Colm McDonald

A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder

Schizophrenia and mania have a number of symptoms and epidemiological characteristics in common, and both respond to dopamine blockade. Family, twin and molecular genetic studies suggest that the reason for these similarities may be that the two conditions share certain susceptibility genes. On the other hand, individuals with schizophrenia have more obvious brain structural and neuropsychological abnormalities than those with bipolar disorder; and pre-schizophrenic children are characterised by cognitive and neuromotor impairments, which are not shared by children who later develop bipolar disorder. Furthermore, the risk-increasing effect of obstetric complications has been demonstrated for schizophrenia but not for bipolar disorder. Perinatal complications such as hypoxia are known to result in smaller volume of the amygdala and hippocampus, which have been frequently reported to be reduced in schizophrenia; familial predisposition to schizophrenia is also associated with decreased volume of these structures. We suggest a model to explain the similarities and differences between the disorders and propose that, on a background of shared genetic predisposition to psychosis, schizophrenia, but not bipolar disorder, is subject to additional genes or early insults, which impair neurodevelopment, especially of the medial temporal lobe.

Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder

BACKGROUND Several studies assessing volumetric measurements of regional brain structure in bipolar disorder have been published in recent years, but their results have been inconsistent. Our aim was to complete a meta-analysis of regional morphometry in bipolar disorder as assessed using magnetic resonance imaging (MRI). METHODS We conducted a systematic literature search of MRI studies of bipolar disorder and identified studies which reported volume measurements in a selected number of regions. Twenty-six studies comprising volumetric measurements on up to 404 independent patients with bipolar disorder were included. A meta-analysis was carried out comparing the volumes of regions in bipolar disorder to comparison subjects using a random effects model. RESULTS Patients with bipolar disorder had enlargement of the right lateral ventricle, but no other regional volumetric deviations which reached significance. Strong heterogeneity existed for several regions, including the third ventricle, left subgenual prefrontal cortex, bilateral amygdala and thalamus. CONCLUSIONS Regional volume of most structures we studied is preserved in bipolar disorder as a whole, which was significantly associated only with right-sided ventricular enlargement. However the extensive heterogeneity detected indicates the need for further studies to establish if consistent regional brain volume deviation exists in bipolar disorder or in specific clinical subsets of the illness.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25) and intracranial volumes (d=−0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

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.

Association between BDNF val66 met genotype and episodic memory.

The val66 met polymorphism of brain derived neurotrophic factor (BDNF) has been associated with variability in episodic memory [Egan et al., 2003 ]. In an attempt to replicate this finding, we genotyped 206 individuals (92 affected with schizophrenia or a related disorder and 114 unaffected relatives) from the Maudsley Family Study for the BDNF val66 met polymorphism. We analyzed the effect of this polymorphism on episodic memory using the Wechsler Memory Scale, revised version (WMS‐R) by regression analysis between the WMS delayed score of logical memory and genotype (corrected for age, sex, and IQ). We found the met66 allele conferred a lower score on the WMS delayed measure (R2 = 0.014 P = 0.09), which was not significant. When cases and unaffected relatives were analyzed separately, met66 was associated with a lower score on the WMS delayed measure in the relatives only (R2 = 0.077 P = 0.01), which is consistent with previous findings.

Pathways to schizophrenia: the impact of environmental factors

Schizophrenia is an aetiologically complex disorder arising from the interaction of a range of factors acting at various stages of life. Schizophrenic individuals inherit genes that cause structural brain deviations which may be compounded by early environmental insults. As a result some pre-schizophrenic children exhibit subtle developmental delays, cognitive problems, or poor interpersonal relationships. They are susceptible to dysregulation of dopamine, the final pathway leading to the onset of a psychotic illness. Dopamine dysregulation may arise through a process of sensitization, which, in animals, can be caused by repeated administration of dopamine-releasing drugs. It is clear that the same process occurs in humans, and that some individuals are particularly sensitive to the effects of such drugs for either genetic reasons or through early environmental damage. Stress has also been shown to induce dopamine release in animal studies, and epidemiological studies have demonstrated that social stresses can precipitate schizophrenia. Thus, stresses, such as drug use and social adversity, in adolescence or early adult life may propel the neurodevelopmentally impaired individual over a threshold into frank psychosis.

White matter microstructural impairments and genetic liability to familial bipolar I disorder

BACKGROUND Subtle abnormalities in frontal white matter have been reported in bipolar disorder. AIMS To assess whether impaired integrity of white matter tracts is associated with bipolar disorder and genetic liability for the disorder. METHOD A total of 19 patients with psychotic bipolar I disorder from multiply affected families, 21 unaffected first-degree relatives and 18 comparison individuals (controls) underwent diffusion tensor imaging. Whole brain voxel-based analyses compared fractional anisotropy between patients and relatives with controls, and its relationship with a quantitative measure of genetic liability. RESULTS Patients had decreased fractional anisotropy compared with controls in the genu of the corpus callosum, right inferior longitudinal fasciculus and left superior longitudinal fasciculus. Increased genetic liability for bipolar disorder was associated with reduced fractional anisotropy across distributed regions of white matter in patients and their unaffected relatives. CONCLUSIONS Disturbed structural integrity within key intra- and interhemispheric tracts characterises both bipolar disorder and genetic liability for this illness.

Early and late environmental risk factors for schizophrenia

Although a high proportion of liability to schizophrenia is under genetic control, a number of environmental risk factors have been identified. The earliest of these are complications of pregnancy and birth, though whether these cause or reflect disturbed brain development is not absolutely clear. Neurodevelopmental deviance is also indicated by neurological dysfunction, social, behavioural and cognitive deficits during childhood. Immigrant status is a significant risk factor, especially prominent among the African Caribbean population in England, though the mechanism is unknown. Later environmental risk factors include adverse life events and substance abuse. An additive model of multiple genetic and environmental risk factors of small effect may be too simplistic and an interactive model where genetic predisposition is compounded by environmental effects is more in keeping with current evidence. The nature of such interactions can be explored more fully when susceptibility genes for schizophrenia are identified.

Neural response to specific components of fearful faces in healthy and schizophrenic adults

Perception of fearful faces is associated with functional activation of cortico-limbic structures, which has been found altered in individuals with psychiatric disorders such as schizophrenia, autism and major depression. The objective of this study was to isolate the brain response to the features of standardized fearful faces by incorporating principal component analysis (PCA) into the analysis of neuroimaging data of healthy volunteers and individuals with schizophrenia. At the first stage, the visual characteristics of morphed fearful facial expressions (FEEST, Young et al., 2002) were classified with PCA, which produced seven orthogonal factors, with some of them related to emotionally salient facial features (eyes, mouth, brows) and others reflecting non-salient facial features. Subsequently, these PCA-based factors were included into the functional magnetic resonance imaging (fMRI) analysis of 63 healthy volunteers and 32 individuals with schizophrenia performing a task that involved implicit processing of FEEST stimuli. In healthy volunteers, significant neural response was found to visual characteristics of eyes, mouth or brows. In individuals with schizophrenia, PCA-based analysis enabled us to identify several significant clusters of activation that were not detected by the standard approach. These clusters were implicated in processing of visual and emotional information and were attributable to the perception of eyes and brows. PCA-based analysis could be useful in isolating brain response to salient facial features in psychiatric populations.

Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder

BackgroundImpairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses.Methods104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis.ResultsDuring the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls.ConclusionsIn summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.