Search

Background and Hypothesis Hallucinations may be driven by an excessive influence of prior expectations on current experience. Initial work has supported that contention and implicated the anterior insula in the weighting of prior beliefs. Study Design Here we induce hallucinated tones by associating tones with the presentation of a visual cue. We find that people with schizophrenia who hear voices are more prone to the effect and using computational modeling we show they overweight their prior beliefs. In the same participants, we also measured glutamate levels in anterior insula, anterior cingulate, dorsolateral prefrontal, and auditory cortices, using magnetic resonance spectroscopy. Study Results We found a negative relationship between prior-overweighting and glutamate levels in the insula that was not present for any of the other voxels or parameters. Conclusions Through computational psychiatry, we bridge a pathophysiological theory of psychosis (glutamate hypofunction) with a cognitive model of hallucinations (prior-overweighting) with implications for the development of new treatments for hallucinations. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental illness with visual learning and memory deficits, and reduced long term potentiation (LTP) may underlie these impairments. Recent human fMRI and EEG studies have assessed visual plasticity that was induced with high frequency visual stimulation, which is thought to mimic an LTP-like phenomenon. This study investigated the differences in visual plasticity in participants with schizophrenia and healthy controls. An fMRI visual plasticity paradigm was implemented, and proton magnetic resonance spectroscopy data were acquired to determine whether baseline resting levels of glutamatergic and GABA metabolites were related to visual plasticity response. Adults with schizophrenia did not demonstrate visual plasticity after family-wise error correction; whereas, the healthy control group did. There was a significant regional difference in visual plasticity in the left visual cortical area V2 when assessing group differences, and baseline GABA levels were associated with this specific ROI in the SZ group only. Overall, this study suggests that visual plasticity is altered in schizophrenia and related to basal GABA levels. [ABSTRACT FROM AUTHOR]

Occupational exposure to hypobaria (low atmospheric pressure) is a risk factor for reduced white matter integrity, increased white matter hyperintensive burden, and decline in cognitive function. We tested the hypothesis that a discrete hypobaric exposure will have a transient impact on cerebral physiology. Cerebral blood flow, fractional anisotropy of water diffusion in cerebral white matter, white matter hyperintensity volume, and concentrations of neurochemicals were measured at baseline and 24 hr and 72 hr postexposure in N = 64 healthy aircrew undergoing standard US Air Force altitude chamber training and compared to N = 60 controls not exposed to hypobaria. We observed that hypobaric exposure led to a significant rise in white matter cerebral blood flow (CBF) 24 hr postexposure that remained elevated, albeit not significantly, at 72 hr. No significant changes were observed in structural measurements or gray matter CBF. Subjects with higher baseline concentrations of neurochemicals associated with neuroprotection and maintenance of normal white matter physiology (glutathione, N‐acetylaspartate, glutamate/glutamine) showed proportionally less white matter CBF changes. Our findings suggest that discrete hypobaric exposure may provide a model to study white matter injury associated with occupational hypobaric exposure. [ABSTRACT FROM AUTHOR]

Regulation of stress response involves top-down mechanisms of the frontal-limbic glutamatergic system. As schizophrenia is associated with glutamatergic abnormalities, we hypothesized that schizophrenia patients may have abnormal glutamatergic reactivity within the dorsal anterior cingulate cortex (dACC), a key region involved in perception of and reaction to stress. To test this, we developed a somatic stress paradigm involving pseudorandom application of safe but painfully hot stimuli to the forearm of participants while they were undergoing serial proton magnetic resonance spectroscopy to measure changes in glutamate and glutamine levels in the dACC. This paradigm was tested in a sample of 21 healthy controls and 23 patients with schizophrenia. Across groups, glutamate levels significantly decreased following exposure to thermal pain, while ratio of glutamine to glutamate significantly increased. However, schizophrenia patients exhibited an initial increase in glutamate levels during challenge that was significantly different from controls, after controlling for heat pain tolerance. Furthermore, in patients, the acute glutamate response was positively correlated with childhood trauma (r = .41, P = .050) and inversely correlated with working memory (r = -.49, P = .023). These results provide preliminary evidence for abnormal glutamatergic response to stress in schizophrenia patients, which may point toward novel approaches to understanding how stress contributes to the illness. [ABSTRACT FROM AUTHOR]

Importance: Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge.Objective: To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia.Design, Setting, and Participants: Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015.Main Outcomes and Measures: Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance.Results: The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia.Conclusions and Relevance: The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia. [ABSTRACT FROM AUTHOR]

The major excitatory and inhibitory neurotransmitters, glutamate (Glu) and gamma-aminobutyric acid (GABA), respectively, are implicated in the pathophysiology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide that modulates the Glu system, may also be altered in schizophrenia. This study investigated GABA, Glu + glutamine (Glx), and NAAG levels in younger and older subjects with schizophrenia. Forty-one subjects, 21 with chronic schizophrenia and 20 healthy controls, participated in this study. Proton magnetic resonance spectroscopy (1H-MRS) was used to measure GABA, Glx, and NAAG levels in the anterior cingulate (AC) and centrum semiovale (CSO) regions. NAAG in the CSO was higher in younger schizophrenia subjects compared with younger control subjects. The opposite pattern was observed in the older groups. Glx was reduced in the schizophrenia group irrespective of age group and brain region. There was a trend for reduced AC GABA in older schizophrenia subjects compared with older control subjects. Poor attention performance was correlated to lower AC GABA levels in both groups. Higher levels of CSO NAAG were associated with greater negative symptom severity in schizophrenia. These results provide support for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia. The study also highlights the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia. [ABSTRACT FROM PUBLISHER]

Abstract: Glutamate, a major excitatory neurotransmitter, has been implicated as an important mediator in the neurotransmission, potentiation, and negative affect associated with pain. We present results showing that a painful stimulus elicits a dynamic increase in glutamate (9.3% from baseline) concentrations in the anterior cingulate cortex, detectable using proton Magnetic Resonance Spectroscopy (1H-MRS). Increases in glutamine levels were also seen, which correlate strongly with the subjective level of pain experienced by participants (r 2 = 0.58, P &#60; 0.01). These novel findings are the first time a dynamic change in glutamate and glutamine levels from baseline in response to an external stimuli has been measured in a single proton MRS scanning session. As such, this report demonstrates the efficacy of 1H-MRS as a non-invasive tool for the study of neural responses to pain in vivo. The paradigm used in this study demonstrates that dynamic glutamate/glutamine changes due to stimulation are measurable by proton MRS, and could provide a means of testing novel pharmaceutical agents and other treatments for chronic pain. [Copyright &y& Elsevier]

Objective: Previous proton magnetic resonance spectroscopy (1H-MRS) studies in posttraumatic stress disorder (PTSD) report decreased hippocampal N-acetylaspartate (NAA), an indicator of neuronal integrity. However, other areas of the brain need to be explored. The objective of this study was to investigate the specificity of hippocampal NAA concentration changes in PTSD by also examining a control region, the occipital white matter (OWM).Methods: Eight patients with PTSD and 5 control subjects underwent single-voxel 1H-MRS of the hippocampi and bilateral OWM. Absolute neurometabolite concentrations were determined.Preliminary Results: Trends toward reduced left hippocampal NAA and creatine (Cre) were found in the PTSD group. PTSD subjects also had reduced bilateral OWM Cre.Conclusions: The preliminary results of our study in civilians with PTSD replicate previous MRS studies and are consistent with decreased hippocampal neuronal integrity without effects in the OWM. Replication of our findings is needed. [ABSTRACT FROM AUTHOR]

Reduced frontal N-acetylaspartate (NAA) has been repeatedly found in chronic schizophrenia and suggests neuronal loss or dysfunction. However, the potential confounding effect of antipsychotic drugs on NAA has not been resolved. The few studies of antipsychotic-naı̈ve patients are inconclusive. A recent report suggests that antipsychotic drugs may increase NAA in the dorsolateral prefrontal cortex (DLPFC). We studied 10 minimally treated (less than 3 weeks lifetime exposure) schizophrenia patients and 10 normal controls with single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the left frontal and occipital lobes. Concentrations of NAA, Cho, and Cre were determined and corrected for the proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a randomized-controlled double-blind design with either haloperidol or quetiapine. 1H-MRS was repeated within a year. There were no differences in frontal or occipital NAA between patients and controls at baseline. However, frontal NAA was reduced in the schizophrenia group within the first year of treatment. Patients had a clear clinical response to treatment but changes in frontal NAA were not correlated with symptom improvement. The well-described reduced frontal NAA in schizophrenia may not be a trait of the illness but may represent medication effect or progression of the disease. [Copyright &y& Elsevier]

Background: Magnetic resonance spectroscopy (MRS) methods have quantified changes in levels of neurotransmitters and neurometabolites in patients with major depression across the lifespan. The application of 7T field strengths and greater have not been a major focus of study in patients with late-life depression (LLD).Methods: Nine LLD patients who met DSM-IV criteria for a current major depressive episode and nine non-depressed, healthy, age-matched controls underwent clinical and neuropsychological assessment and single-voxel 7T 1H-MRS at baseline and after 10-12 weeks of antidepressant treatment (Citalopram; patients only). Spectra were acquired from two brain regions implicated in both depressive symptoms and neuropsychological deficits in LLD, the anterior (ACC) and posterior cingulate (PCC). Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr) using linear-combination modeling.Results: Baseline Glu/tCr levels were not significantly different between groups. Decreased Glu/tCr levels after Citalopram treatment were observed in a subset of LLD patients. Exploratory analyses showed that LLD patients had lower NAA levels in the PCC relative to controls. Higher levels of ml in the LLD patients relative to the controls and decreases after Citalopram treatment had large effect sizes but were not statistically significant. Further, decreases in PCC Glu/tCr and increases in ACC GSH/tCr were associated with improvement in depressive symptoms.Limitations: Sample size.Conclusions: These preliminary results suggest a role of neurochemicals and neurometabolites in the neurobiology of LLD and antidepressant treatment response. [ABSTRACT FROM AUTHOR]

Memory is robustly impaired in schizophrenia (SZ) and related to functional outcome. Memory dysfunction has been shown to be related to altered brain glucose metabolism and brain insulin resistance in animal models and human studies of Alzheimer's disease. In this study, differences in brain glucose using magnetic resonance spectroscopy (MRS) and blood Extracellular Vesicle (EV) biomarkers of neuronal insulin resistance (i.e. Akt and signaling effectors) between SZ and controls were investigated, as well as whether these measures were related to memory impairments. Neuronal insulin resistance biomarkers showed a trend for being lower in SZ compared to controls, and memory measures were lower in SZ compared to controls. Occipital cortex glucose was higher in SZ compared to controls indicating lower brain glucose utilization. Linear regression analyses revealed significant relationships between neuronal insulin resistance biomarkers, memory measures, and brain glucose. More specifically, p70S6K, an insulin signaling effector, was related to verbal learning and brain MRS glucose in the SZ group. For the first time, we show that memory impairments in SZ may be related to brain glucose and brain insulin resistance. These data suggest that brain insulin resistance may play a role in the pathophysiology of learning and memory dysfunction in SZ. [ABSTRACT FROM AUTHOR]

Highlights • 1H-magnetic resonance spectroscopy (1H-MRS) was performed in miniature pigs. • Age effects on 1H-MRS measures were similar to those reported in adolescent humans. • 1H-MRS predicted diffusion metrics, suggesting cerebral white matter maturation. Abstract Background We are developing the miniature pig (Sus scrofa domestica), an in-vivo translational, gyrencephalic model for brain development, as an alternative to laboratory rodents/non-human primates. We analyzed longitudinal changes in adolescent pigs using proton magnetic resonance spectroscopy (1H-MRS) and examined the relationship with white matter (WM) integrity derived from diffusion weighted imaging (DWI). New method Twelve female Sinclair™ pigs underwent three imaging/spectroscopy sessions every 23.95 ± 3.73 days beginning at three months of age using a clinical 3 T scanner. 1H-MRS data were collected using 1.2 × 1.0 × 3.0 cm voxels placed in left and right hemisphere WM using a Point Resolved Spectroscopy sequence (TR = 2000 ms, TE = 30 ms). Concentrations of N -acetylaspartate, myo-inositol (MI), glutamate + glutamine, choline, creatine, and macromolecules (MM) 09 and 14 were averaged from both hemispheres. DWI data were collected using 15 shells of b-values (b = 0–3500 s/mm2) with 32 directions/shell and fit using the WM Tract Integrity model to calculate fractional anisotropy (FA), kurtosis anisotropy (KA) and permeability-diffusivity index. Results MI and MM09 significantly declined with age. Increased FA and KA significantly correlated with decline in MI and MM09. Correlations lost significance once corrected for age. Comparison with existing methods MRI scanners/protocols can be used to collect 1H-MRS and DWI data in pigs. Pigs have a larger, more complex, gyrencephalic brain than laboratory rodents but are less complex than non-human primates, thus satisfying the "replacement" principle of animal research. Conclusions Longitudinal effects in MRS measurements were similar to those reported in adolescent humans. MRS changes correlated with diffusion measurements indicating ongoing WM myelination/maturation. [ABSTRACT FROM AUTHOR]

In vivo measurement of neurotransmitters and modulators is now feasible with advanced proton magnetic resonance spectroscopy ( 1 H MRS) techniques. This review provides a basic tutorial of MRS, describes the methods available to measure brain glutamate, glutamine, γ-aminobutyric acid, glutathione, N -acetylaspartylglutamate, glycine, and serine at magnetic field strengths of 3 T or higher, and summarizes the neurochemical findings in schizophrenia. Overall, 1 H MRS holds great promise for producing biomarkers that can serve as treatment targets, prediction of disease onset, or illness exacerbation in schizophrenia and other brain diseases. [ABSTRACT FROM AUTHOR]