Sustained attention in bipolar I disorder patients with familial psychosis and their first-degree relatives.

Sustained attention (SA) was examined in patients with familial, psychotic Bipolar Disorder (BD) (n=43), their non-bipolar, non-psychotic relatives (n=44) and controls (n=47). Patients were impaired compared to relatives, but the latter did not differ from controls. Having a relative with familial, psychotic BD does not confer risk for SA deficits.

Association between hippocampal volume and P300 event related potential in psychosis: support for the Kraepelinian divide.

INTRODUCTION: Abnormalities of the P300 event related potential (ERP) and of hippocampal structure are observed in individuals with psychotic disorders and their unaffected relatives. The understanding and clinical management of psychotic disorders are largely based on the descriptive Kraepelinian distinction between 'dementia praecox' and 'manic depressive psychosis', and not dependant on any well demarcated biological underpinnings. The hippocampus is postulated to be one of the main P300 generators, yet it remains unknown whether hippocampal volume decrements are associated with P300 deficits in psychosis, and whether any association is shared across non-affective and affective psychotic disorders. METHODS: 228 subjects from the Maudsley Family Psychosis Study comprising 55 patients with non-affective psychosis, 23 patients with psychotic bipolar disorder, 98 unaffected relatives, and 52 unrelated controls contributed structural MRI and ERP data. To study the relationship between hippocampal volume and P300 ERP, a seemingly unrelated regression methodology was used, accounting for whole brain volumes, clinical groups, age and gender in the analysis. RESULTS: An association between left hippocampal volume and P300 latency in the combined sample comprising non-affective and affective psychotic patients, their relatives and controls was observed. There was an inverse relationship between brain structure and function in that prolongation of P300 latencies was associated with smaller left hippocampal volumes. On subdividing the sample based on Kraepelinian dichotomy, this association remained significant only for the non-affective psychosis group, comprising patients and their unaffected relatives. CONCLUSIONS: Based on our findings, P300 latency, a measure of the speed of neural transmission, appears to be related to the size of the left hippocampus in schizophrenia, but not in psychotic bipolar disorder. It seems that underlying neuro-biological characteristics could help in unravelling the traditional Kraepelinian differentiation between the two major psychoses. The specificity of this brain structure-function association for schizophrenia opens the scope for further research using integration of multimodal biological data for objective categorisation of psychosis.

Executive functioning in familial bipolar I disorder patients and their unaffected relatives.

OBJECTIVE: To compare the executive function of patients with familial bipolar I disorder (BP-I) with a history of psychotic symptoms to their first-degree relatives and normal controls. METHODS: Three domains of executive function: response inhibition, working memory, and cognitive set shifting were assessed in 44 familial patients with a lifetime diagnosis of BP-I who had experienced psychotic symptoms, 42 of their unaffected first-degree relatives, and 47 controls. RESULTS: Bipolar disorder patients and their unaffected relatives had significantly worse scores for response inhibition compared to healthy controls. The groups did not differ in working memory or cognitive set shifting. CONCLUSIONS: Impairments in response inhibition are associated with both psychotic bipolar disorder and genetic liability for this illness. Our results indicate that deficits in this specific domain of executive functioning are a promising candidate endophenotype for psychotic bipolar disorder.

Emotion processing in schizophrenia: fMRI study of patients treated with risperidone long-acting injections or conventional depot medication.

We employed two event-related functional magnetic resonance imaging tasks using the pictures of mild and intense facial emotions of fear or happiness. The sample comprised 16 chronic schizophrenia patients treated with risperidone long-acting injections (RLAI), 16 patients treated with conventional antipsychotic depots (CONV) and 16 healthy controls (HC). The HC and RLAI groups demonstrated greater activation in the left amygdala in response to intensively fearful faces, and in right cerebellum to intensively happy faces compared with CONV patients. The CONV group demonstrated under-activation in the right temporal pole in response to intensively happy faces (compared with HC) and over-activation in ventro-medial prefrontal cortex (VMPFC) in response to both intensively happy and fearful expressions, compared with HC and RLAI groups. Our results suggest that networks implicated in the allocation of attentional resources (VMPFC) and emotion processing (amygdala, cerebellum) are differentially affected in patients on CONV versus RLAI.

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.

p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age.

Aging is a complex organismal process that is controlled by genetic, environmental, and behavioral factors. Accumulating evidence supports a role for different cell cycle inhibitors in mammalian aging. Little is known, however, about the upstream signals that induce their expression. Here, we explore the role of p38MAPK by generating a dominant-negative allele (p38(AF)) in which activating phosphorylation sites Thr180 and Tyr182 are mutated. Heterozygous p38(AF) mice show a marked attenuation of p38-dependent signaling and age-induced expression of multiple cell cycle inhibitors in different organs, including pancreatic islets. As a result, aged p38(AF/+) mice show enhanced proliferation and regeneration of islets when compared to wild-type littermates. We further find an age-related reduction in expression of the p38-specific phosphatase Wip1. Wip1-deficient mice demonstrate decreased islet proliferation, while Wip1 overexpression rescues aging-related decline in proliferation and regenerative capacity. We propose that modulation of p38MAPK activity may provide new avenues for treating certain age-related degenerative diseases.

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.

Increased inferior frontal activation during word generation: a marker of genetic risk for schizophrenia but not bipolar disorder?

During verbal-fluency tasks, impairments in performance and functional abnormalities in the inferior frontal cortex have been observed in both schizophrenia patients and their unaffected relatives. We sought to examine whether such functional abnormalities are a specific marker of genetic vulnerability to schizophrenia. We studied a sample of 132 subjects, comprising 39 patients with schizophrenia, 10 unaffected monozygotic (MZ) cotwins of schizophrenia probands, 28 patients with bipolar disorder, 7 unaffected MZ cotwins of bipolar disorder probands and 48 healthy controls. Blood oxygen level-dependent response was measured using functional magnetic resonance imaging during the performance of an overt verbal-fluency task with two levels of task difficulty, in a cytoarchitectonic region of interest encompassing Brodmann areas 44 and 45 bilaterally. Patients with schizophrenia and the unaffected MZ cotwins of schizophrenia probands showed increased activation in the inferior frontal cortex relative to healthy controls and bipolar patients. Increased engagement of the inferior frontal cortex during verbal-fluency may thus be a marker of genetic vulnerability to schizophrenia.

Stroop-test interference in bipolar disorder.

We analysed Stroop (neuropsychological screening test) measures of response inhibition in 18 twin pairs discordant for bipolar I disorder compared with 17 healthy control pairs, as well as 40 singletons with bipolar disorder with psychotic features and a family history of psychosis, 46 of their first-degree relatives without bipolar disorder or psychosis and 48 controls. In both studies, individuals with bipolar disorder showed Stroop deficits and their first-degree relatives showed intact performance. In the twin patients, an interference score was associated with depressive symptoms. Having a first-degree relative with bipolar disorder, even a familial, psychotic form, did not confer risk for enhanced susceptibility to interference in our studies.

Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. METHODS: MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. RESULTS: We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). CONCLUSIONS: These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.

Genetic liability for bipolar disorder is characterized by excess frontal activation in response to a working memory task.

BACKGROUND: There is evidence that patients with bipolar disorder have working memory deficits even during periods of euthymia. The neural basis of such deficits and its relationship with genetic risk remain unclear. We utilized functional magnetic resonance imaging (fMRI) to investigate neural activity in samples of bipolar disorder patients and their unaffected first-degree relatives while performing working memory tasks of increasing difficulty. METHODS: Twenty remitted bipolar I disorder patients, 20 of their unaffected first-degree relatives, and 20 healthy volunteers were recruited and successfully completed scanning. Subjects participated in fMRI scans consisting of an n-back working memory task with three stages of increasing difficulty (1-back, 2-back, and 3-back), alternating with a baseline attention task. Groups were analyzed separately to produce brain activation maps, and a group-by-task analysis of variance (ANOVA) with post hoc comparisons was completed. RESULTS: Patients performed more poorly online than control subjects and relatives on the 2-back and 3-back tasks. The group-by-task ANOVA demonstrated a significantly altered region of neural activity involving a cluster located in the left frontal pole/ventrolateral gyrus. Post hoc analyses demonstrated that this cluster was accounted for by significantly greater activation in relatives compared with control subjects for the 2-back task. Patients demonstrated a trend to significantly greater activation than control subjects in the same cluster during 1-back performance. CONCLUSIONS: Left prefrontal hyperactivation during working memory is associated with genetic liability for bipolar disorder and represents a potential neurobiological endophenotype for the illness.

Auditory P300 in patients with bipolar disorder and their unaffected relatives.

OBJECTIVES: There is evidence that genetic susceptibility may be shared between bipolar disorder (BD) and schizophrenia, but electrophysiological phenotypes which have been extensively used in studies of genetic susceptibility for schizophrenia remain far less explored in bipolar illness. This study assesses whether auditory P300 latency delays and amplitude reductions, which have been demonstrated in patients with schizophrenia and their unaffected first-degree relatives, are associated with familial liability to psychotic bipolar illness. METHODS: The P300 auditory evoked potential was obtained using an oddball task from 37 participants with BD who had a history of psychotic symptoms, 38 of their unaffected first-degree relatives and 42 healthy unrelated comparison subjects. Patients and relatives came from families multiply affected with BD or another functional psychotic disorder. P300 amplitude and latency at midline sites were compared between the groups, using linear regression analyses and robust variance estimators for clustered data, including age and gender as covariates. RESULTS: Bipolar disorder patients with a history of psychosis and their unaffected relatives showed significantly delayed P300 latency at Pz compared to controls. The groups did not differ in P300 amplitude. CONCLUSIONS: P300 latency delays are associated with both psychotic BD and familial liability for this illness. Sample size limited our ability to test for multimodal distribution of P300 measures among relatives, which might be expected if only a subgroup inherits any deficits. In future it will be of interest to directly compare groups of families with psychotic and non-psychotic forms of BD to explore further the role of psychotic symptoms with regard to P300 measures in the disorder. Our results indicate that delayed P300 latency is a promising candidate endophenotype for psychotic BD, as well as schizophrenia, and may reflect the impact of shared susceptibility genes for both types of psychosis.

Magnetic resonance imaging of the thalamus and adhesio interthalamica in twins with schizophrenia.

CONTEXT: Abnormalities of the thalamus are thought to be central to the pathophysiology of schizophrenia. These abnormalities include altered structure and shape of the thalamus itself and possibly changes to the adhesio interthalamica (or massa intermedia), the gray matter bridge connecting the 2 thalamic lobes. However, it is not clear to what extent these abnormalities are determined by the genetic liability for schizophrenia. OBJECTIVE: To investigate thalamic volume and the presence of the adhesio interthalamica in monozygotic (MZ) twins concordant or discordant for schizophrenia. DESIGN: Study of MZ twins. SETTING: Patients were drawn from inpatient and outpatient clinics. Twin controls were recruited from a volunteer twin register and through media advertisements. PARTICIPANTS: A total of 123 twins participated: 19 MZ twin pairs concordant for schizophrenia, 15 MZ schizophrenic twins and 16 MZ nonschizophrenic twins drawn from 17 pairs discordant for schizophrenia, and 27 MZ twin pairs without schizophrenia. Groups were matched for age, sex, handedness, level of education, parental socioeconomic status, and ethnicity. MAIN OUTCOME MEASURES: The volume of the thalamus (including right and left hemispheres) was measured (in cubic centimeters) and the presence of the adhesio interthalamica was ascertained from structural magnetic resonance images. RESULTS: Concordant twin pairs displayed significantly reduced thalamic volume compared with control twins, even when covarying for effects of whole-brain volume, age, and sex. There was a significant linear decrease in thalamic volume (control greater than discordant nonschizophrenic greater than discordant schizophrenic greater than concordant). In all groups, right thalamus was larger than left thalamus. There was no difference across groups in the frequency of the adhesio interthalamica. CONCLUSIONS: Volumetric thalamic abnormalities in schizophrenia occur in twin pairs concordant for schizophrenia. These abnormalities may mark the substantial genetic contribution to the illness seen in concordant twin pairs, whereas the adhesio interthalamica is unlikely to be affected in schizophrenia.

P50 auditory evoked potential suppression in bipolar disorder patients with psychotic features and their unaffected relatives.

BACKGROUND: Diminished suppression of the P50 response, a consistent finding in schizophrenia, has also been reported in patients with psychotic bipolar disorder. It is a promising endophenotype for schizophrenia, but its relationship to genetic liability in bipolar disorder is unknown. We therefore assessed whether diminished P50 suppression is associated with familial risk for psychotic bipolar disorder. METHODS: The P50 response was collected in a conditioning (C)--testing (T) paradigm from 42 outpatients with bipolar 1 disorder who had experienced psychotic symptoms and 44 of their unaffected first-degree relatives, all from families multiply affected with bipolar disorder or another non-organic psychotic disorder; 48 healthy control subjects were also studied. The T/C ratio was compared between the groups, with linear regression analyses and robust variance estimators for clustered data. RESULTS: Both patients (estimated mean difference in T/C ratio to control subjects, 32, 95% confidence interval [CI] 15-48, p=.001) and unaffected relatives (20, 95% CI 7-32, p=.002) demonstrated higher T/C ratio, thus indicating diminished P50 suppression compared with control subjects. CONCLUSIONS: To our knowledge, this is the first report of diminished P50 gating in unaffected relatives of psychotic bipolar disorder patients from multiply affected families. Our results suggest that impaired P50 gating is a putative endophenotype for psychotic bipolar disorder and thus might reflect the impact of susceptibility genes across psychosis.

Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives.

OBJECTIVE: Schizophrenia and psychotic bipolar disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. The authors used region-of-interest morphometry to volumetrically assess brain structures frequently implicated in psychotic illness in families affected with schizophrenia or psychotic bipolar disorder. METHOD: Magnetic resonance imaging brain scans were obtained from 243 subjects, comprising 42 patients with schizophrenia or schizoaffective disorder, 57 of their unaffected first-degree relatives, 38 patients with psychotic bipolar disorder, 52 of their unaffected first-degree relatives, and 54 healthy comparison subjects. Most of the families affected with schizophrenia and all of the families affected with bipolar disorder were multiply affected with the illness. Volumetric measurements of the cerebrum, lateral ventricles, third ventricle, and hippocampus were completed with stereological methods. RESULTS: Patients with schizophrenia had increased volume of the lateral and third ventricles and reduced hippocampal volume. None of these volumetric abnormalities was present in psychotic bipolar disorder. Unaffected relatives of patients with schizophrenia from multiply affected families had enlarged lateral ventricles but no other volumetric deviations. Unaffected relatives of patients with bipolar disorder showed preservation of ventricular and hippocampal volume. CONCLUSIONS: Schizophrenia and psychotic bipolar disorder are characterized by morphometric distinctions in ventricular and hippocampal regions. Lateral ventricular enlargement represents a potential morphometric endophenotype for schizophrenia.

The relationship between eye movement and brain structural abnormalities in patients with schizophrenia and their unaffected relatives.

Schizophrenia is associated with subtle eye movement and brain structural abnormalities, but the extent to which these abnormalities occur in the same individuals is unclear. The relationship between quantitative measures of eye movement task performance (smooth pursuit and antisaccade) and MRI volumetric measurements (whole brain volume, prefrontal region, lateral ventricles, third ventricle, hippocampus, and cerebellum) was assessed in 70 patients with schizophrenia or schizoaffective disorder, 105 of their unaffected first-degree relatives and 68 controls. There was a lack of correlation between eye movement and morphometric abnormalities suggesting largely separable neurobiological pathways underlying the morphological and the eye movement deviations that have previously been identified in these patients. However, in the total sample, smaller prefrontal lobe volume was significantly associated with longer latency of correct antisaccades (partial correlation r=-0.22, p=0.01) in line with previous studies demonstrating the importance of frontal lobe structures in performance of the antisaccade task. Also larger third ventricular volume was associated with larger mean amplitude of intrusive saccades during smooth pursuit (r=0.28, p=0.01). There were no significant between-group differences in the relationship between measures of eye movement and morphometry.

A controlled study of brain structure in monozygotic twins concordant and discordant for schizophrenia.

BACKGROUND: We examined monozygotic twins concordant and discordant for schizophrenia to clarify the role of genetic and environmental factors in determining brain abnormalities. METHODS: Magnetic resonance imaging brain scans were obtained from 14 monozygotic twin pairs concordant and 10 monozygotic pairs discordant for schizophrenia, as well as 17 pairs of monozygotic control twins. Twenty-two discordant sibling-pairs and 56 pairs of unrelated control subjects were included to assess the extent of genetic control over these structures. RESULTS: Within-pair similarities for whole brain volume increased as pair members were more closely related genetically (monozygotic twins > siblings > unrelated control subjects). Schizophrenic twins, whether from concordant or discordant pairs, had smaller whole brain volumes than control twins. The probands of discordant pairs showed more abnormalities in hippocampal, third and lateral ventricular volumes than concordant twins. CONCLUSIONS: Whole brain volume is under high genetic control and smaller whole brain volume is a reflection of the genetic liability to develop schizophrenia. The variation in hippocampal and ventricular volumes within discordant monozygotic pairs indicates a role for environmental factors in determining these volume abnormalities in schizophrenia. Such factors may also underlie the more extensive morphometric deviations in patients from monozygotic discordant twins than in their counterparts from concordant twins.

Temporal lobe abnormalities in first-episode psychosis.

OBJECTIVE: The nature and time course of temporal lobe abnormalities in psychotic illness remain controversial. Confounds include disease chronicity, gender, and handedness. The present study investigated temporal substructures in right-handed male patients experiencing their first episode of psychotic illness. METHOD: Magnetic resonance imaging scans were obtained for 25 minimally treated patients experiencing their first psychotic episode and 16 healthy comparison subjects. Group differences in volumes of the hippocampus, amygdala, planum temporale, and Heschl's gyrus were tested. RESULTS: The patients had smaller bilateral hippocampal and left planum temporale volumes than the comparison subjects. Paranoid and nonparanoid patients differed in left amygdala volume. CONCLUSIONS: The authors conclude that bilateral hippocampal and left planum temporale abnormalities are present near the onset of psychosis.