Meredith A. Reid

Neurometabolites in schizophrenia and bipolar disorder — A systematic review and meta-analysis

This meta-analysis evaluates alterations of neurometabolites in schizophrenia and bipolar disorder. PubMed was searched to find controlled studies evaluating N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr) assessed with ((1))H-MRS (proton magnetic resonance spectroscopy) in patients with schizophrenia and bipolar disorder up to September 2010. Random effects meta-analyses were conducted to estimate pooled standardized mean differences. The statistic was used to quantify inconsistencies. Subgroup analyses were conducted to explore potential explanations for inconsistencies. The systematic review included 146 studies with 5643 participants. NAA levels were affected in schizophrenia and bipolar disorder. Decreased levels in the basal ganglia and frontal lobe were the most consistent findings in schizophrenia; decreased levels in the basal ganglia were the most consistent findings in bipolar disorder. Cho and Cr levels were not altered in either disorder. Findings for Cr were most consistent in the thalamus, frontal lobe and dorsolateral prefrontal cortex in schizophrenia and the basal ganglia and frontal lobe in bipolar disorder. Findings for Cho were most consistent in the thalamus, frontal lobe and anterior cingulate cortex in schizophrenia and basal ganglia in bipolar disorder. Large, carefully designed studies are needed to better estimate the extent of alterations in neurometabolites.

Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia.

IMPORTANCE Alterations in glutamatergic neurotransmission have been postulated to be a key pathophysiologic mechanism in schizophrenia. OBJECTIVE To evaluate hippocampal volumetric measures and neurometabolites in unmedicated patients with schizophrenia and the correlations between these markers. Our a priori hypothesis was that glutamate levels would negatively correlate with hippocampal volume in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Combined 3-T structural magnetic resonance imaging and single-voxel proton magnetic resonance spectroscopy study at the Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, of 27 unmedicated patients with schizophrenia and 27 healthy controls. MAIN OUTCOMES AND MEASURES Hippocampal volumetric measures and neurometabolites, and the correlations between volumetric measurements and neurometabolites. RESULTS Hippocampal volumetric deficits, increased ratios of hippocampal glutamate and glutamine to creatine (Glx/Cr), and a loss of correlation between hippocampal N-acetylaspartate (NAA)/Cr and Glx/Cr in patients with schizophrenia were found. Significant correlations between hippocampal volumetric measures and Glx/Cr were also found in patients with schizophrenia but not healthy controls. CONCLUSIONS AND RELEVANCE Our findings support the theory that alterations in hippocampal glutamate levels potentially account for structural deficits in the hippocampus observed in schizophrenia neuroimaging studies.

Assessments of Function and Biochemistry of the Anterior Cingulate Cortex in Schizophrenia

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.

Regional Decoupling of N -acetyl-aspartate and Glutamate in Schizophrenia

Proton magnetic resonance spectroscopy (1H-MRS) allows the non-invasive measurement of several metabolites, including N-acetyl-aspartate (NAA), an amino acid exclusively synthesized in the mitochondria of neurons, and glutamate, an amino acid involved in excitatory neurotransmission and metabolism. In view of recent postmortem studies in schizophrenia (SZ) revealing mitochondrial abnormalities as well as perturbed expression of the enzymes regulating the glutamate–glutamine cycle, we hypothesized that a disruption in the homeostasis of NAA and glutamate in SZ is present. Fifty subjects with SZ and 48 matched healthy controls (HC) were enrolled in this 1H-MRS study. Voxels were placed in the anterior cingulate cortex (ACC) and hippocampus; NAA/Cr and glutamate + glutamine (Glx)/Cr ratios were obtained. We did not find any significant differences between the groups in metabolite levels in both the ACC and hippocampus. In the hippocampus we found that NAA/Cr and Glx/Cr ratios were significantly correlated in HC (r=0.40, p<0.01 (corrected p=0.048)) but not in SZ (r=−0.06; p=0.71), a difference that was statistically significant (z=2.22, p=0.02). Although no differences in neurometabolites between SZ and HC were apparent, correlations between NAA/Cr and Glx/Cr in healthy subjects in the hippocampus were found, and this correlation was lost in subjects with SZ. To our knowledge, this is the first study to suggest decoupling of these metabolites, a pathophysiological change that may be unique to SZ. However, these results warrant replication and further exploration before definite conclusions can be drawn.

SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma

SLC7A11, the catalytic subunit of the cystine/glutamate antiporter, System xc− (SXC), is up-regulated in a subpopulation of patient gliomas, where it is responsible for excitotoxic glutamate release, accelerated tumor growth, and tumor-associated seizures. Seizing an opportunity to study glioma Gliomas are the most common type of malignant brain tumors, and they frequently cause seizures. A new study by Robert et al. uncovers some of the mechanisms involved in this process, showing how a specific cystine/glutamate transporter contributes to excitotoxic glutamate release, causing the death of surrounding cells and inducing seizures. The authors also showed that tumors expressing this transporter were more aggressive and grew more quickly, possibly because the destruction of surrounding normal cells allowed the tumors to expand more rapidly. These findings suggest that the expression of this cystine/glutamate transporter may be useful as a predictor of outcome and a potential therapeutic target in glioma. Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc− (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse-propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration–approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures.

Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication.

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto‐temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto‐temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1‐week of antipsychotic treatment. Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto‐temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1‐week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto‐temporal dysconnectivity. Patterns of fronto‐temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits. Hum Brain Mapp 36:1442–1457, 2015.

Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging

BACKGROUND Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia. METHODS We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC). RESULTS The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr. CONCLUSIONS We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.

Hippocampal-parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia.

Abnormalities in resting state connectivity in schizophrenia (SZ) are now well established, but the biological substrates of these functional alterations remain to be elucidated. We performed a combined functional magnetic resonance imaging and magnetic resonance spectroscopy study in 22 unmedicated patients with SZ and 22 matched healthy controls (HCs) to evaluate resting state functional connectivity of the hippocampus and Glx/Cr (a combined glutamate + glutamine peak normalized to creatine) in the hippocampus and investigate functional and neurometabolic abnormalities and examine the relationship between these. Functional connectivity between the left hippocampus and bilateral precuneus was significantly decreased in unmedicated patients with SZ when compared to HCs [t(4.22), cluster extent (kE) = 751, PFDRcorr = 0.001, Montreal Neurological Institute coordinates: x = −4, y = −56, z = 44]. Glx/Cr in the hippocampus was significantly elevated in SZ (HC: mean = 0.60+/−0.10 SZ: 0.67+/−0.10; F = 5.742; P = 0.02), but was not correlated with functional connectivity deficits (P > 0.05). In this study, we found hippocampal resting state functional connectivity deficits to the precuneus in unmedicated patients with SZ and an increase of Glx/Cr in the hippocampus, but did not observe a direct relationship between these abnormalities. However, our findings do not exclude the possibility of a shared underlying pathology, which warrants further investigation.

An fMRI investigation of delay discounting in patients with schizophrenia

Schizophrenia (SZ) is associated with a reduced ability to set meaningful goals to reach desired outcomes. The delay‐discounting (DD) task, in which one chooses between sooner smaller and later larger rewards, has proven useful in revealing executive function and reward deficits in various clinical groups. We used fMRI in patients with SZ and healthy controls (HC) to compare brain activation during performance of a DD task. Prior to the neuroimaging session, we obtained each participants rate of DD, k, on a DD task and used it to select a version of the DD task for each participants fMRI session. Because of the importance of comparing fMRI results from groups matched on performance, we used a criterion value of R2 > 0.60 for response consistency on the DD task to analyze fMRI activation to DD task versus control trials from consistent SZ (n = 14) and consistent HC (n = 14). We also compared activation between the groups on contrasts related to trial difficulty. Finally, we contrasted the inconsistent SZ (n = 9) with the consistent HC and consistent SZ; these results should be interpreted with caution because of inconsistent SZs aberrant performance on the task. Compared with consistent HC, consistent SZ showed reduced activation to DD task versus control trials in executive function and reward areas. In contrast, consistent SZ showed more activation in the precuneus and posterior cingulate, regions of the default mode network (DMN) that are typically deactivated during tasks, and in the insula, a region linked to emotional processing. Furthermore, consistent SZ had abnormal activation of lateral and medial frontal regions in relation to trial difficulty. These results point to disruption of several neural networks during decision making, including the executive, reward, default mode, and emotional networks, and suggest processes that are impaired during decision making in schizophrenia.

Delay discounting and task performance consistency in patients with schizophrenia

To study impaired goal-oriented behavior in schizophrenia (SZ), we used a delay discounting task, which consists of a series of choices between receiving a small immediate or larger delayed reward. Few studies of delay discounting have evaluated response consistency (R(2)), which is especially relevant in SZ because of documented inconsistency in task performance. We calculated the rate of discounting (k) and R(2) in SZ (n=35) and healthy controls (HC; n=21). Using a criterion value of R(2)>0.60 to define consistent performance allowed us to compare discounting in consistent SZ and HC, as well as in inconsistent SZ. Groups did not differ significantly in smoking. Compared to HC, consistent SZ showed greater delay discounting. Both groups exhibited similar patterns of decreasing immediate choices across trial categories, although the decrease was less for SZ. Separate analyses on smokers and non-smokers showed that this group difference was carried by the non-smokers. Inconsistent SZ discounted more than HC and consistent SZ, but their aberrant pattern of choices casts doubt on the validity of their calculated k values.