A broad cortical reserve accelerates response to cognitive enhancement therapy in early course schizophrenia.

OBJECTIVES: Cognitive rehabilitation can improve cognition in schizophrenia and prevent disability. It is unknown, however, whether a greater neurobiologic reserve, as measured by cortical volumes, will predict a favorable response to rehabilitation. We investigated this question in early course schizophrenia patients treated with Cognitive Enhancement Therapy (CET). METHODS: Outpatients in the early course of schizophrenia or schizoaffective disorder were randomly assigned to CET (n=29) or an Enriched Supportive Therapy control (n=21) and treated for two years. Cortical surface area and gray matter volume data were collected before treatment using structural magnetic resonance imaging. Neurocognition and social cognition were assessed before, and after one and two years of treatment. Moderator analyses examined the impact of pre-treatment cortical surface area and gray matter volume on differential neurocognitive and social-cognitive response to CET. RESULTS: Pre-treatment, whole brain cortical surface area and gray matter volume significantly moderated the effects of CET on social cognition, but not neurocognition. Greater neurobiologic reserve predicted a rapid social-cognitive response to CET in the first year of treatment; patients with less neurobiologic reserve achieved a comparable social-cognitive response by the second year. While nearly every regional measurement significantly contributed to this accelerated social-cognitive treatment response, effects were the strongest in the temporal cortex. CONCLUSIONS: A broad cortical surface area and gray matter reserve is associated with an accelerated social-cognitive response to CET in early schizophrenia, yet the benefits of cognitive rehabilitation are achieved in those with less initial cognitive resources after a longer duration of treatment.

Neuroprotective effects of cognitive enhancement therapy against gray matter loss in early schizophrenia: results from a 2-year randomized controlled trial.

CONTEXT: Cognitive rehabilitation has shown efficacy in improving cognition in patients with schizophrenia but the underlying neurobiologic changes that occur during these treatments and support cognitive improvement are not well known. OBJECTIVE: To examine differential changes in brain morphology in early course schizophrenia during cognitive rehabilitation vs supportive therapy. DESIGN: Randomized controlled trial. SETTING: An outpatient research clinic at a university-based medical center that provides comprehensive care services for patients with severe mental illness. PATIENTS: A total of 53 symptomatically stable but cognitively disabled outpatients in the early course of schizophrenia or schizoaffective disorder. INTERVENTIONS: A 2-year trial with annual structural magnetic resonance imaging and cognitive assessments. Cognitive enhancement therapy is an integrated approach to the remediation of cognitive impairment in schizophrenia that uses computer-assisted neurocognitive training and group-based social-cognitive exercises. Enriched supportive therapy is an illness management approach that provides psychoeducation and teaches applied coping strategies. MAIN OUTCOME MEASURES: Broad areas of frontal and temporal gray matter change were analyzed with longitudinal, voxel-based morphometry methods using mixed-effects models followed by volumetric analyses of regions that demonstrated significant differential changes between treatment groups. RESULTS: Patients who received cognitive enhancement therapy demonstrated significantly greater preservation of gray matter volume over 2 years in the left hippocampus, parahippocampal gyrus, and fusiform gyrus, and significantly greater gray matter increases in the left amygdala (all corrected P < .04) compared with those who received enriched supportive therapy. Less gray matter loss in the left parahippocampal and fusiform gyrus and greater gray matter increases in the left amygdala were significantly related to improved cognition and mediated the beneficial cognitive effects of cognitive enhancement therapy. CONCLUSION: Cognitive enhancement therapy may offer neurobiologic protective and enhancing effects in early schizophrenia that are associated with improved long-term cognitive outcomes.

Untreated illness duration correlates with gray matter loss in first-episode psychoses.

Frontolimbic neural circuit dysfunction has been thought to underlie schizophrenia. Prolonged duration of untreated illness (DUI) is associated with frontolimbic structural changes. We present data addressing this question in minimally treated first-episode patients with psychoses. To determine the relationship between DUI and gray matter changes in schizophrenia, we analyzed the structural magnetic resonance images of 82 minimally treated first-episode patients with psychotic disorder by using optimized voxel-based morphometry. DUI inversely correlated with gray matter in the left fusiform gyrus extending into the lingual gyrus, cerebellum, and the parahippocampal gyrus. The observed inverse relationship between DUI and temporal gray matter density is consistent with a progressive process during the early course of schizophrenia.

Do premorbid impairments predict emergent 'prodromal' symptoms in young relatives at risk for schizophrenia?

AIMS: Individuals at risk for developing schizophrenia (SZ) in the future frequently exhibit subtle behavioural and neurobiological abnormalities in their childhood. A better understanding of the role of these abnormalities in predicting later onset of 'prodromal' symptoms or psychosis may help in early identification of SZ. METHODS: In an ongoing prospective follow-up study of young genetically at-risk relatives of patients with SZ, we studied the prevalence of problems in premorbid social adjustment and childhood psychopathology and examined their relationship with the presence and progression of 'prodromal' symptoms of SZ. RESULTS: Growth curve analyses showed that 'prodromal' symptoms, as measured by the Scale of 'Prodromal' Symptoms, increased during follow-up. Premorbid maladjustment and childhood behavioural disturbances were cross-sectionally correlated broadly with 'prodromal' symptomatology scores. Longitudinal analyses revealed that behavioural disturbances, but not childhood maladjustment at baseline, significantly predicted increases in 'prodromal' symptomatology during the 2-year study period. CONCLUSION: Premorbid behavioural disturbance and maladjustment may predict the later emergence of 'prodromal' symptoms. 'Prodromal' symptoms in young at-risk relatives may define a subgroup worthy of follow-up into the age of risk for psychosis in order to cost-effectively characterize the predictors of psychotic symptoms and SZ.

An integrated psychobiological predictive model of emergent psychopathology among young relatives at risk for schizophrenia.

OBJECTIVE: Studies of young relatives at elevated risk for schizophrenia have pointed to the importance of a variety of neurobiological, cognitive, and clinical risk factors for the disorder; yet few have employed integrated models to estimate the joint contribution of these factors to heightened schizophrenic risk. We tested the predictive power of an integrated psychobiological model of schizophrenia risk to subsequent psychopathology development among young relatives at risk for the disorder. METHODS: Young first (n=66) and second (n=20) degree relatives of schizophrenia probands were followed for an average of 3 (SD=1.13) years to examine their trajectories toward psychopathology development. Neurobiologic, cognitive, and clinical measures were employed in an integrated structural equation model to estimate their contribution to the prospective emergence of psychopathology. RESULTS: Results indicated that neurobiological, neurocognitive, and psychosis proneness factors at baseline were all uniquely predictive of subsequent psychopathology development, and that an integrated model of psychopathology development that took into account these factors provided an excellent fit to the observed data. Subsequent classification analyses of model accuracy using likelihood ratios adjusting for the base-rate of psychopathology development in this sample revealed that individuals identified by this model had a 71% chance of developing psychopathology in the future. CONCLUSIONS: An integrated model of biobehavioral risk factors may provide a powerful method for predicting psychopathology and schizophrenia risk in at-risk samples. If validated, this model may be useful for early detection and intervention programs. Future research will need to focus particularly on predicting schizophrenia development and refining models to further enhance sensitivity.

Neuroanatomical substrates of foresight in schizophrenia.

The ability to think of the long-term consequences of one's behavior and use this information to guide present and future actions, commonly referred to as foresight, is a key higher-order cognitive ability that may be deficient among persons with schizophrenia and substantially limit the degree to which such individuals experience a functional recovery from the disease. This research investigated the neuroanatomical basis of foresight in schizophrenia, in order to identify potential brain regions that may underlie impaired foresight among this population. Participants in the early course of schizophrenia or schizoaffective disorder (N=50) were assessed using structural magnetic resonance imaging and clinician-rated measures of foresight and psychopathology. Voxel-based morphometry was used to examine the relationship between foresight and regional gray matter volume in the ventromedial prefrontal, orbitofrontal and cingulate cortices. Significant positive associations were observed between foresight and gray matter volume density in the right orbitofrontal, ventromedial prefrontal, and posterior cingulate cortices, as well as the left ventromedial prefrontal and anterior cingulate cortices, after correcting for multiple comparisons. These relationships persisted after adjusting for age, gender, illness duration, and psychopathology. Better foresight was most strongly associated with increased gray matter in the right orbitofrontal/ventromedial prefrontal cortex, suggesting that reductions in gray matter volume in this region may be associated with impaired foresight in schizophrenia. Implications and directions for future research are discussed.

Cannabis use and brain structural alterations in first episode schizophrenia--a region of interest, voxel based morphometric study.

Structural alterations of the brain in schizophrenia have been associated with genetic and environmental factors. Among the environmental factors, cannabis use has been associated with increased risk for patients with schizophrenia, but the effect of cannabis on their brain structure is unclear. We examined gray matter alterations in first episode schizophrenia patients (FES) with cannabis use (FES+C; n=15) compared to FES without cannabis use (FES-C; n=24) and 42 healthy controls who did not use cannabis. We conducted a voxel based morphometric analysis of a priori determined regions of interest consisting of the CB1 receptor rich brain regions. We observed a decrease in gray matter density in the right posterior cingulate cortex (PCC) in FES+C when compared with FES-C. The results suggest that cannabis use may be associated with altered brain structure, in particular regions rich in CB1 receptors. These findings need to be confirmed by larger, prospective studies.

Dorsolateral prefrontal cortex morphology and short-term outcome in first-episode schizophrenia.

Several clinical predictors of outcome in schizophrenia have been described; however, very few studies have examined neurobiological factors that predict outcome. The objective of this study was to examine the value of the morphology of the dorsolateral prefrontal cortex (DLPFC) determined by magnetic resonance imaging (MRI) as a predictor of short-term functional outcome in antipsychotic-naive patients with first-episode schizophrenia or schizoaffective disorder. Twenty-seven consecutive patients with first-episode schizophrenia or schizoaffective disorder underwent structural MRI at baseline. Functional outcome - a composite measure of social and employment subscales of the Strauss-Carpenter Scale - was assessed at 1 and 2 years. Volume of the left DLPFC at baseline predicted functional outcome in schizophrenia at 1 but not at 2 years. Specific cognitive functions regulated by the left DLPFC may be critical for functional outcome.

The entorhinal cortex in first-episode psychotic disorders: a structural magnetic resonance imaging study.

OBJECTIVE: Neuropathological findings regarding the entorhinal cortex in schizophrenia are conflicting. The authors used structural magnetic resonance imaging to examine the entorhinal cortex volumes of healthy subjects and medication-naive patients experiencing their first episode of psychotic illness. METHOD: The study included 33 patients with schizophrenia and related disorders, 11 patients with nonschizophrenic disorders, and 43 matched healthy subjects. All subjects were rated on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, and volumetric measurements of the entorhinal cortex were obtained for all subjects. The authors examined differences across the groups as well as clinical correlations of entorhinal cortex volumes adjusted for intracranial volume. RESULTS: A significant diagnosis effect was seen in the left entorhinal cortex: patients with schizophrenia and related disorders and patients with nonschizophrenic psychotic disorders had smaller left entorhinal cortex volumes than healthy subjects. The mean entorhinal cortex volume of patients with schizophrenic disorders did not differ from that of patients with nonschizophrenic psychotic disorders. In patients with schizophrenic disorders, the entorhinal cortex volume positively correlated with severity of delusions. The mean entorhinal cortex volume of patients with nondelusional psychotic disorders was significantly smaller than that of patients with delusional psychotic disorders and healthy subjects. CONCLUSIONS: Smaller entorhinal cortex volume in first-episode, neuroleptic-naive psychotic disorders may not be a confound of the effects of illness chronicity or antipsychotic treatment. Entorhinal cortex pathology appears to have a significant association with positive symptoms, specifically delusions. The impairment of functions in which the entorhinal cortex participates-such as novelty detection, associative learning, and processing episodic, recognition, and autobiographical memory-could be responsible for its association with psychotic disorders and delusions.

Parahippocampal gyrus in first episode psychotic disorders: a structural magnetic resonance imaging study.

Neuropathological abnormalities in schizophrenia have been demonstrated in the parahippocampal gyrus (PHG). Only a few studies on first-episode neuroleptic-naive schizophrenia patients have been done using in vivo neuroimaging techniques. The authors examined the PHG morphology using structural MRI in neuroleptic-naive subjects with first episode psychoses. Volumetric measurements of PHG and intracranial volume (ICV) were obtained on subjects with schizophrenia and schizoaffective disorders (SCZ; n = 33), nonschizophrenia psychotic disorders (NSCZ; n = 11) and matched healthy subjects (HS; n = 43). The subjects were rated on the Brief Psychiatric Rating Scale (BPRS). Group differences and clinical correlations of ICV-adjusted PHG volumes were examined. Left PHG was significantly different across the groups consisting of SCZ, NSCZ and HS. PHG was larger in NSCZ compared to SCZ but not relative to HS. Bilaterally, PHG was no different between SCZ and HS. In pooled psychotic patients, the PHG volume negatively correlated with total positive symptom, delusion and conceptual disorganization scores on BPRS. Patients with delusions had relatively smaller PHG compared to nondelusional subjects. Observed differences in PHG volume in first-episode neuroleptic-naive patients suggest that these observations are not confounded by illness chronicity or medication effects. Significant association of PHG volume with psychotic symptoms suggests that PHG pathology plays an important role in the etiopathology of psychosis and its symptoms.