The functional neuroanatomy of schizophrenic subsyndromes.

BACKGROUND: There is considerable variability between patients in their expression of the diverse range of symptoms encompassed by the syndrome of schizophrenia, which may modulate functional activation to cognitive processing. METHOD: Here we investigate associations between schizophrenic subsyndrome scores, identified by factor analysis, and experimentally controlled brain activation. Five factors were defined by rotated principal components analysis of PANSS rating scale measurements in 100 patients with schizophrenia. A subsample of 30 patients and a group of 27 comparison subjects were studied using functional magnetic resonance imaging (fMRI) during the performance of two periodically designed cognitive activation experiments: verbal working memory and psychomotor sequencing. RESULTS: Factor analysis replicated the five dimensions consistently reported. Within the patient group. power of activation by working memory was negatively associated with global symptom severity in left lingual and temporo-parietal cortices; negatively associated with positive subsyndrome scores in left inferior frontal and superior temporal cortices and basal ganglia; and positively associated with negative subsyndrome scores in lateral and medial premotor cortex. No relationship was observed between subsyndrome scores and functional activation during the motor task. Between-group comparisons demonstrated reduced power of response to the working memory task by patients in bilateral dorsolateral prefrontal and left pre- and post-central cortices. CONCLUSIONS: In this study we observed task-specific modulation of functional response associated with symptom expression in schizophrenia. Our findings are compatible with previous empirical findings and theoretical conceptualization of human brain function, in terms of capacity constraints on activation in the face of competing demands from pathological and task-related cognitive activity.

An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function.

Functional magnetic resonance imaging (fMRI) was used to investigate the hypothesis that schizophrenia is associated with a dysfunction of prefrontal brain regions during motor response inhibition. Generic brain activation of six male medicated patients with schizophrenia was compared to that of seven healthy comparison subjects matched for sex, age, and education level while performing 'stop' and 'go-no-go' tasks. No group differences were observed in task performance. Patients, however, showed reduced BOLD signal response in left anterior cingulate during both inhibition tasks and reduced left rostral dorsolateral prefrontal and increased thalamus and putamen BOLD signal response during stop task performance. Despite good task performance, patients with schizophrenia thus showed abnormal neural network patterns of reduced left prefrontal activation and increased subcortical activation when challenged with motor response inhibition.

Experience of caregiving: relatives of people experiencing a first episode of psychosis.

BACKGROUND: There has been relatively little research on caregivers of people experiencing their first episode of psychosis. AIMS: To investigate dimensions of caregiving and morbidity in caregivers of people with first-episode psychosis. METHOD: Caregivers of 40 people with first-episode psychosis were interviewed at home about their experience of caregiving, coping strategies and distress. RESULTS: Caregivers used emotional and practical strategies to cope with participants' negative symptoms and difficult behaviours and experienced more worry about these problems. They increased supervision when the participants displayed difficult behaviours. Twelve per cent of caregivers were suffering from psychiatric morbidity as defined by the General Health Questionnaire. Those living with the participant had more frequent visits to their general practitioner. CONCLUSIONS: At first-episode psychosis, caregivers are already having to cope with a wide range of problems and are developing coping strategies. Caregivers worried most about difficult behaviours and negative symptoms in participants.

Third ventricle enlargement and developmental delay in first-episode psychosis: preliminary findings.

BACKGROUND: Third rather than lateral ventriculomegaly may be a more specific finding in psychosis. The relevance of ventricular abnormality remains unclear. AIMS: To investigate the developmental correlates of ventricular enlargement. METHOD: Information on childhood development and magnetic resonance images in 1.5-mm contiguous sections were collected on 21 patients experiencing a first episode of psychosis. RESULTS: Patients (n = 21) had significantly less whole brain volume and enlarged third and lateral ventricles compared to controls (n = 25). Third ventricle (r = 0.48, P < 0.03) and lateral ventricle (r = 0.65, P < 0.01) volumes correlated with developmental score. Patients with developmental delay had significantly larger third and lateral ventricles than those without. CONCLUSIONS: Enlargement of both third and lateral ventricles is found in first-episode psychosis and is related to developmental delay in childhood. Insult to periventricular areas is relevant to the neurobiology of the disease. These findings support the view that schizophrenia involves disturbance of neurodevelopmental processes in some patients.

Exploring the social brain in schizophrenia: left prefrontal underactivation during mental state attribution.

OBJECTIVE: Evidence suggests that patients with schizophrenia have a deficit in "theory of mind," i.e., interpretation of the mental state of others. The authors used functional magnetic resonance imaging (MRI) to investigate the hypothesis that patients with schizophrenia have a dysfunction in brain regions responsible for mental state attribution. METHOD: Mean brain activation in five male patients with schizophrenia was compared to that in seven comparison subjects during performance of a task involving attribution of mental state. RESULTS: During performance of the mental state attribution task, the patients made more errors and showed less blood-oxygen-level-dependent signal in the left inferior frontal gyrus. CONCLUSIONS: To the authors' knowledge, this is the first functional MRI study to show a deficit in the left prefrontal cortex in schizophrenia during a socioemotional task.

Features of structural brain abnormality detected in first-episode psychosis.

OBJECTIVE: Structural magnetic resonance imaging (MRI) studies that focus on first-episode psychosis avoid some common confounds, such as chronicity of illness, treatment effects, and long-term substance abuse. However, such studies may select subjects with poor short-term treatment response or outcome. In this study, the authors focus on structural brain abnormalities in never or minimally treated patients who underwent MRI scanning early in their first episode of psychosis. METHOD: The authors examined 37 patients (13 medication naive, 24 previously treated) who were experiencing their first episode of psychosis; the mean duration of symptoms was short (31 weeks). These patients were comparable in age, gender, handedness, ethnicity, and parental socioeconomic status to a group of 25 healthy comparison subjects. A three-dimensional, inversion recovery prepared, fast spoiled gradient/recall in the steady state scan of the whole brain that used 1.5-mm contiguous sections was performed to acquire a T(1)-weighted data set. Human ratings of volumetric measurement of brain structures were performed with stereological techniques on three-dimensional reconstructed MRIs. RESULTS: The patient group had significant deficits in cortical gray matter, temporal lobe gray matter, and whole brain volume as well as significant enlargement of the lateral and third ventricles. Structural deviations were found in both treatment-naive and minimally treated subjects. No relationships were found between any brain matter volumes and positive or negative symptoms. CONCLUSIONS: Structural brain abnormalities were distributed throughout the cortex with particular decrement evident in gray matter. This feature is consistent with altered cell structure and disturbed neuronal connectivity, which accounts for the functional abnormality of psychosis.

Neuropsychological functioning in first-episode psychosis--evidence of specific deficits.

Neuropsychological impairment is ubiquitous in schizophrenia even at the first presentation of psychotic symptoms. We sought to elucidate the nature of the neuropsychological profile at the onset of the illness by examining the neuropsychological functioning of 40 patients experiencing their first episode of psychosis and 22 matched controls. All participants completed a battery of neuropsychological tasks designed to assess attention, verbal learning/memory, non-verbal memory, spatial ability, psychomotor speed, and executive function. First-episode patients showed significant impairment on tasks of executive function, including those requiring the ability to form and initiate a strategy, to inhibit prepotent responses, and to shift cognitive set, and also on tasks of verbal fluency. Memory impairments were seen on verbal learning and delayed non-verbal memory only. Impairment on tasks of psychomotor speed suggests that there may be a significant amount of cognitive slowing even at the first onset of psychosis. We suggest that our patients may be experiencing difficulty in specific aspects of executive functions, including the ability to form and execute a strategy, and these difficulties may be mediating the deficits observed on tasks of verbal learning.

Prepulse inhibition of the startle response in men with schizophrenia: effects of age of onset of illness, symptoms, and medication.

BACKGROUND: Prepulse inhibition of the startle reflex response refers to the ability of a weak prestimulus to transiently inhibit the response to a closely following strong sensory stimulus. This effect represents an operational index of sensorimotor gating and is found to be deficient in schizophrenia. Prepulse inhibition deficits in schizophrenia seem to be partially normalized by typical antipsychotics and more fully by some atypical antipsychotics. Early onset of schizophrenia, particularly in men, has been associated with abnormal brain maturation, profound neuropsychological deficits, and less responsiveness to antipsychotic medication. We evaluated the effects of the age of onset of illness, current positive and negative symptoms, and the type of medication (typical vs atypical) on prepulse inhibition of the startle response in schizophrenia. METHODS: Thirty-eight male schizophrenic patients and 20 healthy male controls underwent testing for prepulse inhibition of the acoustic startle response. RESULTS: Earlier onset of illness was associated with reduced prepulse inhibition, while adult onset of illness was not. No significant relationships occurred between current symptoms and prepulse inhibition. Patients given typical, but not atypical, antipsychotics exhibited less prepulse inhibition compared with healthy controls. CONCLUSION: Early onset of illness is associated with profound deficits in prepulse inhibition of the startle response in men with schizophrenia.

Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia.

Antipsychotic drug treatment of schizophrenia may be complicated by side effects of widespread dopaminergic antagonism, including exacerbation of negative and cognitive symptoms due to frontal cortical hypodopaminergia. Atypical antipsychotics have been shown to enhance frontal dopaminergic activity in animal models. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of schizophrenia would be associated with enhanced functional activation of frontal cortex. We measured cerebral blood oxygenation changes during periodic performance of a verbal working memory task, using functional MRI, on two occasions (baseline and 6 weeks later) in two cohorts of schizophrenic patients. One cohort (n = 10) was treated with typical antipsychotic drugs throughout the study. Risperidone was substituted for typical antipsychotics after baseline assessment in the second cohort (n = 10). A matched group of healthy volunteers (n = 10) was also studied on a single occasion. A network comprising bilateral dorsolateral prefrontal and lateral premotor cortex, the supplementary motor area, and posterior parietal cortex was activated by working memory task performance in both the patients and comparison subjects. A two-way analysis of covariance was used to estimate the effect of substituting risperidone for typical antipsychotics on power of functional response in the patient group. Substitution of risperidone increased functional activation in right prefrontal cortex, supplementary motor area, and posterior parietal cortex at both voxel and regional levels of analysis. This study provides direct evidence for significantly enhanced frontal function in schizophrenic patients after substitution of risperidone for typical antipsychotic drugs, and it indicates the potential value of functional MRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.

Normalization of information processing deficits in schizophrenia with clozapine.

OBJECTIVE: The authors tested the hypothesis that the use of an atypical drug, clozapine, for patients with schizophrenia is related to less impairment in information processing deficits (assessed by prepulse inhibition of the startle response) than is the use of typical antipsychotics. METHOD: Two groups of schizophrenic patients--receiving either clozapine or a range of typical antipsychotics--were tested for prepulse inhibition (a reduction in response to a starting stimulus, if preceded briefly by a weak, nonstartling stimulus; measured at prepulse-to-pulse intervals of 30 msec, 60 msec, and 120 msec) of the acoustic startle response and compared with a group of healthy volunteers. RESULTS: Patients receiving typical antipsychotics showed less prepulse inhibition with 30-msec and 60-msec prepulse trials than did comparison subjects. Clozapine-treated patients showed normal levels of prepulse inhibition. CONCLUSIONS: Clozapine is superior to typical antipsychotics in normalizing prepulse inhibition, presumably because of its pharmacological effects on prefrontal regions of the brain or its effects on a broader range of neuroreceptors.

Effective treatment of schizophrenia with quetiapine in a 34-year-old Caucasian man.

This case history reports on the sustained clinical efficacy of quetiapine in a 34-year-old man with chronic paranoid schizophrenia, who was a partial responder to traditional therapy. Quetiapine was found to be effective against both positive and negative symptoms of schizophrenia, and had an excellent safety profile. The patient, who had also suffered from alcohol dependency, decreased his alcohol consumption as a result of responding to therapy, and successfully became re-integrated into society.