Papers by Andrew McIntosh
Biological Psychiatry, 2004
Background: Structural brain abnormalities in schizophrenia are well replicated; many emerge befo... more Background: Structural brain abnormalities in schizophrenia are well replicated; many emerge before the onset of illness and are present in relatives who remain well. Structural changes in bipolar disorder are less clearly established. The possibility that structural abnormalities might provide a means by which the disorders might be separated is one that has attracted limited research effort. This study sought to examine these issues and clarify the associations of phenotypic expression and genetic liability. Methods: Forty-nine control subjects, 71 patients, and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone, and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives were recruited from the families of the three patient groups. Subjects underwent a magnetic resonance imaging scan of the brain, which was analyzed with a grey-matter-optimized, voxel-based morphometry technique. Results: Compared with control subjects, all patient and relative groups showed evidence of reduced anterior thalamic gray matter. Reductions in middle prefrontal gyrus and dorsomedial thalamus were specific to participants with schizophrenia. Conclusions: Whereas prefrontal and dorsomedial thalamic gray matter reductions seem to be specific to schizophrenia, anterior thalamic reductions seem to be a marker of liability to psychosis in general. These results are discussed in the context of their functional role and in terms of their connections with other cortical and subcortical structures.
Evidence-based Mental Health, 2004
Psychiatry Research, 2004
Repetitive transcranial magnetic stimulation (rTMS) has been reported to be an effective treatmen... more Repetitive transcranial magnetic stimulation (rTMS) has been reported to be an effective treatment for auditory hallucination (AH) in schizophrenia patients. The efficacy of rTMS and immediate changes in cardiac autonomic function (CAF) after rTMS in severe schizophrenia patients with AH (n = 8) were investigated. Three patients reported a Ն50% reduction of AH after rTMS. The ratio of low-frequency power to high-frequency power, an index of sympathetic modulation, increased significantly after rTMS. Further replication studies with larger sample sizes are indicated.
Journal of Psychopharmacology, 2005
Various lines of evidence suggest an association between cannabis and psychosis. Five years ago, ... more Various lines of evidence suggest an association between cannabis and psychosis. Five years ago, the only significant case-control study addressing this question was the Swedish Conscript Cohort. Within the last few years, other studies have emerged, allowing the evidence for cannabis as a risk factor to be more systematically reviewed and assessed. Using specific search criteria on Embase, PsychINFO and Medline, all studies examining cannabis as an independent risk factor for schizophrenia, psychosis or psychotic symptoms, published between January 1966 and January 2004, were examined. Additional studies were also reviewed from references found in retrieved articles, reviews, and a cited reference search (ISI-Web of Science). Studies selected for meta-analysis included: (i) case-control studies where exposure to cannabis preceded the onset of schizophrenia or schizophrenia-like psychosis and (ii) cohort studies of healthy individuals recruited before the median age of illness onset, with cannabis exposure determined prospectively and blind to eventual diagnosis. Studies of psychotic symptoms were also tabulated for further discussion. Eleven studies were identified examining the relationship between cannabis use and psychosis. Seven were included in the meta-analysis, with a derived odds ratio (fixed effects) of 2-9 (95 % confidence interval = 2.4-3.6). No evidence of publication bias or heterogeneity was found. Early use of cannabis did appear to increase the risk of psychosis. For psychotic symptoms, a dose-related effect of cannabis use was seen, with vulnerable groups including individuals who used cannabis during adolescence, those who had previously experienced psychotic symptoms, and those at high genetic risk of developing schizophrenia. In conclusion, the available evidence supports the hypothesis that cannabis is an independent risk factor, both for psychosis and the development of psychotic symptoms. Addressing cannabis use, particularly in vulnerable populations, is likely to have beneficial effects on psychiatric morbidity.
This article reviews the evidence for changes in the structure and function of the brain in subje... more This article reviews the evidence for changes in the structure and function of the brain in subjects at high risk of schizophrenia for genetic reasons during the genesis of the disorder. We first highlight the structural and functional abnormalities in schizophrenia and whether any similar or lesser abnormalities are apparent in unaffected relatives. There is good evidence for subtle abnormalities of hippocampal and ventricle volume in relatives that are not as marked as the deficits in schizophrenia. In addition, the functional imaging literature suggests that prefrontal cortex function may deteriorate in those at risk who go on to develop the disorder. We then review the findings from longitudinal imaging studies of those at high risk, particularly the Edinburgh High-Risk Study, which report gray matter density reductions in medial and lateral temporal lobe because people develop schizophrenia, as well as functional abnormalities which precede onset. We conclude by quoting our own and others' imaging studies of the associations of genetic and other risk factors for schizophrenia, including stressful life events and cannabis use, which provide mechanistic examples of how these changes may be brought about. Overall, the literature supports the view that there are measurable changes in brain structure and function during the genesis of the disorder, which provide opportunities for early detection and intervention.
Biological Psychiatry, 2006
Prospective studies of young individuals at high risk of schizophrenia allow the investigation of... more Prospective studies of young individuals at high risk of schizophrenia allow the investigation of whether neural abnormalities predate development of illness and, if present, have the potential to identify those who may become ill. We studied young individuals with at least two relatives with the disorder. At baseline functional magnetic resonance imaging (fMRI) scan, none met criteria for any psychiatric disorder, but four subjects subsequently developed schizophrenia. We report the baseline functional imaging findings in these subjects performing a sentence completion task compared with normal control subjects (n = 21) and those at high risk with (n = 21) and without (n = 41) psychotic symptoms who have not developed the disorder. High-risk subjects who became ill demonstrated increased activation of the parietal lobe, decreased activation of the anterior cingulate, and smaller increases in activation with increasing task difficulty in the right lingual gyrus and bilateral temporal regions. The hypothesized predictive power of parietal activation was supported only in combination with lingual gyrus activity, which gave a positive predictive value in this sample of .80. Although these findings should be considered cautiously, as only four subjects who had an fMRI scan subsequently became ill, they suggest functional abnormalities are present in high-risk subjects who later became ill, which distinguish them not only from normal control subjects but also those at high risk who had not developed the disorder. These differences are detectable with fMRI and may have clinical utility.
Neuroimage, 2007
A three-fold enhanced risk of schizophrenia is conferred by learning disability. Here we use voxe... more A three-fold enhanced risk of schizophrenia is conferred by learning disability. Here we use voxel-based morphometry (VBM) to investigate grey matter correlates of early psychotic and related symptoms in 137 adolescents at enhanced risk of this disorder because of intellectual disability. Anxiety, hallucinations, incoherence of speech and delusions were assessed at clinical interview, and VBM was used to examine linear associations between symptom severity and grey matter density (GMD). We found significant correlations between anxiety and GMD in the right dorsomedial thalamic nucleus, left parahippocampal gyrus and left hippocampus. Incoherence of speech was associated with GMD in the left cerebellar hemisphere. Gender-separate analysis demonstrated correlations between anxiety and GMD in the right dorsomedial thalamic nucleus of males and the right pulvinar nucleus of females, hallucinations and GMD in the right STG of males, delusions and GMD in the left middle temporal gyrus (MTG) of females, and incoherence of speech and GMD in the right MTG of males and both cerebellar hemispheres and right inferior temporal gyrus of females. Findings are consistent with symptomstructure associates previously reported in populations with schizophrenia or at enhanced genetic risk, and suggest an anatomical basis for the psychopathology found in this young nonclinical population.
Biological Psychiatry, 2007
Structural brain abnormalities of the medial temporal lobe have been found in people with bipolar... more Structural brain abnormalities of the medial temporal lobe have been found in people with bipolar disorder (BPD). It is not known whether these abnormalities progress over the course of the illness or how they relate to neuropsychologic functioning. We sought to address these uncertainties in a prospective cohort study of people with bipolar I disorder. Twenty patients with bipolar I disorder and 21 control subjects were recruited from the community. Participants were group matched for age, sex, and premorbid IQ. Longitudinal change in gray matter density was assessed using magnetic resonance imaging and evaluated using the technique of tensor-based morphometry with SPM2 software. Changes in gray and white matter density were estimated and compared with changes in cognitive function and clinical outcome. Patients with BPD showed a larger decline in hippocampal, fusiform, and cerebellar gray matter density over 4 years than control subjects. No significant changes in white matter density were found. Reductions in temporal lobe gray matter correlated with decline in intellectual function and with the number of intervening mood episodes over the follow-up period. Patients with BPD lose hippocampal, fusiform and cerebellar gray matter at an accelerated rate compared with healthy control subjects. This tissue loss is associated with deterioration in cognitive function and illness course.
Nature Neuroscience, 2006
Biological Psychiatry, 2005
This study sought to assess white matter density in patients and relatives with histories of bipo... more This study sought to assess white matter density in patients and relatives with histories of bipolar disorder and/or schizophrenia. Subjects included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives of the three patient groups were also recruited. Subjects underwent an MRI brain scan which was analyzed using a white-matter optimized technique. Subjects with schizophrenia and bipolar disorder showed reduced white matter density in the anterior limb of the internal capsule which was not found in unaffected relatives. Reductions were found in frontal subgyral white matter density in affected subjects with a family history of schizophrenia only. Abnormal anterior internal capsule white matter may provide a structural substrate for both disorders.
Psychiatry Research, 2006
Theory of Mind (ToM) is the ability to correctly determine the intentions and behaviours of other... more Theory of Mind (ToM) is the ability to correctly determine the intentions and behaviours of others. It is known that this capability is compromised in individuals with schizophrenia. It is has not been fully elucidated whether this observed phenomenon is of a state or trait nature. This study investigated whether ToM impairments could be linked to schizophrenia liability. A battery of ToM tests (the Hinting Task, a Self-Monitoring drawing task and cartoon picture stories) were used to compare healthy controls (n = 13) with relatives of individuals with schizophrenia who had experienced psychotic symptoms (HR+, n = 12) and those relatives who had not (HR−, n = 13). All participants belonged to the Edinburgh High Risk Study. Significant group differences were seen on the Self-Monitoring and cartoon tasks for the HR+ group, particularly those who had experienced symptoms at or around the time of testing. The observed ToM deficits measured by this battery of ToM tasks appeared to be related to state effects rather than enhanced risk of schizophrenia.
Bipolar Disorders, 2009
Objectives: Strong qualitative and quantitative evidence exists of white matter abnormalities in... more Objectives: Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders.Methods: DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis.Results: Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication.Conclusions: Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.
Biological Psychiatry, 2008
Abnormalities of white matter integrity have been repeatedly demonstrated in both schizophrenia a... more Abnormalities of white matter integrity have been repeatedly demonstrated in both schizophrenia and bipolar disorder with voxel based methods. Because these methods are limited in their ability to localize deficits to specific tracts, we sought to investigate alterations in fractional anisotropy (FA) in the uncinate fasciculus and anterior thalamic radiation with probabilistic tractography. Individuals with schizophrenia (n = 25) or bipolar disorder (n = 40) were recruited from families with two or more affected members and age-matched to a control group (n = 49). All participants underwent diffusion tensor magnetic resonance imaging that was subsequently analyzed with probabilistic tractography. Mean FA was calculated bilaterally for the uncinate and anterior thalamic radiation and compared between groups with repeated measures analysis of variance. Patients with schizophrenia or bipolar disorder showed common reductions in the uncinate fasciculus and anterior thalamic radiation. These reductions were unrelated to age, duration of illness, current medication, or current psychiatric symptoms in all patients or the lifetime presence of psychotic symptoms in bipolar subjects. Patients with schizophrenia or bipolar disorder show common abnormalities in the uncinate fasciculus and anterior thalamic radiation that fail to respect traditional diagnostic boundaries. These deficits might be related to shared risk factors and disease mechanisms common to both disorders.
Large-scale clinical studies in neuro-imaging are hampered by several factors including variances... more Large-scale clinical studies in neuro-imaging are hampered by several factors including variances in acquisition techniques, quality assurance and access to remote datasets. The Neurogrid project will build on the experience of other UK e-science projects to assemble a grid infrastructure, and apply this to three exemplar areas: stroke, dementia and psychosis, to conduct collaborative neuroscience research.
European Psychiatry, 2008
Background. e Structural brain abnormalities have been described in autism but studies are often ... more Background. e Structural brain abnormalities have been described in autism but studies are often small and contradictory. We aimed to identify which brain regions can reliably be regarded as different in autism compared to healthy controls.
Biological Psychiatry, 2007
There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the et... more There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons. In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known. The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance. The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples.
American Journal of Medical Genetics Part B-neuropsychiatric Genetics, 2006
Bipolar disorder and schizophrenia are highly heritable conditions that are associated with struc... more Bipolar disorder and schizophrenia are highly heritable conditions that are associated with structural brain abnormalities. Although brain abnormalities are found in the well relatives of people with schizophrenia, the extent to which genetic liability relates to brain structure in either disorder is still unclear. This study sought to ascertain the effects of genetic liability to schizophrenia and bipolar disorder on white and grey matter volume in patients with these diagnoses and their well relatives. Seventy-one patients and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Samples of unaffected relatives of each patient group were also recruited. Subjects underwent an MRI scan of the brain, which was analysed using optimised voxel-based morphometry (VBM). Grey and white matter volume was then related to a continuous measure of genetic liability based on a threshold-liability model. Genetic liability to schizophrenia was associated with decreased grey matter volume in dorso- (DLPFC) and ventrolateral prefrontal (VLPFC) cortices. The relationship remained after diagnostic status had been taken into account. Complementary white matter changes were also demonstrated. No relationship was demonstrated between a genetic liability to bipolar disorder and either white or grey matter volume. Genes that raise the likelihood of developing schizophrenia may exert their effects by diminishing grey matter volume in the DLPFC and VLPFC and their associated white matter connections. Genes for bipolar illness might have subtle effects on brain structure, which may need particularly large samples to detect. © 2005 Wiley-Liss, Inc.
Neuroimage, 2006
Theory of Mind (ToM) or mentalizing is the ability of individuals to determine the intentions and... more Theory of Mind (ToM) or mentalizing is the ability of individuals to determine the intentions and behavior of others. This ability is known to be compromised in schizophrenia and has been shown to fluctuate with symptom severity. Neuropsychological investigations into relatives of individuals with schizophrenia have shown that some relatives also show a deficit in this area of social cognition. In order to address this state and trait issue, we investigated the performance of high-risk relatives of individuals with schizophrenia to those of a matched control group (n = 13) on a blocked design visual joke fMRI paradigm. The task involved looking at two sets of cartoon jokes, one set which required mentalizing abilities to understand the jokes and another set that did not require such abilities. Relatives were divided into two groups based on the presence (HR+, n = 12) or absence (HRÀ, n = 12) of positive symptoms. The task provided robust activations across the groups in areas previously associated with mentalizing abilities, such as the PFC, precuneus, and temporal lobes. Significant between-group activations were observed in the PFC (primarily BA6, 8, and 9) with the HRÀ activating significantly greater than the HR+ in these regions. Both a secondary state-specific analysis and a third post hoc analysis further investigating state effects showed significant PFC betweengroup differences. This study is the first time relatives of individuals with schizophrenia have been imaged using a ToM paradigm, and the results provide evidence of both a state and state-mediated trait effect. D
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Papers by Andrew McIntosh