Showing papers by "Robin M. Murray published in 2011"
TL;DR: It is suggested that DTI-derived maps can be used together with a previous histological atlas to establish the relationship of focal lesions with nearby tracts and improve clinico-anatomical correlation.
611 citations
TL;DR: A genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis provides further evidence to support a role forDNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.
Abstract: Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.
448 citations
TL;DR: The reliability and comparability of first-presentation psychosis patients' reports of childhood abuse are explored and justification for the use in future studies of retrospective reports of Childhood abuse obtained from individuals with psychotic disorders is provided.
Abstract: An increasing number of studies are demonstrating an association between childhood abuse and psychosis. However, the majority of these rely on retrospective self-reports in adulthood that may be unduly influenced by current psychopathology. We therefore set out to explore the reliability and comparability of first-presentation psychosis patients’ reports of childhood abuse. Psychosis case subjects were drawn from the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (AESOP) epidemiological study and completed the Childhood Experience of Care and Abuse Questionnaire to elicit abusive experiences that occurred prior to 16 years of age. High levels of concurrent validity were demonstrated with the Parental Bonding Instrument (antipathy: rs = 0.350–0.737, P < .001; neglect: rs = 0.688–0.715, P < .001), and good convergent validity was shown with clinical case notes (sexual abuse: κ = 0.526, P < .001; physical abuse: κ = 0.394, P < .001). Psychosis patients’ reports were also reasonably stable over a 7-year period (sexual abuse: κ = 0.590, P < .01; physical abuse: κ = 0.634, P < .001; antipathy: κ = 0.492, P < .01; neglect: κ = 0.432, P < .05). Additionally, their reports of childhood abuse were not associated with current severity of psychotic symptoms (sexual abuse: U = 1768.5, P = .998; physical abuse: U = 2167.5, P = .815; antipathy: U = 2216.5, P = .988; neglect: U = 1906.0, P = .835) or depressed mood (sexual abuse: χ2 = 0.634, P = .277; physical abuse: χ2 = 0.159, P = .419; antipathy: χ2 = 0.868, P = .229; neglect: χ2 = 0.639, P = .274). These findings provide justification for the use in future studies of retrospective reports of childhood abuse obtained from individuals with psychotic disorders.
400 citations
TL;DR: Findings provide evidence that the onset of frank psychosis is preceded by presynaptic dopaminergic dysfunction and further research is needed to determine the specificity of elevated dopamine synthesis capacity to particular psychotic disorders.
Abstract: Objective:While there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. The authors addressed this issue by measuring dopamine synthesis capacity in individuals at ultra-high risk of psychosis and then following them to determine their clinical outcome. Method:This prospective study included 30 patients who met standard criteria for being at ultra-high risk of psychosis and 29 healthy volunteers. Participants were scanned using [18F]6-fluoro-l-dopa positron emission tomography. The ultra-high-risk patients were scanned at presentation and followed up for at least 3 years to determine their clinical outcome. Six patients had comorbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining patients, nine developed a psychotic disorder (psychotic transition group) and 15 did not (nontransition group). Resul...
305 citations
National University of Ireland, Galway1, University of Texas Health Science Center at San Antonio2, University of North Carolina at Chapel Hill3, University of Udine4, University of Cincinnati Academic Health Center5, Helsinki University Central Hospital6, University of California, Los Angeles7, University of Cambridge8, University of Sydney9, Royal Edinburgh Hospital10, University of Utah11, Duke University12, University of Western Ontario13, University of Calgary14
TL;DR: An international collaborative mega-analysis of regional volumetric measurements of individual patient and healthy subject data identified lithium use and illness duration as substantial and consistent sources of heterogeneity, with lithium use associated with regionally specific increased brain volume.
275 citations
deCODE genetics1, Copenhagen University Hospital2, Ludwig Maximilian University of Munich3, University of Bonn4, Utrecht University5, GlaxoSmithKline6, University of Aberdeen7, King's College London8, Radboud University Nijmegen Medical Centre9, University of Verona10, University of Oslo11, University of California, Los Angeles12, Heidelberg University13, Broad Institute14, Wellcome Trust Sanger Institute15
TL;DR: It is concluded that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
Abstract: Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
258 citations
TL;DR: Biological changes activated by stress represent a significant factor influencing brain structure and function in first-episode psychosis through an effect on BDNF.
Abstract: Background
Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this study was to investigate potential causes and consequences of reduced BDNF expression in these patients, by examining the association between BDNF levels and measures of stress, inflammation and hippocampal volume in first-episode psychosis.
253 citations
TL;DR: Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study shows a steady progression towards a plateau.
Abstract: Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study
251 citations
TL;DR: This review examines the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia.
Abstract: The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia.
218 citations
deCODE genetics1, Utrecht University2, University of Oslo3, University of Copenhagen4, Aarhus University5, Oslo University Hospital6, Wellcome Trust Sanger Institute7, Max Planck Society8, University of Tübingen9, University of Bonn10, Heidelberg University11, King's College London12, Ludwig Maximilian University of Munich13, University of Aberdeen14, National Institutes of Health15, Karolinska Institutet16, Statens Serum Institut17, Lundbeck18, Maastricht University19, Russian Academy20, University of Valencia21, Complutense University of Madrid22, University of Rome Tor Vergata23, Radboud University Nijmegen24, GlaxoSmithKline25, University of Iceland26, Katholieke Universiteit Leuven27, Semmelweis University28, University of Santiago de Compostela29, Cardiff University30, University of Verona31, Broad Institute32, University of California, Los Angeles33
TL;DR: An expanded set of variants in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), and two novel variants showing genome-wide significant association are found.
Abstract: Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10−9] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10−9).
209 citations
TL;DR: 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.
Abstract: Impairments 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. 104 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. During 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. In 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.
TL;DR: Evidence from both epidemiological and animal studies indicates that cannabis use during adolescence carries particular risk in addiction, and further studies are warranted given the increase in the concentration of the main active ingredient in street preparations of cannabis and a decreasing age of first-time exposure to cannabis.
deCODE genetics1, Aarhus University Hospital2, Aarhus University3, University of Oslo4, Copenhagen University Hospital5, University of Iceland6, Utrecht University7, University of California, Los Angeles8, University of Bonn9, Wellcome Trust Sanger Institute10, University of Helsinki11, National Institutes of Health12, Ludwig Maximilian University of Munich13, Glostrup Hospital14, Heidelberg University15, Semmelweis University16, University of Verona17, Radboud University Nijmegen Medical Centre18, Russian Academy19, King's College London20, Sichuan University21, Royal Cornhill Hospital22, Karolinska Institutet23
TL;DR: As it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, ZNF804A is searched for large copy number variants (CNVs) in psychosis patients and patients with other psychiatric disorders and 39 481 controls.
Abstract: A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).
TL;DR: Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function.
Abstract: BACKGROUND AND PURPOSE: Individuals born very preterm (before 33 weeks of gestation, VPT) are at risk of damage to developing white matter, which may affect later cognition and behaviour. METHODS: We used diffusion tensor MRI (DT-MRI) to assess white matter microstructure (fractional anisotropy; FA) in 80 VPT and 41 term-born individuals (mean age 19.1 years, range 17-22, and 18.5 years, range 17-22 years, respectively). VPT individuals were part of a 1982-1984 birth cohort which had been followed up since birth; term individuals were recruited by local press advertisement. General intellectual function, executive function and memory were assessed. RESULTS: The VPT group had reduced FA in four clusters, and increased FA in four clusters relative to the Term group, involving several association tracts of both hemispheres. Clusters of increased FA were associated with more severe neonatal brain injury in the VPT group. Clusters of reduced FA were associated with lower birth weight and perinatal hypoxia, and with reduced adult cognitive performance in the VPT group only. CONCLUSIONS: Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function.
TL;DR: Data support a role for the HPA axis, as measured by cortisol awakening response, in modulating cognitive function in patients with psychosis; however, this association does not seem to be related to the increased exposure to psychosocial stressors described in these patients.
Abstract: Background
Cognitive impairment, particularly in memory and executive function, is a core feature of psychosis. Moreover, psychosis is characterized by a more prominent history of stress exposure, and by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. In turn, stress exposure and abnormal levels of the main HPA axis hormone cortisol are associated with cognitive impairments in a variety of clinical and experimental samples; however, this association has never been examined in first-episode psychosis (FEP).
TL;DR: A history of childhood trauma was associated with worse cognitive performances, predominantly in affective psychoses, and in male patients, and underline the necessity of investigating biological and psychosocial mechanisms underlying subjects' sensitivity to the negative effect of childhood stress.
TL;DR: The results support EAGBR measures as putative endophenotypes of schizophrenia, likely reflecting an ubiquitous local cortical circuit deficit.
Abstract: BACKGROUND: Reduced power and phase locking of the early auditory gamma-band response (EAGBR) have been reported in schizophrenia, but findings are equivocal. Further, little is known about genetic (heritability) and environmental influences on the EAGBR or its potential as an endophenotype of schizophrenia. The present study used a twin design to examine whether EAGBR power and phase locking are heritable and reduced in schizophrenic patients and their unaffected co-twins and thus putative endophenotypes of schizophrenia. METHODS: The study sample included a total of 194 individuals, consisting of 15 monozygotic [MZ] twin pairs concordant for schizophrenia, 9 MZ twin pairs discordant for schizophrenia, and 42 MZ and 31 dizygotic (DZ) control pairs. Evoked power and phase-locking factor of the EAGBR were computed on Morlet wavelet-transformed electroencephalogram responses to standard tones during an auditory oddball target detection task. Structural equation modeling was applied to estimate heritability and genetic and environmental correlations with schizophrenia for the EAGBR measures. RESULTS: Both evoked power and phase-locking phenotypes were heritable traits (power: h(2) = 0.65; phase locking: h(2) = 0.63). Impaired EAGBR measures were significantly associated with schizophrenia. Patients with schizophrenia and their unaffected identical co-twins exhibited significantly reduced EAGBR power compared with control subjects. In each phenotype, shared genetic factors were likely the source of the observed associations with schizophrenia. CONCLUSIONS: Our results support EAGBR measures as putative endophenotypes of schizophrenia, likely reflecting an ubiquitous local cortical circuit deficit.
TL;DR: Findings do not support a central role for striatal DA in THC-elicited psychosis, and positive psychotic symptoms and DA release were unrelated.
Abstract: Intravenous (IV) Δ9-tetrahydrocannabinol (THC) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients, but the psychotomimetic mechanism is unknown. One possibility is that THC stimulates dopamine (DA) release in the striatum. In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo. We also investigated whether DA release and positive psychotic symptoms were related. Eleven healthy male volunteers completed two 123I-iodobenzamide ([123I]IBZM) single photon emission tomography (SPET) sessions and received IV THC (2.5 mg) or placebo in a randomized counterbalanced order, under double-blind conditions. Analysable data were obtained from nine participants. The Positive and Negative Syndrome Scale (PANSS) was used to rate psychotomimetic effects. Striatal binding index values were calculated using the occipital cortex as a reference region. Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC. There were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms. These findings do not support a central role for striatal DA in THC-elicited psychosis.
TL;DR: Suicide risk was associated with a cumulative threshold effect of symptoms and manic symptoms and there was a suggestion that early manic symptoms might increase the risk of later suicide irrespective of initial diagnosis.
TL;DR: The results reveal that the pro-psychotic effects of THC might be related to impaired network dynamics with impaired communication between the right and left frontal lobes.
TL;DR: There is a lack of research reporting on whether psychotic patients are ready to change their use of cannabis, which has obvious implications for identifying which treatment strategies are likely to be effective.
TL;DR: In this paper, the authors investigated whether these risk factors interact in an additive manner to further increase risk for schizophrenia in individuals born in Helsinki between 1962 and 1969 who had developmental records archived in the Helsinki City Archives.
Abstract: Objective:Obstetric complications and developmental delay are well-established risk factors for schizophrenia. The authors investigated whether these risk factors interact in an additive manner to further increase risk for schizophrenia. Method:The study population encompassed all individuals born in Helsinki between 1962 and 1969 who had developmental records archived in the Helsinki City Archives. Through linkage between the Finnish Population Register, the Finnish Hospital Discharge Register, and the Child Health Archives, child health cards were traced for 189 individuals who had received a diagnosis of schizophrenia and 189 healthy comparison subjects, individually matched to case subjects on gender and year of birth. Child health cards from the Child Health Archives contain detailed prospective developmental data from birth as well as an indicator of fetal distress, as measured by the Apgar score. Detailed developmental data from the first year of life were extracted. Results:Delayed attainment of m...
TL;DR: Striatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia, suggesting that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.
Abstract: BackgroundElevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia.MethodIn vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs.ResultsStriatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic.ConclusionsStriatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.
TL;DR: While there was no longitudinal difference in ventricle:brain ratios between first-episode psychosis subjects and controls, patients exhibited grey matter volume changes, indicating a reversible course in the superior temporal cortex and hippocampus compared with controls.
Abstract: BackgroundSome neuroimaging studies have supported the hypothesis of progressive brain changes after a first episode of psychosis. We aimed to determine whether (i) first-episode psychosis patients would exhibit more pronounced brain volumetric changes than controls over time and (ii) illness course/treatment would relate to those changes.MethodLongitudinal regional grey matter volume and ventricle:brain ratio differences between 39 patients with first-episode psychosis (including schizophrenia and schizophreniform disorder) and 52 non-psychotic controls enrolled in a population-based case-control study.ResultsWhile there was no longitudinal difference in ventricle:brain ratios between first-episode psychosis subjects and controls, patients exhibited grey matter volume changes, indicating a reversible course in the superior temporal cortex and hippocampus compared with controls. A remitting course was related to reversal of baseline temporal grey matter deficits.ConclusionsOur findings do not support the hypothesis of brain changes indicating a progressive course in the initial phase of psychosis. Rather, some brain volume abnormalities may be reversible, possibly associated with a better illness course.
TL;DR: Findings reinforce the view that there are important pathophysiological distinctions between BD and MDD, and indicate that subtle dorsal anterior cingulate abnormalities may be relevant to the pathophysiology of BD.
Abstract: Perico CA-M, Duran FLS, Zanetti MV, Santos LC, Murray RM, Scazufca M, Menezes PR, Busatto GF, Schaufelberger MS. A population-based morphometric MRI study in patients with first-episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects. Bipolar Disord 2011: 13: 28–40. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S.
Objectives: Many morphometric magnetic resonance imaging (MRI) studies that have investigated the presence of gray matter (GM) volume abnormalities associated with the diagnosis of bipolar disorder (BD) have reported conflicting findings. None of these studies has compared patients with recent-onset psychotic BD with asymptomatic controls selected from exactly the same environment using epidemiological methods, or has directly contrasted BD patients against subjects with first-onset psychotic major depressive disorder (MDD). We examined structural brain differences between (i) BD (type I) subjects and MDD subjects with psychotic features in their first contact with the healthcare system in Brazil, and (ii) these two mood disorder groups relative to a sample of geographically matched asymptomatic controls.
Methods: A total of 26 BD subjects, 20 subjects with MDD, and 94 healthy controls were examined using either of two identical MRI scanners and acquisition protocols. Diagnoses were based on DSM-IV criteria and confirmed one year after brain scanning. Image processing was conducted using voxel-based morphometry.
Results: The BD group showed increased volume of the right dorsal anterior cingulate cortex relative to controls, while the MDD subjects exhibited bilateral foci GM deficits in the dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons). Direct comparison between BD and MDD patients showed a focus of GM reduction in the right-sided dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons) and a trend (p < 0.10, corrected) toward left-sided GM deficits in the dorsolateral prefrontal cortex of MDD patients. When analyses were repeated with scanner site as a confounding covariate the finding of increased right anterior cingulate volumes in BD patients relative to controls remained statistically significant (p = 0.01, corrected for multiple comparisons).
Conclusions: These findings reinforce the view that there are important pathophysiological distinctions between BD and MDD, and indicate that subtle dorsal anterior cingulate abnormalities may be relevant to the pathophysiology of BD.
TL;DR: Impairments in response inhibition are associated with both psychotic bipolar disorder and genetic liability for this illness and deficits in this specific domain of executive functioning are a promising candidate endophenotype for psychotic bipolar Disorder.
Abstract: Schulze KK, Walshe M, Stahl D, Hall MH, Kravariti E, Morris R, Marshall N, McDonald C, Murray RM, Bramon E. Executive functioning in familial bipolar I disorder patients and their unaffected relatives. Bipolar Disord 2011: 13: 208–216. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S.
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.
Book•
01 Oct 2011
TL;DR: I was left with the impression that marijuana is a very exciting and underused drug in neuroscience, as well as in other medical areas, and the authors have only scratched the surface of its many benefits.
Abstract: book as a stocking filler for my 19year-old son who, like many of his generation, is not a stranger to marijuana. However, the usual delays on the London transport system resulted in my thumbing through the very expensive pages of this slim hardbacked book before it reached his stocking. I devoured this academic yet compulsive book as I would a novel, unable to release it until it was finished. I had read with interest all the press coverage in recent times about the supposed links between marijuana consumption and the development of psychosis in some individuals, which made the government’s downgrading of the drug seem incongruous. I therefore anticipated that this compilation of all the available research into the drug would be just the shock that my son required, as its editors are leading lights in the study of the psychiatry of marijuana users. Several points emerge from this book, the salient one being that the links between the use of marijuana and the development of schizophrenia and other psychoses in some individuals are not entirely conclusive. It would appear that marijuana may be a component of several risk factors which may contribute towards such conditions. It is possible that there is a potential dysfunction in the endogenous cannabinoid system in schizophrenia sufferers, but whether the changes are the result of the disease pathology or are responses to exogenous cannabinoids, antipsychotics or other medications is as yet unknown. As the authors admit, much of the available research is inconclusive owing to compounding variables, yet a specific cannabis psychosis appears likely (often the psychosis goes into remission following withdrawal of the substance). I was left with the impression that marijuana is a very exciting and underused drug in neuroscience, as well as in other medical areas, and we have only scratched the surface of its many benefits. The potential for future research is enormous. Marijuana’s use as an anticonvulsant, analgesic, antidepressant and anti-anxiety drug is beginning to be explored. Its benefit in food intake and weight regulation are already known, and its natural presence in the body also invites further research. I strongly recommend this book to anyone (except my own son and others like him who I think would not be dissuaded from the use of marijuana by reading it). It raises debate in the political arena and has radically altered my own views of the use of marijuana. My own copy is thick with Post-it notes scribbled with observations, and I anticipate it being a vital aid to teaching for many years to come.
TL;DR: Very preterm adolescents compared with controls demonstrated differential structural covariance between medial, frontal and cingulate gyri, caudate nucleus, thalamus, primary visual cortex, cerebellum and several other cortical and subcortical regions of the cortex, suggesting that developmental changes in one brain region may result in a cascade of alterations in multiple regions.
Abstract: On the basis of findings in normative samples that different cortical brain regions covary in gray matter volume, most likely as a result of mutually trophic influences during cortical development, we aimed to study whether patterns of covariation in regional gray matter, i.e., structural covariance, differed between adolescents who were born very preterm and full-term controls. Optimized voxel-based morphometry was used to study structural magnetic resonance imaging scans from 218 very preterm adolescents (gestational age <33 weeks) and 127 controls at 14-15 years of age. Local gray matter volumes were obtained for 18 regions of interest involved in sensorimotor and higher-order cognitive functions. These were then used to predict local volumes in the remaining areas of the cortex, with total gray matter volume, age and gender used as confounding variables. Very preterm adolescents compared with controls demonstrated differential (i.e., both increased and decreased) structural covariance between medial, frontal and cingulate gyri, caudate nucleus, thalamus, primary visual cortex, cerebellum and several other cortical and subcortical regions of the cortex. These findings support previous research indicating that preterm birth is associated with altered cortical development, and suggest that developmental changes in one brain region may result in a cascade of alterations in multiple regions.
TL;DR: The hypothesis that loss of WM integrity may be an important pathophysiological feature of schizophrenia, with particular implications for brain dysmaturation in non-familial and familial schizophrenia, is supported.
Abstract: Abnormalities in the connectivity of white-matter (WM) tracts in schizophrenia are supported by evidence from post-mortem investigations, functional and structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). The aims of this study were to explore the microstructural changes in first-episode schizophrenia in a Han Chinese population and to investigate whether a family history of psychiatric disorder is related to the severity of WM tract integrity abnormalities in these patients.MethodT1-weighted MR and DT images were collected in 68 patients with first-episode schizophrenia [22 with a positive family history (PFH) and 46 with a negative family history (NFH)] and 100 healthy controls. Voxel-based analysis was performed and WM integrity was quantified by fractional anisotropy (FA). Cluster- and voxel-level analyses were performed by using two-sample t tests between patients and controls and/or using a full factorial model with one factor and three levels among the three sample groups (patients with PFH or NFH, and controls), as appropriate.ResultsFA deficits were observed in the patient group, especially in the left temporal lobe and right corpus callosum. This effect was more severe in the non-familial schizophrenia than in the familial schizophrenia subgroup.ConclusionsOverall, these findings support the hypothesis that loss of WM integrity may be an important pathophysiological feature of schizophrenia, with particular implications for brain dysmaturation in non-familial and familial schizophrenia.
TL;DR: Verbal memory and visual learning and memory are moderately heritable, share a genetic overlap with schizophrenia and are valid endophenotypes for the condition.
Abstract: BackgroundVisual and verbal episodic memory deficits are putative endophenotypes for schizophrenia; however, the extent of any genetic overlap of these with schizophrenia is unclear. In this study, we set out to quantify the genetic and environmental contributions to variance in visual and verbal memory performance, and to quantify their genetic relationship with schizophrenia.MethodWe applied bivariate genetic modelling to 280 twins in a classic twin study design, including monozygotic (MZ) and dizygotic (DZ) pairs concordant and discordant for schizophrenia, and healthy control twins. We assessed episodic memory using subtests of the Wechsler Memory Scale – Revised (WMS-R).ResultsGenetic influences (i.e. heritability) contributed significantly to variance in immediate recall of both verbal memory and visual learning, and the delayed recall of verbal and visual memory. Liability to schizophrenia was associated with memory impairment, with evidence of significant phenotypic correlations between all episodic memory measures and schizophrenia. Genetic factors were the main source of the phenotypic correlations for immediate recall of visual learning material; both immediate and delayed recall of verbal memory; and delayed recall of visual memory that, for example, shared genetic variance with schizophrenia, which accounted for 88% of the phenotypic correlation (rph=0.41) between the two.ConclusionsVerbal memory and visual learning and memory are moderately heritable, share a genetic overlap with schizophrenia and are valid endophenotypes for the condition. The inclusion of these endophenotypes in genetic association studies may improve the power to detect susceptibility genes for schizophrenia.