Sophia Frangou

The neurodevelopmental model of schizophrenia: update 2005

Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental ‘hits’, but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier ‘lesions’. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia.

Neuropsychology of bipolar disorder: a review

BACKGROUND Bipolar disorder (BD) may be associated with significant and persistent cognitive impairment. The aim of this study was to describe the profile of cognitive deficits in BD at different phases of the illness and determine whether it is different from that of schizophrenia and unipolar (UP) depression. METHODS A systematic review of the computerised literature of neuropsychological studies of BD published between 1980 and 2000. RESULTS General intellectual function: this was largely preserved in BD. Impairments when present were limited to acute episodes and to performance scores. Attention: attentional abnormalities were seen in symptomatic BD patients and persisted in remission in measures of sustained attention and inhibitory control. Memory: verbal memory was impaired even in euthymic patients while visuo-spatial memory deficits were variable depending on the tasks used. Executive function: all aspects of executive function (planning, abstract concept formation, set shifting) were impaired in symptomatic BD patients. Performance on executive function tests was sensitive to the presence of even residual symptoms but it may be normal in fully recovered patients with uncomplicated BD. Comparison to other patient groups: no major differences in cognitive profile between BD and UP depression were found. Remitted BD patients out-performed stable schizophrenics on most cognitive measures but this advantage disappeared when they were acutely symptomatic. CONCLUSIONS Symptomatic BD patients have widespread cognitive abnormalities. Trait related deficits appear to be present in verbal memory and sustained attention. Executive function and visual memory may be also affected at least in some recovered BD patients.

Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression

BACKGROUND Bipolar disorder (BD) is characterised by abnormalities in mood and emotional processing, but the neural correlates of these, their relationship to depressive symptoms, and the similarities with deficits in major depressive disorder (MDD) remain unclear. We compared responses within subcortical and prefrontal cortical regions to emotionally salient material in patients with BP and MDD using functional magnetic resonance imaging. METHODS We measured neural responses to mild and intense expressions of fear, happiness, and sadness in euthymic and depressed BD patients, healthy control subjects, and depressed MDD patients. RESULTS Bipolar disorder patients demonstrated increased subcortical (ventral striatal, thalamic, hippocampal) and ventral prefrontal cortical responses particularly to mild and intense fear, mild happy, and mild sad expressions. Healthy control subjects demonstrated increased subcortical responses to intense happy and mild fear, and increased dorsal prefrontal cortical responses to intense sad expressions. Overall, MDD patients showed diminished neural responses to all emotional expressions except mild sadness. Depression severity correlated positively with hippocampal response to mild sadness in both patient groups. CONCLUSIONS Compared with healthy controls and MDD patients, BD patients demonstrated increased subcortical and ventral prefrontal cortical responses to both positive and negative emotional expressions.

Structural Neuroimaging Studies in Major Depressive Disorder: Meta-analysis and Comparison With Bipolar Disorder

CONTEXT Although differences in clinical characteristics exist between major depressive disorder (MDD) and bipolar disorder (BD), consistent structural brain abnormalities that distinguish the disorders have not been identified. OBJECTIVES To investigate structural brain changes in MDD using meta-analysis of primary studies; assess the effects of medication, demographic, and clinical variables; and compare the findings with those of a meta-analysis of studies on BD. DATA SOURCES The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1980, to February 2, 2010. STUDY SELECTION Two hundred twenty-five studies that used magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with MDD with that of controls were included in an online database, and 143 that measured common brain structures were selected for meta-analysis. DATA EXTRACTION Twenty-five variables, including demographic and clinical data, were extracted from each study, when available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and the proportion of patients and controls with an abnormality in brain structure was extracted for categorical variables. DATA SYNTHESIS Compared with the structure of a healthy brain, MDD was associated with lateral ventricle enlargement; larger cerebrospinal fluid volume; and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients during depressive episodes had significantly smaller hippocampal volume than patients during remission. Compared with BD patients, those with MDD had reduced rates of deep white matter hyperintensities, increased corpus callosum cross-sectional area, and smaller hippocampus and basal ganglia. Both disorders were associated with increased lateral ventricle volume and increased rates of subcortical gray matter hyperintensities compared with healthy controls. CONCLUSIONS The meta-analyses revealed structural brain abnormalities in MDD that are distinct from those observed in BD. These findings may aid investigators attempting to discriminate mood disorders using structural magnetic resonance imaging data.

Meta-analysis of the P300 and P50 waveforms in schizophrenia

OBJECTIVE To determine whether patients with schizophrenia have abnormalities in the P300 and P50 waves and to quantify the magnitude of any differences from controls. METHOD We conducted a systematic search for articles published between January 1994 and August 2003 that reported P50 or P300 measures in schizophrenic patients and controls. Metaregression analyses were performed using a random effects model. The pooled standardised effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation. RESULTS We identified 46 studies suitable for analysis of P300 measures, including 1443 patients and 1251 controls. There were 20 P50 studies including 421 patients and 401 controls. The PSES for the P300 amplitude was 0.85 (95% CI: 0.65 to 1.05; p<0.001), and for the P300 latency was -0.57 (95% CI: -0.75 to -0.38; p<0.001). The PSES of the P50 ratio was -1.56 (95% CI: -2.05 to -1.06; p<0.001). There were no significant differences between patients and controls in P50 latency. Across-study variations in filters, task difficulty, antipsychotic medication and duration of illness did not influence the PSES significantly. CONCLUSIONS This meta-analysis confirms the existence of ERP deficits in schizophrenia. The magnitude of these deficits is similar to the most robust findings reported in neuroimaging and neuropsychology in schizophrenia.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta‐analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view.

The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia

Two separate theories that attempt to explain different aspects of schizophrenia have recently attracted much attention. The first, the neurodevelopmental hypothesis, postulates that deviations in early development establish a neuronal phenotype that predisposes to, or, in some versions, determines the later onset of schizophrenia. The second theory proposes that schizophrenic symptoms arise from abnormalities in neuronal connectivity. Here, we suggest that the findings from these two separate lines of inquiry can be integrated into a unitary framework: the dysplastic net hypothesis. In essence, this proposes that anatomical and physiological dysconnectivity of the adult schizophrenic brain is determined by dysplastic fetal brain development. We also indicate how abnormal connectivity between brain regions constituting large-scale neurocognitive networks is expressed in both the prepsychotic and psychotic phases of schizophrenia, and we examine possible risk factors (genetic and environmental) for dysplastic formation of these networks.

Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study

INTRODUCTION We assessed the usefulness of the P300 wave as endophenotype for schizophrenia by means of a meta-analysis of the literature as well as our own family study. METHOD Meta-analysis: We conducted a systematic search for articles published between 1983 and 2003 that reported P300 measures in non-psychotic relatives of schizophrenic patients and in healthy controls. Meta-regression analyses were performed using a random effects procedure. The pooled standardized effect size (PSES) was calculated as the difference between the means of the two groups divided by the common standard deviation. Local study: We examined the P300 wave with a standard two-tone oddball paradigm in 30 patients with schizophrenia, 40 non-psychotic relatives, and 40 controls using linear mixed models. RESULTS Meta-analysis: We pooled 472 relatives and 513 controls. The P300 amplitude was significantly reduced in relatives (PSES = 0.61; 95% CI: 0.30 to 0.91; P < 0.001). The P300 latency was significantly delayed in relatives (PSES of -0.50; 95% CI: -0.88 to -0.13; P = 0.009]. Local study: The patients showed a trend for amplitude reductions (P = 0.06) and significant latency delays (P < 0.01). The relatives displayed normal amplitude but had significant latency delays (P = 0.01). The P300 amplitude and especially the P300 latency are promising alternative phenotypes for genetic research into schizophrenia.

Mapping IQ and gray matter density in healthy young people

Magnetic resonance imaging (MRI) studies suggest that significant changes in gray matter density occur during adolescence because of brain maturation. It has also been reported that gray matter volume correlates with measures of intellectual ability. This study examined whether the relationship between general intellectual ability (IQ) and gray matter morphometry reflects differential involvement of particular cytoarchitectonic areas. We found positive correlations between IQ and gray matter density in the orbitofrontal cortex, cingulate gyrus, the cerebellum, and thalamus and negative correlations in the caudate nucleus. These findings suggest that general intellectual ability in healthy young people is related to specific brain regions known to be involved in the executive control of attention, working memory, and response selection.

Cognitive remediation therapy (CRT) for young early onset patients with schizophrenia: an exploratory randomized controlled trial.

BACKGROUND Schizophrenia with an onset in adolescence is known to be associated with a poorer outcome and cognitive difficulties. These impairments have an impact on quality of life and represent treatment targets. Cognitive remediation therapy (CRT) attempts to improve cognitive deficits by teaching information processing strategies through guided mental exercises. The objective of this study is to evaluate the efficacy of CRT in alleviating cognitive deficits compared to treatment as usual and explore the mediating and moderating effects of cognitive improvement. METHOD Single-blind randomized controlled trial with two groups, one receiving CRT (N21) and the other standard care (N19) assessed at baseline, 3 months (post therapy) and follow-up (3 months post therapy). Participants were recruited from specialist inpatient and community mental health services and were young patients with recent onset schizophrenia (average age of 18) and evidence of cognitive and social behavioural difficulties. The intervention was individual cognitive remediation therapy delivered over a period of 3 months with at least three sessions per week. The main outcome measures were cognition (memory, cognitive flexibility and planning) and secondary outcomes (symptoms, social contacts and self-esteem). RESULTS Compared to standard care, CRT produced significant additional improvements in cognitive flexibility as measured by the Wisconsin Card Sort Test (WCST). Therapy moderated the effects of improved planning ability on symptoms such that improvements only had a beneficial effect when they were achieved in the context of CRT. Improvements in cognition in all domains had a direct effect on social functioning and improvements in WCST had a direct effect on overall symptom improvement. CONCLUSIONS Cognitive remediation therapy can contribute to the improvement in WCST even in adolescents. The changes in cognitive outcomes also contributed to improvements in functioning either directly or solely in the context of CRT. Evidence of the mediator and moderator effects of cognitive changes should lead to more effective therapy development.