José M. Cañive

Baseline neurocognitive deficits in the CATIE schizophrenia trial

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An ‘all-comer’ approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13–0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an ‘all-comer’ clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Substance use in persons with schizophrenia: Baseline prevalence and correlates from the NIMH CATIE study

This study examined baseline correlates of substance use in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness project. Approximately 60% of the sample was found to use substances, including 37% with current evidence of substance use disorders. Users (with and without substance use disorders), compared with nonusers, were significantly more likely to be male, be African-American, have lower educational attainment, have a recent period of homelessness, report more childhood conduct problems, have a history of major depression, have lower negative symptom and higher positive symptom scores on the Positive and Negative Syndrome Scale, and have a recent illness exacerbation. Individuals with comorbid substance use disorders were significantly more likely to be male, report more childhood conduct problems, have higher positive symptom scores on the Positive and Negative Syndrome Scale, and have a recent illness exacerbation. These analyses suggest that substance use disorders in schizophrenia are especially common among men with a history of childhood conduct disorder problems and that childhood conduct disorder problems are potent risk factors for substance use disorders in schizophrenia.

Resting state and task-induced deactivation: A methodological comparison in patients with schizophrenia and healthy controls

Changes in the default mode network (DMN) have been linked to multiple neurological disorders including schizophrenia. The anticorrelated relationship the DMN shares with task‐related networks permits the quantification of this network both during task (task‐induced deactivations: TID) and during periods of passive mental activity (extended rest). However, the effects of different methodologies (TID vs. extended rest) for quantifying the DMN in the same clinical population are currently not well understood. Moreover, several different analytic techniques, including independent component analyses (ICA) and seed‐based correlation analyses, exist for examining functional connectivity during extended resting states. The current study compared both methodologies and analytic techniques in a group of patients with schizophrenia (SP) and matched healthy controls. Results indicated that TID analyses, ICA, and seed‐based correlation all consistently identified the midline (anterior and posterior cingulate gyrus) and lateral parietal cortex as core regions of the DMN, as well as more variable involvement of temporal lobe structures. In addition, SP exhibited increased deactivation during task, as well as decreased functional connectivity with frontal regions and increased connectivity with posterior and subcortical areas during periods of extended rest. The increased posterior and reduced anterior connectivity may partially explain some of the cognitive dysfunction and clinical symptoms that are frequently associated with schizophrenia. Hum Brain Mapp, 2010.

Commonalities and Differences Among Vectorized Beamformers in Electromagnetic Source Imaging

A number of beamformers have been introduced to localize neuronal activity using magnetoencephalography (MEG) and electroencephalography (EEG). However, currently available information about the major aspects of existing beamformers is incomplete. In the present study, detailed analyses are performed to study the commonalities and differences among vectorized versions of existing beamformers in both theory and practice. In addition, a novel beamformer based on higher-order covariance analysis is introduced. Theoretical formulas are provided on all major aspects of each beamformer; to examine their performance, computer simulations with different levels of correlation and signal-to-noise ratio are studied. Then, an empirical data set of human MEG median-nerve responses with a large number of neuronal generators is analyzed using the different beamformers. The results show substantial differences among existing MEG/EEG beamformers in their ways of describing the spatial map of neuronal activity. Differences in performance are observed among existing beamformers in terms of their spatial resolution, false-positive background activity, and robustness to highly correlated signals. Superior performance is obtained using our novel beamformer with higher-order covariance analysis in simulated data. Excellent agreement is also found between the results of our beamformer and the known neurophysiology of the median-nerve MEG response.

Divalproex in posttraumatic stress disorder: An open-label clinical trial

Posttraumatic stress disorder (PTSD) is characterized by intrusive, avoidance, and hyperarousal symptoms. This study was conducted to investigate the effectiveness of divalproex in reducing PTSD symptoms, depression, and anxiety in patients with PTSD. Sixteen patients with a DSM-IV diagnosis of PTSD at the Albuquerque VAMC outpatient PTSD treatment program received an open-label trial of divalproex. The patients were evaluated at baseline and at 8 weeks by a trained rater using the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A). Plasma valproate levels were measured at the 8-week post-treatment assessment. Three patients stopped the medications due to side effects. Intrusion and hyperarousal symptoms decreased significantly, while no significant change was seen in avoidance/numbing symptoms. Depressive symptoms, as measured by the HAM-D, unexpectedly decreased at post-treatment assessment. HAM-A scores also decreased significantly. Controlled trials are needed to further study the efficacy of divalproex in the treatment of PTSD.

Patterns of Gray Matter Abnormalities in Schizophrenia Based on an International Mega-analysis

Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both source-based morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects.

M50 sensory gating predicts negative symptoms in schizophrenia.

Impaired auditory sensory gating is considered characteristic of schizophrenia and a marker of the information processing deficit inherent to that disorder. Predominance of negative symptoms also reflects the degree of deficit in schizophrenia and is associated with poorer pre-morbid functioning, lower IQ, and poorer outcomes. However, a consistent relationship between auditory sensory gating and negative symptoms in schizophrenia has yet to be demonstrated. The absence of such a finding is surprising, since both impaired auditory gating and negative symptoms have been linked with impaired fronto-temporal cortical function. The present study measured auditory gating using the P50 event related potential (ERP) in a paired-click paradigm and capitalized on the relative localization advantage of magnetoencephalography (MEG) to assess auditory sensory gating in terms of the event related field (ERF) M50 source dipoles on bilateral superior temporal gyrus (STG). The primary hypothesis was that there would be a positive correlation between lateralized M50 auditory sensory gating measures and negative symptoms in patients with schizophrenia. A standard paired-click paradigm was used during simultaneous EEG and MEG data collection to determine S2/S1 sensory gating ratios in a group of 20 patients for both neuroimaging techniques. Participants were administered the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Consistent with previous reports, there was no relationship between ERP P50 sensory gating and negative symptoms. However, right (not left) hemisphere ERF M50 sensory gating ratio was significantly and positively correlated with negative symptoms. This finding is compatible with information processing theories of negative symptoms and with more recent findings of fronto-temporal abnormality in patients with predominantly negative symptoms.

Predicting EEG responses using MEG sources in superior temporal gyrus reveals source asynchrony in patients with schizophrenia

OBJECTIVE An integrated analysis using Electroencephalography (EEG) and magnetoencephalography (MEG) is introduced to study abnormalities in early cortical responses to auditory stimuli in schizophrenia. METHODS Auditory responses were recorded simultaneously using EEG and MEG from 20 patients with schizophrenia and 19 control subjects. Bilateral superior temporal gyrus (STG) sources and their time courses were obtained using MEG for the 30-100 ms post-stimulus interval. The MEG STG source time courses were used to predict the EEG signal at electrode Cz. RESULTS In control subjects, the STG sources predicted the EEG Cz recording very well (97% variance explained). In schizophrenia patients, the STG sources accounted for substantially (86%) and significantly (P<0.0002) less variance. After MEG-derived STG activity was removed from the EEG Cz signal, the residual signal was dominated by 40 Hz activity, an indication that the remaining variance in EEG is probably contributed by other brain generators, rather than by random noise. CONCLUSIONS Integrated MEG and EEG analysis can differentiate patients and controls, and suggests a basis for a well established abnormality in the cortical auditory response in schizophrenia, implicating a disorder of functional connectivity in the relationship between STG sources and other brain generators.

Interpreting abnormality: an EEG and MEG study of P50 and the auditory paired-stimulus paradigm.

Interpretation of neurophysiological differences between control and patient groups on the basis of scalp-recorded event-related brain potentials (ERPs), although common and promising, is often complicated in the absence of information on the distinct neural generators contributing to the ERP, particularly information regarding individual differences in the generators. For example, while sensory gating differences frequently observed in patients with schizophrenia in the P50 paired-click gating paradigm are typically interpreted as reflecting group differences in generator source strength, differences in the latency and/or orientation of P50 generators may also account for observed group differences. The present study examined how variability in source strength, amplitude, or orientation affects the P50 component of the scalp-recorded ERP. In Experiment 1, simulations examined the effect of changes in source strength, orientation, or latency in superior temporal gyrus (STG) dipoles on P50 recorded at Cz. In Experiment 2, within- and between-subject variability in left and right M50 STG dipole source strength, latency, and orientation was examined in 19 subjects. Given the frequently reported differences in left and right STG anatomy and function, substantial inter-subject and inter-hemispheric variability in these parameters were expected, with important consequences for how P50 at Cz reflects brain activity from relevant generators. In Experiment 1, simulated P50 responses were computed from hypothetical left- and right-hemisphere STG generators, with latency, amplitude, and orientation of the generators varied systematically. In Experiment 2, electroencephalographic (EEG) and magnetoencephalographic (MEG) data were collected from 19 subjects. Generators were modeled from the MEG data to assess and illustrate the generator variability evaluated parametrically in Experiment 1. In Experiment 1, realistic amounts of variability in generator latency, amplitude, and orientation produced ERPs in which P50 scoring was compromised and interpretation complicated. In Experiment 2, significant within and between subject variability was observed in the left and right hemisphere STG M50 sources. Given the variability in M50 source strength, orientation, and amplitude observed here in nonpatient subjects, future studies should examine whether group differences in P50 gating ratios typically observed for patient vs. control groups are specific to a particular hemisphere, as well as whether the group differences are due to differences in dipole source strength, latency, orientation, or a combination of these parameters. Present analyses focused on P50/M50 merely as an example of the broader need to evaluate scalp phenomena in light of underlying generators. The development and widespread use of EEG/MEG source localization methods will greatly enhance the interpretation and value of EEG/MEG data.

Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

OBJECTIVE The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. METHOD In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. RESULTS Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. CONCLUSIONS Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.