Philip McGuire

Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison

BACKGROUND Psychotic disorders, such as schizophrenia, are associated with neuroanatomical abnormalities, but whether these predate the onset of symptoms or develop progressively over the course of illness is unclear. We investigated this issue with MRI to study people with prodromal symptoms who are at ultra high-risk for the development of psychosis. METHODS We did two comparisons, cross-sectional and longitudinal. For the cross-sectional comparison, 75 people with prodromal signs of psychosis were scanned with MRI. After at least 12 months of follow-up, 23 (31%) had developed psychosis and 52 (69%) had not. Baseline MRI data from these two subgroups were compared. For the longitudinal comparison, 21 of the ultra high-risk individuals were scanned again with MRI after at least 12 months. Ten of these had developed psychosis and 11 had not. MRI data from baseline and follow-up were compared within each group of people. FINDINGS In the cross-sectional comparison, compared with people who did not develop psychosis, those who did develop the disorder had less grey matter in the right medial temporal, lateral temporal, and inferior frontal cortex, and in the cingulate cortex bilaterally. In the longitudinal comparison, when re-scanned, individuals who had developed psychosis showed a reduction in grey matter in the left parahippocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri. In those who had not become psychotic, longitudinal changes were restricted to the cerebellum. INTERPRETATION Some of the grey-matter abnormalities associated with psychotic disorders predate the onset of frank symptoms, whereas others appear in association with their first expression.

Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk.

CONTEXT A substantial proportion of people at clinical high risk of psychosis will develop a psychotic disorder over time. However, the risk of transition to psychosis varies between centers, and some recent work suggests that the risk of transition may be declining. OBJECTIVE To quantitatively examine the literature to date reporting the transition risk to psychosis in subjects at clinical high risk. DATA SOURCES The electronic databases were searched until January 2011. All studies reporting transition risks in patients at clinical high risk were retrieved. STUDY SELECTION Twenty-seven studies met the inclusion criteria, comprising a total of 2502 patients. DATA EXTRACTION Transition risks, as well as demographic, clinical, and methodologic variables, were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS There was a consistent transition risk, independent of the psychometric instruments used, of 18% after 6 months of follow-up, 22% after 1 year, 29% after 2 years, and 36% after 3 years. Significant moderators accounting for heterogeneity across studies and influencing the transition risks were the age of participants, publication year, treatments received, and diagnostic criteria used. There was no publication bias, and a sensitivity analysis confirmed the robustness of the core findings. CONCLUSIONS The state of clinical high risk is associated with a very high risk of developing psychosis within the first 3 years of clinical presentation, and the risk progressively increases across this period. The transition risk varies with the age of the patient, the nature of the treatment provided, and the way the syndrome and transition to psychosis are defined.

The Psychosis High-Risk State A Comprehensive State-of-the-Art Review

CONTEXT During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. OBJECTIVE To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. DATA SOURCES Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. STUDY SELECTION AND DATA EXTRACTION Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. DATA SYNTHESIS Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. CONCLUSIONS The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

Elevated striatal dopamine function linked to prodromal signs of schizophrenia.

CONTEXT A major limitation on the development of biomarkers and novel interventions for schizophrenia is that its pathogenesis is unknown. Although elevated striatal dopamine activity is thought to be fundamental to schizophrenia, it is unclear when this neurochemical abnormality develops in relation to the onset of illness and how this relates to the symptoms and neurocognitive impairment seen in individuals with prodromal symptoms of schizophrenia. OBJECTIVES To determine whether striatal dopamine function is elevated in individuals with prodromal symptoms of schizophrenia before the onset of psychosis and to assess how this relates to the symptoms and neurocognitive impairment. DESIGN Case-control study of in vivo striatal dopaminergic function. SETTING Academic research. Patients Patients were recruited from a community mental health service. Twenty-four patients having prodromal symptoms of schizophrenia were compared with 7 patients having schizophrenia and with 12 matched healthy control subjects from the same community. Main Outcome Measure Striatal 6-fluoro-l-dopa F 18-dopa uptake measured using positron emission tomographic (18)F-dopa imaging. RESULTS Striatal (18)F-dopa uptake was elevated in patients with prodromal symptoms of schizophrenia (effect size, 0.75) to an intermediate degree compared with that in patients with schizophrenia (effect size, 1.25). The elevation was localized in the associative striatum in both groups. Moreover, striatal (18)F-dopa uptake in patients with prodromal symptoms of schizophrenia was correlated with the severity of prodromal psychopathologic and neuropsychological impairment but not with the severity of anxiety or depressive symptoms. CONCLUSIONS These findings indicate that dopamine overactivity predates the onset of schizophrenia in individuals with prodromal psychotic symptoms, is predominantly localized in the associative striatum, and is correlated with the severity of symptoms and neurocognitive dysfunction.

The hubs of the human connectome are generally implicated in the anatomy of brain disorders

See Sporns (doi:10.1093/brain/awu148) for a scientific commentary on this article. Brain networks contain a minority of highly connected hub nodes with high topological value and biological cost. Using network analysis of DTI data from healthy volunteers, and meta-analyses of published MRI studies in 26 brain disorders, Crossley et al. show that lesions across disorders tend to be concentrated at hubs.

Cognitive Functioning in Prodromal Psychosis: A Meta-analysis

CONTEXT A substantial proportion of people at clinical high risk (HR) of psychosis will develop a psychotic disorder over time. Cognitive deficits may predate the onset of psychosis and may be useful as markers of increased vulnerability to illness. OBJECTIVE To quantitatively examine the cognitive functioning in subjects at HR in the literature to date. DATA SOURCES Electronic databases were searched until January 2011. All studies reporting cognitive performance in HR subjects were retrieved. STUDY SELECTION Nineteen studies met the inclusion criteria, comprising a total of 1188 HR subjects and 1029 controls. DATA EXTRACTION Neurocognitive functioning and social cognition as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS Subjects at HR were impaired relative to controls on tests of general intelligence, executive function, verbal and visual memory, verbal fluency, attention and working memory, and social cognition. Processing speed domain was also affected, although the difference was not statistically significant. Later transition to psychosis was associated with even more marked deficits in the verbal fluency and memory domains. The studies included reported relatively homogeneous findings. There was no publication bias and a sensitivity analysis confirmed the robustness of the core results. CONCLUSIONS The HR state for psychosis is associated with significant and widespread impairments in neurocognitive functioning and social cognition. Subsequent transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.

Increased blood flow in Broca's area during auditory hallucinations in schizophrenia

Verbal auditory hallucinations are common in schizophrenia but little is known about how they arise. We have used single photon emission tomography (SPET) to measure regional cerebral blood flow with the aim of identifying brain areas that are especially active during auditory hallucinations. We scanned twelve men with schizophrenia while they were experiencing hallucinations. The subjects were rescanned under identical conditions when their hallucinations had resolved (mean 19 weeks later). Blood flow was significantly greater during hallucinations than in the non-hallucinating state in Brocas area (mean count density on SPET 1.18 [SD 0.04] vs 1.13 [0.06]; p < 0.001); flow was also higher during hallucinations in the left anterior cingulate cortex and regions in the left temporal lobe, but these differences did not achieve significance. The increased flow in Brocas area was not accounted for by changes in other clinical variables nor by changes in the dose of neuroleptic drugs. These findings suggest that the production of auditory hallucinations in schizophrenia is associated with increased activity in a network of cortical areas specialised for language.

The hallucinating brain : A review of structural and functional neuroimaging studies of hallucinations

Hallucinations remains one of the most intriguing phenomena in psychopathology. In the past two decades the advent of neuroimaging techniques have allowed researchers to investigate what is happening in the brain of those who experience hallucinations. In this article we review both structural and functional neuroimaging studies of patients with auditory and visual hallucinations as well as a small number of studies that have assessed cognitive processes associated with hallucinations in healthy volunteers. The current literature suggests that in addition to secondary (and occasionally primary) sensory cortices, dysfunction in prefrontal premotor, cingulate, subcortical and cerebellar regions also seem to contribute to hallucinatory experiences. Based on the findings of these studies we tentatively propose a neurocognitive model in which both bottom-up and top-down processes interact to produce these erroneous percepts. Finally, directions for future work are discussed.

Methods for Diagnosis and Treatment of Stimulus-Correlated Motion in Generic Brain Activation Studies Using fMRI

Movement‐related effects in realigned fMRI timeseries can be corrected by regression on linear functions of estimated positional displacements of an individual subjects head during image acquisition. However, this entails biased (under)estimation of the experimental effect whenever subject motion is not independent of the experimental input function. Methods for diagnosing such stimulus‐correlated motion (SCM) are illustrated by application to fMRI data acquired from 5 schizophrenics and 5 normal controls during periodic performance of a verbal fluency task. The schizophrenic group data were more severely affected by SCM than the control group data. Analysis of covariance (ANCOVA) was used, with a voxelwise measure of SCM as a covariate, to estimate between‐group differences in power of periodic signal change while controlling for variability in SCM across groups. Failure to control for SCM in this way substantially exaggerated the number of voxels, apparently demonstrating a between‐group difference in task response. Hum. Brain Mapping 7:38–48, 1999.

Diffusion tensor imaging in schizophrenia

BACKGROUND Diffusion tensor imaging (DTI) is a relatively new neuroimaging technique that can be used to examine the microstructure of white matter in vivo. A systematic review of DTI studies in schizophrenia was undertaken to test the hypothesis that DTI can detect white matter differences between schizophrenia patients and normal control subjects. METHODS EMBASE, PubMed, Medline, and PsychInfo were searched online and key journals were searched manually for studies comparing anisotropy (a measure of white matter integrity) between patients and control subjects. Nineteen articles were systematically reviewed. RESULTS Though 16 studies found differences, methodological and data differences prevented a meta-analysis. Fourteen studies found reduced anisotropy in patients; two studies found only a loss of normal asymmetry. The region of investigation varied across studies, however, and when the same region (for example, the cingulum) was examined in different studies, as many failed to find a difference as found one. These inconsistencies may be the result of small sample sizes and differences in methodology. CONCLUSIONS Diffusion tensor imaging has yet to provide consistent findings of white matter abnormalities in schizophrenia. Its potential as a means of examining anatomical connectivity may be realized with the study of larger, more homogenous groups of subjects and with ongoing improvements in image analysis.