Altered brain metabolites in male nonhuman primate offspring exposed to maternal immune activation.

Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.

Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model.

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring's neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

Altered behavior, brain structure, and neurometabolites in a rat model of autism-specific maternal autoantibody exposure.

Maternal immune dysregulation is a prenatal risk factor for autism spectrum disorder (ASD). Importantly, a clinically relevant connection exists between inflammation and metabolic stress that can result in aberrant cytokine signaling and autoimmunity. In this study we examined the potential for maternal autoantibodies (aAbs) to disrupt metabolic signaling and induce neuroanatomical changes in the brains of exposed offspring. To accomplish this, we developed a model of maternal aAb exposure in rats based on the clinical phenomenon of maternal autoantibody-related ASD (MAR-ASD). Following confirmation of aAb production in rat dams and antigen-specific immunoglobulin G (IgG) transfer to offspring, we assessed offspring behavior and brain structure longitudinally. MAR-ASD rat offspring displayed a reduction in pup ultrasonic vocalizations and a pronounced deficit in social play behavior when allowed to freely interact with a novel partner. Additionally, longitudinal in vivo structural magnetic resonance imaging (sMRI) at postnatal day 30 (PND30) and PND70, conducted in a separate cohort of animals, revealed sex-specific differences in total and regional brain volume. Treatment-specific effects by region appeared to converge on midbrain and cerebellar structures in MAR-ASD offspring. Simultaneously, in vivo 1H magnetic resonance spectroscopy (1H-MRS) data were collected to examine brain metabolite levels in the medial prefrontal cortex. Results showed that MAR-ASD offspring displayed decreased levels of choline-containing compounds and glutathione, accompanied by increased taurine compared to control animals. Overall, we found that rats exposed to MAR-ASD aAbs present with alterations in behavior, brain structure, and neurometabolites; reminiscent of findings observed in clinical ASD.

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.

Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = -.48 and -.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function-GSH-and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention.

Brain glutathione levels and age at onset of illness in chronic schizophrenia.

OBJECTIVE: Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia. METHODS: GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms. RESULTS: We found a negative correlation between GSH levels and age at onset (r = -0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076). CONCLUSION: Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.

Individual Differences in Resting Corticospinal Excitability Are Correlated with Reaction Time and GABA Content in Motor Cortex.

Individuals differ in the intrinsic excitability of their corticospinal pathways and, perhaps more generally, their entire nervous system. At present, we have little understanding of the mechanisms underlying these differences and how variation in intrinsic excitability relates to behavior. Here, we examined the relationship between individual differences in intrinsic corticospinal excitability, local cortical GABA levels, and reaction time (RT) in a group of 20 healthy human adults. We measured corticospinal excitability at rest with transcranial magnetic stimulation, local concentrations of basal GABA with magnetic resonance spectroscopy, and RT with a behavioral task. All measurements were repeated in two separate sessions, and tests of reliability confirmed the presence of stable individual differences. There was a negative correlation between corticospinal excitability and RT, such that larger motor-evoked potentials (MEPs) measured at rest were associated with faster RTs. Interestingly, larger MEPs were associated with higher levels of GABA in M1, but not in three other cortical regions. Together, these results suggest that individuals with more excitable corticospinal pathways are faster to initiate planned responses and have higher levels of GABA within M1, possibly to compensate for a more excitable motor system.SIGNIFICANCE STATEMENT This study brings together physiological, behavioral, and neurochemical evidence to examine variability in the excitability of the human motor system. Previous work has focused on state-based factors (e.g., preparedness, uncertainty), with little attention given to the influence of inherent stable characteristics. Here, we examined how the excitability of the motor system relates to reaction time and the regional content of the inhibitory neurotransmitter GABA. Importantly, motor pathway excitability and GABA concentrations were measured at rest, outside a task context, providing assays of intrinsic properties of the individuals. Individuals with more excitable motor pathways had faster reaction times and, paradoxically, higher concentrations of GABA. We propose that greater GABA capacity in the motor cortex counteracts an intrinsically more excitable motor system.

Dorsolateral Prefrontal Cortex GABA Concentration in Humans Predicts Working Memory Load Processing Capacity.

The discovery of neural mechanisms of working memory (WM) would significantly enhance our understanding of complex human behaviors and guide treatment development for WM-related impairments found in neuropsychiatric conditions and aging. Although the dorsolateral prefrontal cortex (DLPFC) has long been considered critical for WM, we still know little about the neural elements and pathways within the DLPFC that support WM in humans. In this study, we tested whether an individual's DLPFC gamma-aminobutryic acid (GABA) content predicts individual differences in WM task performance using a novel behavioral approach. Twenty-three healthy adults completed a task that measured the unique contribution of major WM components (memory load, maintenance, and distraction resistance) to performance. This was done to address the possibility that components have differing GABA dependencies and the failure to parse WM into components would lead to missing true associations with GABA. The subjects then had their DLPFC GABA content measured by single-voxel proton magnetic spectroscopy. We found that individuals with lower DLPFC GABA showed greater performance degradation with higher load, accounting for 31% of variance, p(corrected) = 0.015. This relationship was component, neurochemical, and brain region specific. DLPFC GABA content did not predict performance sensitivity to other components tested; DLPFC glutamate + glutamine and visual cortical GABA content did not predict load sensitivity. These results confirm the involvement of DLPFC GABA in WM load processing in humans and implicate factors controlling DLPFC GABA content in the neural mechanisms of WM and its impairments. SIGNIFICANCE STATEMENT: This study demonstrated for the first time that the amount of gamma-aminobutryic acid (GABA), the major inhibitory neurotransmitter of the brain, in an individual's prefrontal cortex predicts working memory (WM) task performance. Given that WM is required for many of the most characteristic cognitive and behavioral capabilities in humans, this finding could have a significant impact on our understanding of the neural basis of complex human behavior. Furthermore, this finding suggests that efforts to preserve or increase brain GABA levels could be fruitful in remediating WM-related deficits associated with neuropsychiatric conditions.

Acute Modulation of Cortical Glutamate and GABA Content by Physical Activity.

Converging evidence demonstrates that physical activity evokes a brain state characterized by distinctive changes in brain metabolism and cortical function. Human studies have shown that physical activity leads to a generalized increase in electroencephalography power across regions and frequencies, and a global increase in brain nonoxidative metabolism of carbohydrate substrates. This nonoxidative consumption of carbohydrate has been hypothesized to include increased de novo synthesis of amino acid neurotransmitters, especially glutamate and GABA. Here, we conducted a series of proton magnetic resonance spectroscopy studies in human volunteers before and after vigorous exercise (≥80% of predicted maximal heart rate). Results showed that the resonance signals of both glutamate and GABA increased significantly in the visual cortex following exercise. We further demonstrated a similar increase in glutamate following exercise in an executive region, the anterior cingulate cortex. The increase in glutamate was similar when using echo times of 30 and 144 ms, indicating that exercise-related T2 relaxation effects across this range of relaxation times did not account for the findings. In addition, we found preliminary evidence that more physical activity during the preceding week predicts higher resting glutamate levels. Overall, the results are consistent with an exercise-induced expansion of the cortical pools of glutamate and GABA, and add to a growing understanding of the distinctive brain state associated with physical activity. A more complete understanding of this brain state may reveal important insights into mechanisms underlying the beneficial effects of physical exercise in neuropsychiatric disorders, neurorehabilitation, aging, and cognition.

Individual differences in GABA content are reliable but are not uniform across the human cortex.

1H magnetic resonance spectroscopy (MRS) provides a powerful tool to measure gamma-aminobutyric acid (GABA), the principle inhibitory neurotransmitter in the human brain. We asked whether individual differences in MRS estimates of GABA are uniform across the cortex or vary between regions. In two sessions, resting GABA concentrations in the lateral prefrontal, sensorimotor, dorsal premotor, and occipital cortices were measured in twenty-eight healthy individuals. GABA estimates within each region were stable across weeks, with low coefficients of variation. Despite this stability, the GABA estimates were not correlated between regions. In contrast, the percentage of brain tissue per volume, a control measure, was correlated between the three anterior regions. These results provide an interesting dissociation between an anatomical measure of individual differences and a neurochemical measure. The different patterns of anatomy and GABA concentrations have implications for understanding regional variation in the molecular topography of the brain in health and disease.

Greater Choline-Containing Compounds and Myo-inositol in Treatment-Resistant Versus Responsive Schizophrenia: A 1H-Magnetic Resonance Spectroscopy Meta-analysis.

BACKGROUND: The neurobiology of treatment-resistant schizophrenia (TRS) is poorly understood, and meta-analytic consensus regarding magnetic resonance spectroscopic profiles of glutamate, choline-containing compounds, myo-inositol, and other metabolites in the condition is lacking. METHODS: In this meta-analysis, we examined published findings for N-acetylaspartate, choline-containing compounds (phosphocholine+glycerophosphocholine), myo-inositol, creatine+phosphocreatine, glutamate, and glutamate+glutamine in the anterior cingulate cortex and dorsal striatum in people with TRS versus non-TRS as well as TRS versus healthy control participants (HCs) and TRS versus ultra TRS (i.e., TRS with clozapine resistance). A MEDLINE search revealed 9 articles including 239 people with pooled TRS and ultra TRS, 59 with ultra TRS, 175 with non-TRS, and 153 (HCs) that met meta-analytic criteria. RESULTS: Significant effects included higher anterior cingulate cortex phosphocholine+glycerophosphocholine and myo-inositol in the pooled TRS and ultra TRS group than in both the non-TRS group and HCs as well as higher dorsal striatal phosphocholine+glycerophosphocholine in ultra TRS versus HCs, but no differences in other regional metabolites. CONCLUSIONS: The observed metabolite profile in TRS (higher phosphocholine+glycerophosphocholine and myo-inositol signal) is consistent with the hypothesis that TRS has a neuroinflammatory component, although this meta-analysis is not a critical test of that hypothesis. A similar profile is seen in healthy aging, which is known to involve increased neuroinflammation and glial activation. Because the overall number of datasets was low, however, results should be considered preliminary and highlight the need for additional studies of brain metabolites in TRS and their possible association with inflammatory processes.

Spectroscopic meta-analyses reveal novel metabolite profiles across methamphetamine and cocaine substance use disorder.

BACKGROUND: Although proton magnetic resonance spectroscopy (MRS) has been used to study metabolite alterations in stimulant (methamphetamine and cocaine) substance use disorders (SUDs) for over 25 years, data-driven consensus regarding the nature and magnitude of these alterations is lacking. METHOD: In this meta-analysis, we examined associations between SUD and regional metabolites (N-acetyl aspartate (NAA), choline, myo-inositol, creatine, glutamate, and glutamate+glutamine (glx)) in the medial prefrontal cortex (mPFC), frontal white matter (FWM), occipital cortex, and basal ganglia as measured by 1 H-MRS. We also examined moderating effects of MRS acquisition parameters (echo time (TE), field strength), data quality (coefficient of variation (COV)), and demographic/clinical variables. RESULTS: A MEDLINE search revealed 28 articles that met meta-analytic criteria. Significant effects included lower mPFC NAA, higher mPFC myo-inositol, and lower mPFC creatine in SUD relative to people without SUD. mPFC NAA effects were moderated by TE, with larger effects at longer TEs. For choline, although no group effects were observed, effect sizes in the mPFC were related to MRS technical indicators (field strength, COV). No effects of age, sex, primary drug of use (methamphetamine vs. cocaine), duration of use, or duration of abstinence were observed. Evidence for moderating effects of TE and COV may have implications for future MRS studies in SUDs. CONCLUSIONS: The observed metabolite profile in methamphetamine and cocaine SUD (lower NAA and creatine with higher myo-inositol) parallels that observed in Alzheimer's disease and mild cognitive impairment, suggesting these drugs are associated with neurometabolic differences similar to those characterizing these neurodegenerative conditions.

Meta-analytic evidence of elevated choline, reduced N-acetylaspartate, and normal creatine in schizophrenia and their moderation by measurement quality, echo time, and medication status.

BACKGROUND: Brain metabolite abnormalities measured with magnetic resonance spectroscopy (MRS) provide insight into pathological processes in schizophrenia. Prior meta-analyses have not yet answered important questions about the influence of clinical and technical factors on neurometabolite abnormalities and brain region differences. To address these gaps, we performed an updated meta-analysis of N-acetylaspartate (NAA), choline, and creatine levels in patients with schizophrenia and assessed the moderating effects of medication status, echo time, measurement quality, and other factors. METHODS: We searched citations from three earlier meta-analyses and the PubMed database after the most recent meta-analysis to identify studies for screening. In total, 113 publications reporting 366 regional metabolite datasets met our inclusion criteria and reported findings in medial prefrontal cortex (MPFC), dorsolateral prefrontal cortex, frontal white matter, hippocampus, thalamus, and basal ganglia from a total of 4445 patient and 3944 control observations. RESULTS: Patients with schizophrenia had reduced NAA in five of the six brain regions, with a statistically significant sparing of the basal ganglia. Patients had elevated choline in the basal ganglia and both prefrontal cortical regions. Patient creatine levels were normal in all six regions. In some regions, the NAA and choline differences were greater in studies enrolling predominantly medicated patients compared to studies enrolling predominantly unmedicated patients. Patient NAA levels were more reduced in hippocampus and frontal white matter in studies using longer echo times than those using shorter echo times. MPFC choline and NAA abnormalities were greater in studies reporting better metabolite measurement quality. CONCLUSIONS: Choline is elevated in the basal ganglia and prefrontal cortical regions, suggesting regionally increased membrane turnover or glial activation in schizophrenia. The basal ganglia are significantly spared from the well-established widespread reduction of NAA in schizophrenia suggesting a regional difference in disease-associated factors affecting NAA. The echo time findings agree with prior reports and suggest microstructural changes cause faster NAA T2 relaxation in hippocampus and frontal white matter in schizophrenia. Separating the effects of medication status and illness chronicity on NAA and choline abnormalities will require further patient-level studies. Metabolite measurement quality was shown to be a critical factor in MRS studies of schizophrenia.

Increased Striatal Presynaptic Dopamine in a Nonhuman Primate Model of Maternal Immune Activation: A Longitudinal Neurodevelopmental Positron Emission Tomography Study With Implications for Schizophrenia.

BACKGROUND: Epidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring. METHODS: In this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls. RESULTS: [18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months. CONCLUSIONS: These findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

Magnetic resonance spectroscopic evidence of increased choline in the dorsolateral prefrontal and visual cortices in recent onset schizophrenia.

A complete characterization of neurometabolite profiles in the dorsolateral prefrontal cortex (DLPFC) in recent onset schizophrenia (SZ) remains elusive. Filling in this knowledge gap is essential in order to better understand how the neurochemistry of this region contributes to SZ pathology. To that end, DLPFC N-acetyl aspartate (NAA), myo-inositol, glutamate, choline, and creatine levels were examined by 3 T magnetic resonance spectroscopy (MRS) in recent onset individuals with SZ (n = 40) and healthy controls (HC) (n = 47). Metabolite levels were also examined in the visual cortex (VC) as a control region. People with SZ showed significantly higher choline in both the DLPFC and VC, but no differences in NAA, myo-inositol, glutamate, or creatine in either region. A trend-level negative correlation was also observed between DLPFC NAA and negative symptoms in SZ. Our results suggest that choline is increased in both the prefrontal and occipital cortices in recent onset SZ, and that DLPFC NAA levels may be inversely related to negative symptoms in the illness. The observed increase in choline-containing compounds in both DLPFC and VC in recent onset SZ could reflect increased membrane remodeling such as occurs in activated microglia and astrocytes in response to neuroinflammation.

N-Acetylcysteine effects on glutathione and glutamate in schizophrenia: A preliminary MRS study.

N-acetylcysteine (NAC) is a commonly used antioxidant that may have beneficial effects for schizophrenia. In this double-blind, randomized, placebo-controlled preliminary study, 40 patients with schizophrenia or schizoaffective disorder were randomized to receive 2400 mg NAC daily or placebo over eight weeks to examine the effects of NAC on prefrontal magnetic resonance spectroscopy levels of glutathione and glutamate. Secondary outcomes included negative symptoms, cognition, and plasma glutathione levels. We found that NAC treatment was associated with increased glutathione (statistically significant) and decreased glutamate (trend-level) compared with placebo in medial prefrontal cortex but not dorsolateral prefrontal cortex. We also observed a baseline association between medial prefrontal cortex levels of glutathione and plasma reduced / oxidized glutathione ratios. No treatment effects on symptoms or cognition were observed. Taken together, these findings indicate that treatment with N-acetylcysteine may increase medial prefrontal cortical levels of glutathione after eight weeks of treatment. These changes in cortical levels of glutathione may serve as an early biomarker of later clinical change and may underlie the cognitive and symptomatic improvements reported in longer-term treatment studies.

GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression.

The neural mechanisms underlying cognitive deficits in schizophrenia remain essentially unknown. The GABA hypothesis proposes that reduced neuronal GABA concentration and neurotransmission results in cognitive impairments in schizophrenia. However, few in vivo studies have directly examined this hypothesis. We used magnetic resonance spectroscopy (MRS) at high field to measure visual cortical GABA levels in 13 subjects with schizophrenia and 13 demographically matched healthy control subjects. We found that the schizophrenia group had an approximately 10% reduction in GABA concentration. We further tested the GABA hypothesis by examining the relationship between visual cortical GABA levels and orientation-specific surround suppression (OSSS), a behavioral measure of visual inhibition thought to be dependent on GABAergic synaptic transmission. Previous work has shown that subjects with schizophrenia exhibit reduced OSSS of contrast discrimination (Yoon et al., 2009). For subjects with both MRS and OSSS data (n = 16), we found a highly significant positive correlation (r = 0.76) between these variables. GABA concentration was not correlated with overall contrast discrimination performance for stimuli without a surround (r = -0.10). These results suggest that a neocortical GABA deficit in subjects with schizophrenia leads to impaired cortical inhibition and that GABAergic synaptic transmission in visual cortex plays a critical role in OSSS.

Vigorous exercise increases brain lactate and Glx (glutamate+glutamine): a dynamic 1H-MRS study.

Vigorous exercise increases lactate and glucose uptake by the brain in excess of the increase in brain oxygen uptake. The metabolic fate of this non-oxidized carbohydrate entering the brain is poorly understood, but accumulation of lactate in the brain and/or increased net synthesis of amino acid neurotransmitters are possible explanations. Previous proton magnetic resonance spectroscopy (1H-MRS) studies using conventional pulse sequences have not detected changes in brain lactate following exercise. This contrasts with 1H-MRS studies showing increased brain lactate when blood lactate levels are raised by an intravenous infusion of sodium lactate. Using a J-editing 1H-MRS technique for measuring lactate, we demonstrated a significant 19% increase in lactate in the visual cortex following graded exercise to approximately 85% of predicted maximum heart rate. However, the magnitude of the increase was insufficient to account for more than a small fraction of the non-oxidized carbohydrate entering the brain with exercise. We also report a significant 18% increase in Glx (combined signal from glutamate and glutamine) in visual cortex following exercise, which may represent an activity-dependent increase in glutamate. Future studies will be necessary to test the hypothesis that non-oxidized carbohydrate entering the brain during vigorous exercise is directed, in part, toward increased net synthesis of amino acid neurotransmitters. The possible relevance of these findings to panic disorder and major depression is discussed.

Medial Prefrontal Cortex Glutamate Is Reduced in Schizophrenia and Moderated by Measurement Quality: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.

BACKGROUND: Magnetic resonance spectroscopy studies measuring brain glutamate separately from glutamine are helping elucidate schizophrenia pathophysiology. An expanded literature and improved methodologies motivate an updated meta-analysis examining effects of measurement quality and other moderating factors in characterizing abnormal glutamate levels in schizophrenia. METHODS: Searching previous meta-analyses and the MEDLINE database identified 83 proton magnetic resonance spectroscopy datasets published through March 25, 2020. Three quality metrics were extracted-Cramér-Rao lower bound (CRLB), line width, and coefficient of variation. Pooled effect sizes (Hedges' g) were calculated with random-effects, inverse variance-weighted models. Moderator analyses were conducted using quality metrics, field strength, echo time, medication, age, and stage of illness. RESULTS: Across 36 datasets (2086 participants), medial prefrontal cortex glutamate was significantly reduced in patients (g = -0.19, confidence interval [CI] = -0.07 to -0.32). CRLB and coefficient of variation quality subgroups significantly moderated this effect. Glutamate was significantly more reduced in studies with lower CRLB or coefficient of variation (g = -0.44, CI = -0.29 to -0.60, and g = -0.43, CI = -0.29 to -0.57, respectively). Studies using echo time ≤20 ms also showed significantly greater reduction in glutamate (g = -0.41, CI = -0.26 to -0.55). Across 11 hippocampal datasets, group differences and moderator effects were nonsignificant. Group effects in thalamus and dorsolateral prefrontal cortex were also nonsignificant. CONCLUSIONS: High-quality measurements reveal consistently reduced medial prefrontal cortex glutamate in schizophrenia. Stricter CRLB criteria and reduced nuisance variance may increase the sensitivity of future studies examining additional regions and the pathophysiological significance of abnormal glutamate levels in schizophrenia.

Delay discounting abnormalities are seen in first-episode schizophrenia but not in bipolar disorder.

Delay discounting (DD) is the phenomenon of individuals discounting future rewards as a function of time. It has been studied extensively in chronic schizophrenia (SZ) and the results of these studies have been variable. Comorbidity in chronic samples could be one reason for the mixed findings and studies in first-episode (FE) samples are surprisingly lacking. Bipolar disorder (BP) which shares some genetic and symptom features with SZ could serve as an interesting comparison group for DD but has been underexplored. Here we present the first study that combines FE SZ, FE BP with psychotic features, as well as healthy controls and study DD with two versions of the task. We found that SZ showed steeper discounting than HC and BP on the well-validated Kirby DD task. SZ showed no difference than HC on a separate DD task with smaller rewards presented with decimal places and shorter delays. As a preliminary finding, DD was found to be positively related to positive symptoms in FE SZ, while no relationship was found between negative symptoms and DD. In addition, we found comparable DD in BP compared to HC. Ultimately, our data may help elucidate the psychopathology in SZ and BP during intertemporal decision making.