Corollary discharge dysfunction in schizophrenia: can it explain auditory hallucinations?

Failure of corollary discharge, a mechanism for distinguishing self-generated from externally generated percepts, has been posited to underlie certain positive symptoms of schizophrenia, including auditory hallucinations. Although originally described in the visual system, corollary discharge may exist in the auditory system, whereby signals from motor speech commands prepare auditory cortex for self-generated speech. While associated with sensorimotor systems, it might also apply to inner speech or thought, regarded as our most complex motor act. In this paper, we describe the results of a series of studies in which we have shown that: (1) event-related brain potentials (ERPs) can be used to demonstrate the corollary discharge phenomenon during talking, (2) corollary discharge is abnormal in patients with schizophrenia, (3) EEG gamma band coherence between frontal and temporal lobes is greater during talking than listening and is disrupted by distorted feedback during talking in normals, and (4) patients with schizophrenia do not show this pattern for EEG gamma coherence. While these studies have identified ERPs and EEG gamma coherence indices of the efference copy/corollary discharge system and documented abnormalities in these systems in patients with schizophrenia, we have so far had limited success in establishing a relationship between these neurobiologic indicators of corollary discharge abnormality and reports of hallucinations in patients.     

Increase in brain cerebrospinal fluid volume is greater in older than in younger alcoholic patients: A replication study and CT/MRI comparison

This cross-sectional study used a semi-automated analysis technique to quantify regional brain cerebrospinal fluid (CSF) volumes derived from computed tomography (CT) in 84 healthy men ranging from 21 to 82 years of age and 28 patients meeting Research Diagnostic Criteria for alcohol dependence. The goals were to replicate an earlier CT study of an independent sample of alcoholic and control subjects (Pfefferbaum et al., 1988a; Zipursky et al., 1988) and to compare CT assessments of brain changes with magnetic resonance imaging (MRI) assessments made in the same alcoholic patients (Pfefferbaum et al., 1992). Regional brain changes associated with normal aging were derived by regression analysis, using CT data collected from the healthy control subjects. As in the earlier CT study and in the concurrent MRI study, ventricular and sulcal CSF volumes in alcoholic patients were greater than would be expected for their age. Furthermore, the present CT study replicated the previous CT and MRI findings of a positive relationship between age and CSF volume enlargement in alcoholic patients over and above the normal age-related increase in CSF volume, suggesting greater vulnerability of the aging brain to alcohol. Comparison of CT-and MRI-derived estimates of ventricular and cortical sulcal volume revealed high correlations (>0.80). MRI and CT produced similar absolute ventricular volumes, while MRI produced larger sulcal volume estimates than did CT. The difference in sulcal volume estimate may be due to differences between CT and MRI in slice thickness and sensitivity to partial volume effects.     

Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia

BACKGROUND: It is controversial whether cerebellar tissue volume deficits occur in schizophrenia and, if so, what regions and tissue types are affected. Complicating such investigations is the high incidence of alcoholism comorbidity in patients with schizophrenia that itself can contribute to cerebellar abnormalities. METHOD: We studied 61 healthy men (control subjects), 25 men with alcoholism, 27 men with schizophrenia, and 19 men comorbid for schizophrenia and alcoholism with the use of magnetic resonance imaging. Cerebellar structures were outlined manually, tissue classification was determined statistically, and regional volumes were corrected for normal variation in head size and age. RESULTS: Patients with schizophrenia alone had enlarged fourth ventricles (1.5 SD relative to controls) but showed no cerebellar tissue volume deficits. The alcoholic group had gray and white matter vermian deficits (-0.5 SD), most prominent in anterior superior lobules, and gray matter hemisphere deficits (-0.8 SD), but not fourth ventricle enlargement. The comorbid group had cerebellar hemisphere (-1.3 SD) and vermian gray matter volume deficits (-0.7 SD) and fourth ventricular enlargement (1.6 SD); these abnormalities were greater than in either single-diagnosis group, despite significantly lower levels of alcohol consumption compared with the alcoholic group. Gray matter volume in the anterior superior vermis correlated with lifetime alcohol consumption in the schizophrenic and comorbid groups when combined. CONCLUSIONS: Cerebellar tissue volume deficits were detected in schizophrenia only when accompanied by alcoholism. By contrast, fourth ventricular enlargement occurred in schizophrenia even without alcoholism, although it was exacerbated by alcoholism. These findings support a model of cerebellar supersensitivity to alcohol-related tissue volume deficits in schizophrenia.     

Functional Magnetic Resonance Imaging of Motor Cortex Activation in Schizophrenia

Previous fMRI studies of sensorimotor activation in schizophrenia have found in some cases hypoactivity, no difference, or hyperactivity when comparing patients with controls; similar disagreement exists in studies of motor laterality. In this multi-site fMRI study of a sensorimotor task in individuals with chronic schizophrenia and matched healthy controls, subjects responded with a right-handed finger press to an irregularly flashing visual checker board. The analysis includes eighty-five subjects with schizophrenia diagnosed according to the DSM-IV criteria and eighty-six healthy volunteer subjects. Voxel-wise statistical parametric maps were generated for each subject and analyzed for group differences; the percent Blood Oxygenation Level Dependent (BOLD) signal changes were also calculated over predefined anatomical regions of the primary sensory, motor, and visual cortex. Both healthy controls and subjects with schizophrenia showed strongly lateralized activation in the precentral gyrus, inferior frontal gyrus, and inferior parietal lobule, and strong activations in the visual cortex. There were no significant differences between subjects with schizophrenia and controls in this multi-site fMRI study. Furthermore, there was no significant difference in laterality found between healthy controls and schizophrenic subjects. This study can serve as a baseline measurement of schizophrenic dysfunction in other cognitive processes.

Graphical Abstract

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Brain Gray and White Matter Volume Loss Accelerates with Aging in Chronic Alcoholics: A Quantitative MRI Study

Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.     

Bullying in clinical high risk for psychosis participants from the NAPLS-3 cohort

Purpose

Bullying is associated with a heightened risk for poor outcomes, including psychosis. This study aimed to replicate previous findings on bullying prevalence in clinical high-risk (CHR) individuals, to assess the longitudinal course of clinical and functional variables between bullied and non-bullied CHR and the association of bullying with premorbid functioning, clinical outcome, transition to psychosis and risk of violence.

Methods

The sample consisted of 691 CHR participants and 96 healthy controls. Participants reported whether they had experienced bullying and how long it had lasted. Assessments included DSM-5 diagnoses, attenuated psychotic symptoms, negative symptoms, social and role functioning, depression, stress, premorbid functioning, and risk of violence. The bullied and non-bullied CHR groups were compared at baseline and further longitudinally on clinical and functioning variables and transition to psychosis.

Results

Bullying was more prevalent among CHR individuals than healthy controls. Bullied CHR had a higher prevalence of PTSD and more severe depression and stress at baseline than non-bullied CHR. There was no impact of bullying on clinical and functional variables over time. Bullying was not related to final clinical status or transition to psychosis. However, bullied participants had poorer premorbid functioning and a greater risk of violence.

Conclusion

While bullying may not impact the likelihood of CHR individuals to transition to psychosis, it may be a risk factor for development of the at-risk state and may be related to a greater risk of violence. Future studies should consider bullying perpetration among CHR individuals.

     

Working Memory Overload: Fronto-Limbic Interactions and Effects on Subsequent Working Memory Function

The human working memory system provides an experimentally useful model for examination of neural overload effects on subsequent functioning of the overloaded system. This study employed functional magnetic resonance imaging in conjunction with a parametric working memory task to characterize the behavioral and neural effects of cognitive overload on subsequent cognitive performance, with particular attention to cognitive-limbic interactions. Overloading the working memory system was associated with varying degrees of subsequent decline in performance accuracy and reduced activation of brain regions central to both task performance and suppression of negative affect. The degree of performance decline was independently predicted by three separate factors operating during the overload condition: the degree of task failure, the degree of amygdala activation, and the degree of inverse coupling between the amygdala and dorsolateral prefrontal cortex. These findings suggest that vulnerability to overload effects in cognitive functioning may be mediated by reduced amygdala suppression and subsequent amygdala-prefrontal interaction.     

Fine-tuning of auditory cortex during speech production

The cortex suppresses sensory information when it is the result of a self-produced motor act, including the motor act of speaking. The specificity of the auditory cortical suppression to self-produced speech, a prediction derived from the posited operation of a precise forward model system, has not been established. We examined the auditory N100 component of the event-related brain potential elicited during speech production. While subjects uttered a vowel, they heard real-time feedback of their unaltered voice, their pitch-shifted voice, or an alien voice substituted for their own. The subjects' own unaltered voice feedback elicited a dampened auditory N100 response relative to the N100 elicited by altered or alien auditory feedback. This is consistent with the operation of a precise forward model modulating the auditory cortical response to self-generated speech and allowing immediate distinction of self and externally generated auditory stimuli.     

Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging

BACKGROUND: Schizophrenia is associated with deficits in using context to establish prepotent responses in complex paradigms and failures to inhibit prepotent responses once established. OBJECTIVE: To assess prepotent response establishment and inhibition in patients with schizophrenia using event-related brain potential (ERP) and functional magnetic resonance imaging (fMRI) in a simple NoGo task. To combine fMRI and ERP data to focus on fMRI activations associated with the brief (approximately 200 ms) moment of context updating reflected in the NoGo P300 ERP component. DESIGN AND SETTING: We collected ERP and fMRI data while subjects performed a NoGo task requiring a speedy button press to X stimuli (P=.88) but not to K stimuli (P=.12). The ERPs were collected at the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif; fMRIs were collected at Stanford University, Stanford, Calif. PARTICIPANTS: We recruited patients with DSM-IV schizophrenia (n=11) from the community and the VA hospital and sex- and age-matched healthy control subjects (n=11) from the community. MAIN OUTCOME MEASURES: Behavioral accuracy, P300 amplitudes and latencies, and fMRI activations suggested that patients with schizophrenia did not establish as strong a prepotent tendency to respond to the Go stimulus as healthy subjects. In healthy subjects, NoGo P300 was related to activations in the anterior cingulate cortex, dorsal lateral prefrontal cortex, and right inferior parietal lobule and caudate nucleus, perhaps reflecting conflict experienced when withholding a response, control needed to inhibit a response, and stopping a response in action, respectively. In patients with schizophrenia, NoGo P300 was modestly related to activations in the anterior cingulate cortex, which is consistent with experiencing conflict. CONCLUSIONS: The difference in ERP and fMRI responses to Go and NoGo stimuli suggested that inhibiting a response was easier for patients with schizophrenia than for healthy subjects. Correlations of P300 and fMRI data suggested that patients with schizophrenia and healthy subjects used different neural structures to inhibit responses, with healthy subjects using a more complex system.