Christopher C. Abbott

What have we learned from proton magnetic resonance spectroscopy about schizophrenia? A critical update.

Purpose of review This review discusses recent studies investigating schizophrenia with proton magnetic resonance spectroscopy including the first meta-analysis [Steen RG, Hamer RM, Lieberman JA. Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis. Neuropsychology 2005; 30:1949–1962]. We also highlight methodological issues and suggest a modality for future research to further explore glutamatergic dysfunction in schizophrenia. Recent findings Despite methodological differences, spectroscopy studies with schizophrenia show reductions in N-acetylaspartate in the medial temporal and prefrontal regions. Other areas such as the anterior cingulate, parietal cortex thalamus, and cerebellum may also have N-acetylaspartate reductions. The proton magnetic resonance spectroscopy studies at higher fields and with shorter echo time have revealed abnormalities in glutamate and glutamine. Animal studies have shown that the discrepancies in metabolites between patients and controls are not due to antipsychotic medication exposure, and that chronic exposure to N-methyl-D-aspartate antagonists has produced decreased N-acetylaspartate in the temporal cortex. The human and animal studies both support an excitoxic glutamatergically mediated process that may explain decreased N-acetylaspartate, volume loss, and the poor outcomes of schizophrenia. Summary Use of higher field strengths and longitudinal studies may reveal a progressive excitoxic glutamatergic process that leads to N-acetylaspartate and volume reductions. This may lead to the development of neuroprotective agents that change the course of schizophrenia.

Hippocampal structural and functional changes associated with electroconvulsive therapy response

Previous animal models and structural imaging investigations have linked hippocampal neuroplasticity to electroconvulsive therapy (ECT) response, but the relationship between changes in hippocampal volume and temporal coherence in the context of ECT response is unknown. We hypothesized that ECT response would increase both hippocampal resting-state functional magnetic resonance imaging connectivity and hippocampal volumes. Patients with major depressive disorder (n=19) were scanned before and after the ECT series. Healthy, demographically matched comparisons (n=20) were scanned at one-time interval. Longitudinal changes in functional connectivity of hippocampal regions and volumes of hippocampal subfields were compared with reductions in ratings of depressive symptoms. Right hippocampal connectivity increased (normalized) after the ECT series and correlated with depressive symptom reduction. Similarly, the volumes of the right hippocampal cornu ammonis (CA2/3), dentate gyrus and subiculum regions increased, but the hippocampal subfields were unchanged relative to the comparison group. Connectivity changes were not evident in the left hippocampus, and volume changes were limited to the left CA2/3 subfields. The laterality of the right hippocampal functional connectivity and volume increases may be related to stimulus delivery method, which was predominately right unilateral in this investigation. The findings suggested that increased hippocampal functional connectivity and volumes may be biomarkers for ECT response.

Electroconvulsive therapy response in major depressive disorder: a pilot functional network connectivity resting state fMRI investigation

Major depressive disorder (MDD) is associated with increased functional connectivity in specific neural networks. Electroconvulsive therapy (ECT), the gold-standard treatment for acute, treatment-resistant MDD, but temporal dependencies between networks associated with ECT response have yet to be investigated. In the present longitudinal, case–control investigation, we used independent component analysis to identify distinct networks of brain regions with temporally coherent hemodynamic signal change and functional network connectivity (FNC) to assess component time course correlations across these networks. MDD subjects completed imaging and clinical assessments immediately prior to the ECT series and a minimum of 5 days after the last ECT treatment. We focused our analysis on four networks affected in MDD: the subcallosal cingulate gyrus, default mode, dorsal lateral prefrontal cortex, and dorsal medial prefrontal cortex (DMPFC). In an older sample of ECT subjects (n = 12) with MDD, remission associated with the ECT series reverses the relationship from negative to positive between the posterior default mode (p_DM) and two other networks: the DMPFC and left dorsal lateral prefrontal cortex (l_DLPFC). Relative to demographically healthy subjects (n = 12), the FNC between the p_DM areas and the DMPFC normalizes with ECT response. The FNC changes following treatment did not correlate with symptom improvement; however, a direct comparison between ECT remitters and non-remitters showed the pattern of increased FNC between the p_DM and l_DLPFC following ECT to be specific to those who responded to the treatment. The differences between ECT remitters and non-remitters suggest that this increased FNC between p_DM areas and the left dorsolateral prefrontal cortex is a neural correlate and potential biomarker of recovery from a depressed episode.

Increased Glutamine in Patients Undergoing Long-term Treatment for Schizophrenia : A Proton Magnetic Resonance Spectroscopy Study at 3 T

IMPORTANCE The N-methyl-d-aspartic acid receptor hypofunction model of schizophrenia predicts a paradoxical increase in synaptic glutamate release. In vivo measurement of glutamatergic neurotransmission in humans is challenging, but glutamine, the principal metabolite of synaptic glutamate, can be quantified with proton magnetic resonance spectroscopy (1H-MRS). Although a few studies have measured glutamate, glutamine, and glutamine to glutamate ratio, it is not clear which of these 1H-MRS indices of glutamatergic neurotransmission is altered in schizophrenia. OBJECTIVE To examine glutamine, glutamate, and glutamine to glutamate ratio in the dorsal anterior cingulate, as well as their relationships with symptoms and cognition in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional design using 3-T 1H-MRS in participants recruited from university-based psychiatric outpatient clinics who underwent neuroimaging at an affiliated research facility. Participants were 84 patients with a DSM-IV-TR diagnosis of schizophrenia and 81 psychiatrically healthy volunteers, matched in age, sex, ethnicity, and occupational level to the head of household of family of origin. MAIN OUTCOMES AND MEASURES Glutamine, glutamate, and glutamine to glutamate ratio. Also symptoms and cognition. RESULTS Glutamine was increased in the schizophrenia group (P = .01) as well as the glutamine to glutamate ratio (P = .007) but not glutamate (P = .89). Glutamine levels were positively correlated with severity of psychotic symptoms (P = .02). Choline was also increased in schizophrenia (P = .002). CONCLUSIONS AND RELEVANCE Elevated glutamine, which was directly related to psychotic symptoms, is consistent with increased glutamatergic synaptic release in schizophrenia, as predicted by the N-methyl-d-aspartic acid receptor hypofunction model. Further understanding the underlying mechanism of glutamatergic dysfunction in schizophrenia may lead to new pharmacological strategies to treat psychosis.

Antipsychotic Dose and Diminished Neural Modulation: A Multi-Site fMRI Study

BACKGROUND The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation. METHODS Seventy-nine medicated patients with schizophrenia and 114 comparison subjects from the Mind Clinical Imaging Consortium database completed a paced, auditory motor task during functional magnetic resonance imaging (fMRI). Independent component analysis identified temporally cohesive but spatially distributed neural networks. The independent component analysis time course was regressed with a model time course of the experimental design. The resulting beta weights were evaluated for group comparisons and correlations with chlorpromazine equivalents. RESULTS Group differences between patients and comparison subjects were evident in the cortical and subcortical motor networks, default mode networks, and attentional networks. The chlorpromazine equivalents correlated with the unimotor/bitemporal (rho=-0.32, P=0.0039), motor/caudate (rho=-0.22, P=0.046), posterior default mode (rho=0.26, P=0.020), and anterior default mode networks (rho=0.24, P=0.03). Patients on typical antipsychotics also had less positive modulation of the motor/caudate network relative to patients on atypical antipsychotics (t(77)=2.01, P=0.048). CONCLUSION The results suggest that antipsychotic dose diminishes neural activation in motor (cortical and subcortical) and default mode networks in patients with schizophrenia. The higher potency, typical antipsychotics also diminish positive modulation in subcortical motor networks. Antipsychotics may be a potential confound limiting interpretation of fMRI studies on the disease process in medicated patients with schizophrenia.

Reliability of the amplitude of low-frequency fluctuations in resting state fMRI in chronic schizophrenia

The resting state amplitude of low frequency fluctuations (ALFF) in functional magnetic resonance imaging has been shown to be reliable in healthy subjects, and to correlate with antipsychotic treatment response in antipsychotic-naïve schizophrenia patients. We found moderate to high test-retest stability of ALFF in chronically treated schizophrenia patients assessed twice over a median interval of 2.5 months.

Source-Based Morphometry Analysis of Group Differences in Fractional Anisotropy in Schizophrenia

A multivariate source-based morphometry (SBM) method for processing fractional anisotropy (FA) data is presented. SBM utilizes independent component analysis (ICA) and decomposes an FA image into spatial maps and loading coefficients. The loading coefficients represent the relative degree each component contributes to a given subjects FA map. We hypothesized that SBM analysis on a large dataset of age- and gender-matched patients with schizophrenia (n=65, ages 18-60 years) and healthy controls (n=102, ages 18-60 years) would show a similar, specific pattern of frontal and temporal group differences as a recent voxel-based morphometry meta-analysis. Two approaches using (a) the loading coefficients obtained from the ICA analysis and, alternatively, (b) the weighted mean FA values obtained from the ICA-defined clusters were compared for group analysis. Six of the 10 selected components had significant group differences with the loading coefficients. Each component was composed of several white matter tracts distributed throughout the brain. Nine of the 10 nonartifactual components had significant group differences with the weighted mean FA values. The weighted mean FA values for each ICA spatial map generally had larger effects sizes relative to the loading coefficients. These networks were consistent with regions identified in previous voxel-based studies of schizophrenia. SBM identified several components that covered disjoint brain regions and multiple white matter tracts that would not have been possible with previous voxel-based univariate techniques. Overall, these results suggest the importance of utilizing multivariate approaches in morphometric studies in schizophrenia.

A Review of Longitudinal Electroconvulsive Therapy Neuroimaging Investigations

Electroconvulsive therapy (ECT) is the most effective treatment for a depressive episode but the mechanism of action and neural correlates of response are poorly understood. Different theories have suggested that anticonvulsant properties or neurotrophic effects are related to the unique mechanism of action of ECT. This review assessed longitudinal imaging investigations (both structural and functional) associated with ECT response published from 2002 to August 2013. We identified 26 investigations that used a variety of different imaging modalities and data analysis methods. Despite these methodological differences, we summarized the major findings of each investigation and identified common patterns that exist across multiple investigations. The ECT response is associated with decreased frontal perfusion, metabolism, and functional connectivity and increased volume and neuronal chemical metabolites. The general collective of longitudinal neuroimaging investigations support both the anticonvulsant and the neurotrophic effects of ECT. We propose a conceptual framework that integrates these seemingly contradictory hypotheses.

The Paradoxical Relationship between White Matter, Psychopathology and Cognition in Schizophrenia: A Diffusion Tensor and Proton Spectroscopic Imaging Study.

White matter disruption has been repeatedly documented in schizophrenia consistent with microstructural disorganization (reduced fractional anisotropy (FA)) and axonal dysfunction (reduced N-acetylaspartate NAAc). However, the clinical significance of these abnormalities is poorly understood. Diffusion tensor and proton spectroscopic imaging where used to assess FA, axial diffusivity and radial diffusivity (RD), and supra-ventricular white matter NAAc, respectively, in 64 schizophrenia and 64 healthy subjects. Schizophrenia patients had reduced FA across several regions, with additional regions where FA correlated positively with positive symptoms severity. These regions included genu, body and splenium of corpus callosum, anterior and superior corona radiata, superior longitudinal and inferior fronto-occipital fasciculi, and internal capsule. The FA/symptoms relationships corresponded with opposite correlations between RD and positive symptoms. The schizophrenia group (SP group) had progressively reduced NAAc with age, and NAAc correlated negatively with positive symptoms. Cognition correlated positively with both FA and NAAc in controls, whereas in the SP group it had a negative correlation with NAAc and no significant relationship with FA. Antipsychotic dose did not account for the results. Correlates of psychosis, cognitive and negative symptoms can be found in white matter. The significant correlations between positive symptoms in schizophrenia and diffusion and NAAc measures suggest decreased axonal density with increased glial cells and higher myelination in this subpopulation. A separate set of abnormal relationships between cognition and FA/RD, as well as with NAAc, converge to suggest that in schizophrenia, white matter microstructure supports the two core illness domains: psychosis and cognitive/negative symptoms.

Post-electroconvulsive therapy recovery and reorientation time with methohexital and ketamine: a randomized, longitudinal, crossover design trial.

Objectives Methohexital, a barbiturate anesthetic commonly used for electroconvulsive therapy (ECT), possesses dose-dependent anticonvulsant properties, and its use can interfere with effective seizure therapy in patients with high seizure thresholds. Ketamine, an N-methyl-d-aspartate antagonist with epileptogenic properties not broadly used for ECT inductions, is a commonly used induction agent for general anesthesia. Recent studies suggest that the use of ketamine is effective in allowing successful ECT treatment in patients with high seizure thresholds without an increase in adverse effects. In this preliminary study, we directly compared the recovery and reorientation times of subjects receiving ketamine and methohexital for ECTs. Methods Twenty patients were randomized in a crossover design to receive methohexital and ketamine for ECT inductions in alternating fashion in 6 trials. Primary outcome measures were recovery time (voluntary movement, respiratory effort, blood pressure, consciousness, and O2 saturation) and reorientation time. Secondary outcome measures were individual recovery variables, adverse effect occurrence, and seizure duration. Results Overall recovery time was not significantly different between the 2 treatment arms (F(1, 17) = 0.72; P = 0.41). Reorientation time was faster in the methohexital arm (F(1, 17) = 9.23; P = 0.007). Conclusion Ketamine inductions resulted in higher number of adverse effects, higher subject dropout rates, and a longer reorientation time with respect to methohexital inductions. No significant difference in postanesthesia recovery time was found between the ketamine and methohexital arms. Intolerability to ketamine affected a significant proportion of subjects and suggests that ketamine should remain as an alternative or adjunctive agent for patients with high seizure thresholds.