamate + glutamine (Glx) were made by linear regression analysis of multi-slice MRSI data and compared between groups. Regional estimates of metabolite concentration were also made with multivariate linear regression, allowing for comparisons of frontal, temporal, and occipital gray matter, cerebral white matter, and the cerebellum. Results: Patients with autism exhibited significantly lower levels of gray matter NAA and Glx than control subjects. Deficits were widespread, affecting most cerebral lobes and the cerebellum. No significant differences were detected in cerebral white matter or cerebellar metabolite levels. Conclusions: These results suggest widespread reductions in gray matter neuronal integrity and dysfunction of cortical and cerebellar glutamatergic neurons in patients with autism. [Copyright &y& Elsevier]

Background: Postmortem studies have shown robust prefrontal cortex glial losses and more subtle neuronal changes in major depressive disorder (MDD). Earlier proton magnetic resonance spectroscopy (1H-MRS) studies of the glial marker myo-inositol in MDD were subject to potential confounds. The primary hypothesis of this study was that MDD patients would show reduced prefrontal/anterior cingulate cortex levels of myo-inositol. Methods: Thirteen nonmedicated moderate–severe MDD patients and 13 matched control subjects were studied (six male, seven female per group). Proton magnetic resonance spectroscopy stimulated echo acquisition mode spectra (3.0 T; echo time = 168 msec; mixing time = 28 msec; repetition time = 3000 msec) were obtained from prefrontal/anterior cingulate cortex. Metabolite data were adjusted for tissue composition. Results: Patients with MDD showed significantly lower myo-inositol/creatine ratios (.94 ± .23) than control subjects (1.32 ± .37) [F(1,23) = 6.9; p = .016]. Conclusions: These data suggest a reduction of myo-inositol in prefrontal/anterior cingulate cortex in MDD, which could be a consequence of glial loss or altered glial metabolism. Additional in vivo studies of glial markers could add to the understanding of the pathophysiology of MDD. [Copyright &y& Elsevier]

Isolation rearing of rats is a nonpharmacologic, nonlesion manipulation that leads to deficits in prepulse inhibition (PPI) and other behavioral and neurochemical alterations reminiscent of schizophrenia. N-acetylaspartate (NAA) is present in high concentrations in the central nervous system and is found primarily in neurons. N-acetylaspartate is considered to be a marker of both neuronal loss and cellular dysfunction. Magnetic resonance spectroscopy studies have shown reductions of cortical and hippocampal NAA in schizophrenia, and a recent postmortem study has demonstrated a regionally selective temporal cortex deficit.The aim of the present study was to determine whether rats reared in isolation exhibit deficits in PPI and reductions in NAA in discrete brain regions, namely the temporal cortex, frontal cortex, hippocampus, and striatum.Compared with socially housed rats, isolation rearing resulted in PPI deficits (p < .05) and reductions in NAA in the temporal cortex (p < .001), with no significant change in the other regions investigated.These results suggest a disturbance of neuronal function, reflected by NAA reductions in the temporal cortex in isolation-reared rats, providing further evidence that isolation rearing can mimic aspects of the neuronal pathology of schizophrenia. [Copyright &y& Elsevier]

: BackgroundThis study examined the relationship of hypothalamic–pituitary–adrenal measures and hippocampal N-acetylaspartate (NAA) in posttraumatic stress disorder (PTSD) patients and control subjects.: MethodsEleven patients with combat-related PTSD and 11 control subjects were evaluated with magnetic resonance spectroscopy as well as by morning salivary cortisol samples before and after administration of low-dose dexamethasone (.5 mg).: ResultsLeft hippocampal NAA was strongly associated with both pre-dexamethasone cortisol levels (n = 22, r = .53, p = .013) and post-dexamethasone cortisol levels (n = 22, r = .63, p = .002). After accounting for clinical symptom severity and hippocampal volume, cortisol levels accounted for 21.9% of the variance (F = 5.6, p = .004) in left hippocampal NAA and 12.6% of the variance (F = 3.2, p = .035) in right hippocampal NAA.: ConclusionsThis study shows a positive relationship between cortisol levels and hippocampal NAA in subjects without hypercortisolemia. Within the range of values seen in our subjects, cortisol may have a trophic effect on the hippocampus. [Copyright &y& Elsevier]

: BackgroundN-acetylaspartylglutamate is found in neurons and its metabolite N-acetylaspartate, which can be measured by magnetic resonance spectroscopy, is considered a marker of neuronal integrity. Several magnetic resonance spectroscopy studies have found evidence of N-acetylaspartate deficits in schizophrenia.: MethodsWe employed a high-pressure liquid chromatography method to determine N-acetylaspartate and N-acetylaspartylglutamate in postmortem brain tissues taken from a well-defined series of psychiatric cases. N-acetylaspartate and N-acetylaspartylglutamate concentrations were measured in superior temporal and frontal cortices of patients with schizophrenia, bipolar disorder, and depression and control subjects.: ResultsN-acetylaspartate was significantly decreased below controls in superior temporal cortex in schizophrenia (p < .01) and bipolar disorder (p < .01), but no deficits were found in frontal cortex. N-acetylaspartylglutamate was significantly decreased only in superior temporal cortex in schizophrenia.: ConclusionsThe results are consistent with evidence of superior temporal cortex abnormalities in schizophrenia. The finding in bipolar disorder suggests that temporal cortex N-acetylaspartate deficits may be a common feature of psychotic disorders. [Copyright &y& Elsevier]

: BackgroundThe brain regions involved in the pathophysiology of bipolar disorder have not been definitively determined. Previous studies have suggested possible involvement of the hippocampus and of prefrontal regions. Proton magnetic resonance spectroscopic imaging (1H-MRSI) allows measurement of N-acetylaspartate (NAA, marker of neuronal integrity), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in multiple brain regions. The objective of this study was to assess possible NAA reductions in hippocampus and prefrontal regions in patients with bipolar disorder.: MethodsWe studied 17 patients with bipolar disorder and 17 age- and gender-matched healthy subjects on a 1.5-T nuclear magnetic resonance (NMR) machine. With 1H-MRSI we measured ratios of areas under the metabolite peaks of the proton spectra (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions.: ResultsPatients showed significant reductions of NAA/CRE bilaterally in the hippocampus. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled.: ConclusionsThis study shows that patients with bipolar disorder have a regional reduction of NAA relative signals, suggesting neuronal damage or malfunction of the hippocampus. As suggested by other studies, neuronal pathology in the hippocampus may be involved in the pathophysiology of bipolar disorder and in susceptibility to psychosis. [Copyright &y& Elsevier]

Background: Chronic fatigue syndrome (CFS) is characterized by severe fatigue persisting for ≥6 months and leading to considerable impairment in daily functioning. Neuroimaging studies of patients with CFS have revealed alterations in prefrontal brain morphology. However, it remains to be determined whether these alterations are specific for fatigue or whether they relate to other common CFS symptoms (e.g., chronic pain, lower psychomotor speed, and reduced physical activity)., Methods: We used magnetic resonance imaging to quantify gray matter volume (GMV) and the N-acetylaspartate and N-acetylaspartylglutamate/creatine ratio (NAA/Cr) in a group of 89 women with CFS. Building on previous reports, we tested whether GMV and NAA/Cr in the dorsolateral prefrontal cortex are associated with fatigue severity, pain, psychomotor speed, and physical activity, while controlling for depressive symptoms. We also considered GMV and NAA/Cr differences between patients with CFS and 26 sex-, age-, and education-matched healthy controls., Results: The presence of pain symptoms was the main predictor of both GMV and NAA/Cr in the left dorsolateral prefrontal cortex of patients with CFS. More pain was associated with reduced GMVs and NAA/Cr, over and above the effects of fatigue, depressive symptoms, physical activity, and psychomotor speed. In contrast to previous reports and despite a large representative sample, global GMV did not differ between the CFS and healthy control groups., Conclusions: CFS, as diagnosed by Centers for Disease Control and Prevention criteria, is not a clinical entity reliably associated with reduced GMV. Individual variation in the presence of pain, rather than fatigue, is associated with neuronal alterations in the dorsolateral prefrontal cortex of patients with CFS., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Studies have reported that transcranial direct current stimulation (tDCS) can modulate human behaviors, symptoms, and neural activity; however, the neural effects during stimulation are unknown. Most studies compared the effects of tDCS before and after stimulation. The objective of our study was to measure the neurobiological effect of a single tDCS dose during stimulation., Methods: We conducted an online and offline protocol combining tDCS and magnetic resonance spectroscopy (MRS) in 17 healthy participants. We applied anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) and cathodal tDCS over the right DLPFC for 30 minutes, one of the most common montages used with tDCS. We collected MRS measurements in the left DLPFC and left striatum during tDCS and an additional MRS measurement in the left DLPFC immediately after the end of stimulation., Results: During stimulation, active tDCS, as compared with sham tDCS, elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine but did not induce significant differences in prefrontal or striatal gamma-aminobutyric acid level. Immediately after stimulation, active tDCS, as compared with sham tDCS, did not significantly induce differences in glutamate + glutamine, N-acetylaspartate, or gamma-aminobutyric acid levels in the left DLPFC., Conclusions: These observations indicate that tDCS over the DLPFC has fast excitatory effects, acting on prefrontal and striatal transmissions, and these effects are short lived. One may postulate that repeated sessions of tDCS might induce similar longer lasting effects of elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine levels, which may contribute to its behavioral and clinical effects., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Neuroimaging changes in bipolar disorder (BD) may be secondary to the presence of certain clinical factors. Type 2 diabetes mellitus (T2DM) damages the brain and frequently co-occurs with BD. Studying patients with both T2DM and BD could help identify preventable risk factors for neuroimaging changes in BD., Methods: We used 1.5T magnetic resonance spectroscopy to measure prefrontal N-acetylaspartate (NAA), which is mainly localized in neurons, and total creatine (tCr), an energy metabolite, in 19 BD patients with insulin resistance/glucose intolerance (BD + IR/GI), 14 BD subjects with T2DM (BD + T2DM), 15 euglycemic BD participants, and 11 euglycemic, nonpsychiatric control., Results: The levels of NAA and tCr were lowest among BD + T2DM, intermediate in the BD + IR/GI, and highest among the euglycemic BD and control subjects (F₃,₅₅ = 4.57, p = .006; F₃,₅₅ = 2.92, p = .04, respectively). Even the BD + IR/GI subjects had lower NAA than the euglycemic participants (t₄₃ = 2.13, p = .04). Total Cr was associated with NAA (β = .52, t₅₆ = 5.57, p = .000001). Both NAA and tCr correlated with Global Assessment of Functioning scores (r₄₆ = .28, p = .05; r₄₆ = .48, p = .0004, respectively)., Conclusions: T2DM, but also prediabetes, may be risk factors for prefrontal neurochemical alterations in BD. These changes were associated with poor psychosocial functioning and could indicate impaired energy metabolism. The findings emphasize the importance of improving diabetes care in BD and suggest potential options for treatment of neuroimaging alterations., (© 2014 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.)