Daniel H. Mathalon

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.

Event-Related EEG Time-Frequency Analysis: An Overview of Measures and An Analysis of Early Gamma Band Phase Locking in Schizophrenia

An increasing number of schizophrenia studies have been examining electroencephalography (EEG) data using time-frequency analysis, documenting illness-related abnormalities in neuronal oscillations and their synchronization, particularly in the gamma band. In this article, we review common methods of spectral decomposition of EEG, time-frequency analyses, types of measures that separately quantify magnitude and phase information from the EEG, and the influence of parameter choices on the analysis results. We then compare the degree of phase locking (ie, phase-locking factor) of the gamma band (36-50 Hz) response evoked about 50 milliseconds following the presentation of standard tones in 22 healthy controls and 21 medicated patients with schizophrenia. These tones were presented as part of an auditory oddball task performed by subjects while EEG was recorded from their scalps. The results showed prominent gamma band phase locking at frontal electrodes between 20 and 60 milliseconds following tone onset in healthy controls that was significantly reduced in patients with schizophrenia (P = .03). The finding suggests that the early-evoked gamma band response to auditory stimuli is deficiently synchronized in schizophrenia. We discuss the results in terms of pathophysiological mechanisms compromising event-related gamma phase synchrony in schizophrenia and further attempt to reconcile this finding with prior studies that failed to find this effect.

Anatomy of an error: ERP and fMRI.

Successful inhibition of pre-potent responses involves conflict; failed inhibition involves both conflict and errors, complicating the study of errors. Event-related potential (ERP) and functional magnetic resonance imaging (fMRI) data were collected while ten subjects (26-55 years old) performed a Go/NoGo task, with pre-potent responses (88% Go) and inhibition of responses (12% NoGo). We measured error-related negativity (ERN) to false alarms (FA), correct-related negativity (CRN) to hits, NoGo N2 to correct rejections (CR) and Go N2 to hits. ERP difference scores were derived (ERN-CRN; NoGoN2-GoN2) for correlating with fMRI contrasts (FA-hits; CR-hits). Age effects were removed from ERN and N2 difference scores, and conflict effects, reflected in N2 difference scores, were removed from ERN. The resulting ERN correlated with fMRI activations in both caudal and rostral anterior cingulate cortex (ACC), while N2 correlated with fMRI activations in caudal ACC and in executive control regions including dorsolateral prefrontal cortex. Thus, error and conflict monitoring may be dissociable, subserved by both overlapping and distinct ACC regions.

Reduced communication between frontal and temporal lobes during talking in schizophrenia

BACKGROUND Communication between the frontal lobes, where speech and verbal thoughts are generated, and the temporal lobes, where they are perceived, may occur through the action of a corollary discharge. Its dysfunction may underlie failure to recognize inner speech as self-generated and account for auditory hallucinations in schizophrenia. METHODS Electroencephalogram was recorded from 10 healthy adults and 12 patients with schizophrenia (DSM-IV) in two conditions: talking aloud and listening to their own played-back speech. Event-related electroencephalogram coherence to acoustic stimuli presented during both conditions was calculated between frontal and temporal pairs, for delta, theta, alpha, beta, and gamma frequency bands. RESULTS Talking produced greater coherence than listening between frontal-temporal regions in all frequency bands; however, in the lower frequencies (delta and theta), there were significant interactions of group and condition. This finding revealed that patients failed to show an increase in coherence during talking, especially over the speech production and speech reception areas of the left hemisphere, and especially in patients prone to hallucinate. CONCLUSIONS Reduced fronto-temporal functional connectivity may contribute to the misattribution of inner thoughts to external voices in schizophrenia.

Trait and state aspects of P300 amplitude reduction in schizophrenia: a retrospective longitudinal study.

BACKGROUND The P300 component of the auditory event-related brain potential (ERP) is consistently reduced in schizophrenia. Longitudinal data are examined to determine whether P300 amplitude is a trait marker of schizophrenia or a state marker tracking clinical fluctuations over time. METHODS Schizophrenic men (DSM-III-R) (n = 36) received ERP and the Brief Psychiatric Rating Scale (BPRS) assessments on multiple occasions, at varying intervals, under varying medication states. Automatically elicited auditory P3a and effortfully elicited auditory and visual P3b amplitudes were assessed. Brief Psychiatric Rating Scale scores were regressed on P300 amplitude within patients using both multiple regression models and nonparametric analyses of individual patient slopes. Event related brain potentials in patients were compared to ERPs from 34 age-matched control men, and stability of P300 over time was estimated with intraclass correlations. RESULTS P300 amplitude, regardless of elicitation method or sensory modality, tracked BPRS Total and positive symptom scores over time, decreasing with symptom exacerbations and increasing with improvements. In addition, effortful auditory and visual P3b amplitudes tracked negative symptoms, and automatic auditory P3a tracked depression-anxiety symptoms. When analyses were limited to unmedicated occasions, auditory P3a and P3b persisted in tracking BPRS Total scores, with additional tracking of positive symptoms by P3b and mood symptoms by P3a. Mean auditory and visual P3bs, averaged over all measurement occasions for each individual, were inversely related to mean negative symptoms. Auditory P3a and P3b, but not visual P3b, amplitudes were smaller in patients than control subjects, even when patients were least symptomatic. P300 amplitudes showed high test-retest reliability in control subjects and patients and moderate stability over time in patients. CONCLUSIONS Auditory, and possibly visual, P300 amplitudes track fluctuations in clinical state, but only auditory P300 amplitude is a trait marker of schizophrenia.

Age-related decline in MRI volumes of temporal lobe gray matter but not hippocampus

The effect of normal aging on the volume of the hippocampus and temporal cortex was assessed cross-sectionally with quantitative Magnetic Resonance Imaging (MRI) in 72 healthy men, spanning 5 decades of the adult age range (21 to 70 years). Neither the hippocampal nor cortical white matter volumes were significantly correlated with age. By contrast, left and right temporal lobe gray matter volumes, exclusive of the hippocampal measures, each decreased with age (p < 0.01). Volumes of temporal lobe sulcal CSF and the ventricular system (temporal horns and lateral and third ventricles) significantly increased with age. Measures of verbal and nonverbal working memory showed age-related declines and were related to enlargement of the three ventricular regions, which may be indicative of age-related atrophy of the adjacent cortex but not the hippocampus, at least up to age 70 years.

Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia.

Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical–subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.

Riluzole Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: An Open-Label Trial

BACKGROUND Most patients with obsessive-compulsive disorder (OCD) show only partial reduction of symptoms with standard therapy. Recent imaging data suggests glutamatergic dysfunction in the corticostriatal pathway in OCD. We investigated the efficacy of augmentation therapy with riluzole, a glutamate-modulating agent, in treatment-resistant OCD. METHODS Thirteen patients aged between 18 and 65 years with a primary diagnosis of OCD that had proven resistant to standard treatment were treated with the addition of riluzole to their existing pharmacotherapy. Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Inventory (HAM-D), and Hamilton Anxiety Inventory (HAM-A) scores were obtained weekly. RESULTS Thirteen treatment-resistant OCD patients received riluzole 50 mg twice a day. Y-BOCS scores improved significantly over time. Of 13 patients, 7 (54%) demonstrated a >35% reduction in Y-BOCS scores, and 5 (39%) were categorized as treatment responders. HAM-D and HAM-A scores for the group also significantly improved over time. Riluzole was well tolerated with no serious adverse effects noted. CONCLUSIONS Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties. The addition of this agent may be of practical clinical benefit in patients with OCD.

Working memory and DLPFC inefficiency in schizophrenia: The FBIRN study

BACKGROUND The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25) and intracranial volumes (d=−0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.