Christos Pantelis

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.

Whole-brain anatomical networks: Does the choice of nodes matter?

Whole-brain anatomical connectivity in living humans can be modeled as a network with diffusion-MRI and tractography. Network nodes are associated with distinct grey-matter regions, while white-matter fiber bundles serve as interconnecting network links. However, the lack of a gold standard for regional parcellation in brain MRI makes the definition of nodes arbitrary, meaning that network nodes are defined using templates employing either random or anatomical parcellation criteria. Consequently, the number of nodes included in networks studied by different authors has varied considerably, from less than 100 up to more than 10(4). Here, we systematically and quantitatively assess the behavior, structure and topological attributes of whole-brain anatomical networks over a wide range of nodal scales, a variety of grey-matter parcellations as well as different diffusion-MRI acquisition protocols. We show that simple binary decisions about network organization, such as whether small-worldness or scale-freeness is evident, are unaffected by spatial scale, and that the estimates of various organizational parameters (e.g. small-worldness, clustering, path length, and efficiency) are consistent across different parcellation scales at the same resolution (i.e. the same number of nodes). However, these parameters vary considerably as a function of spatial scale; for example small-worldness exhibited a difference of 95% between the widely-used automated anatomical labeling (AAL) template (approximately 100 nodes) and a 4000-node random parcellation (sigma(AAL)=1.9 vs. sigma(4000)=53.6+/-2.2). These findings indicate that any comparison of network parameters across studies must be made with reference to the spatial scale of the nodal parcellation.

Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives

BACKGROUND Our aim was to delineate neuropsychological deficits related to genetic susceptibility, illness process and iatrogenic factors in bipolar disorder (BD). METHODS Following an extensive publication search on several databases, meta-analyses were conducted for 18 cognitive variables in studies that compared performances of euthymic BD patients (45 studies; 1423 subjects) or first-degree relatives of BD patients (17 studies; 443 subjects) with healthy controls. The effect of demographic variables and confounding factors like age of onset, duration of illness and medication status were analysed using the method of meta-regression. RESULTS While response inhibition, set shifting, executive function, verbal memory and sustained attention deficits were common features for both patient (medium to large effect sizes) and relative groups (small to medium effect sizes), processing speed, visual memory and verbal fluency deficits were only observed in patients. Medication effects contributed to psychomotor slowing in BD patients. Earlier age of onset was associated with verbal memory impairment and psychomotor slowing. LIMITATION Data related to some confounding variables was not reported in a substantial number of extracted studies. CONCLUSIONS Response inhibition deficit, a potential marker of ventral prefrontal dysfunction, seems to be the most prominent endophenotype of BD. The cognitive endophenotype of BD also appears to involve fronto-temporal and fronto-limbic related cognitive impairments. Processing speed impairment is related, at least partly, to medication effects indicating the influence of confounding factors rather than genetic susceptibility. Patterns of sustained attention and processing speed impairments differ from schizophrenia. Future work in this area should differentiate cognitive deficits associated with disease genotype from impairments related to other confounding factors.

Normative Data From the Cantab. I: Development of Executive Function Over the Lifespan

The study of executive function within a developmental framework has proven integral to the advancement of knowledge concerning the acquisition and decline of higher skill processes. Still in its early stages, there exists a discontinuity in the literature between the exploration of executive capacity in young children and the elderly. Research of age-related differences utilising a lifespan approach has been restricted by the lack of assessment tools for the measurement of executive skills that are applicable across all age levels. This paper addresses these issues using the computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB) to identify periods of development in executive capacities using a normative sample of 194 participants ranging in age from 8 to 64 years. Findings of executive function in children as young as 8 years of age were extended, with functional gains found in the efficiency of working memory capacity, planning and problem-solving abilities, between the ages of 15 and 19 years and again at 20–29 years of age. Cognitive flexibility was assessed at adult-levels in even the youngest children. Declines in performance on all tasks were revealed for the 50–64 year old sample, providing support for the vulnerability of executive skills to normal aging.

Schizophrenia, neuroimaging and connectomics

Schizophrenia is frequently characterized as a disorder of brain connectivity. Neuroimaging has played a central role in supporting this view, with nearly two decades of research providing abundant evidence of structural and functional connectivity abnormalities in the disorder. In recent years, our understanding of how schizophrenia affects brain networks has been greatly advanced by attempts to map the complete set of inter-regional interactions comprising the brains intricate web of connectivity; i.e., the human connectome. Imaging connectomics refers to the use of neuroimaging techniques to generate these maps which, combined with the application of graph theoretic methods, has enabled relatively comprehensive mapping of brain network connectivity and topology in unprecedented detail. Here, we review the application of these techniques to the study of schizophrenia, focusing principally on magnetic resonance imaging (MRI) research, while drawing attention to key methodological issues in the field. The published findings suggest that schizophrenia is associated with a widespread and possibly context-independent functional connectivity deficit, upon which are superimposed more circumscribed, context-dependent alterations associated with transient states of hyper- and/or hypo-connectivity. In some cases, these changes in inter-regional functional coupling dynamics can be related to measures of intra-regional dysfunction. Topological disturbances of functional brain networks in schizophrenia point to reduced local network connectivity and modular structure, as well as increased global integration and network robustness. Some, but not all, of these functional abnormalities appear to have an anatomical basis, though the relationship between the two is complex. By comprehensively mapping connectomic disturbances in patients with schizophrenia across the entire brain, this work has provided important insights into the highly distributed character of neural abnormalities in the disorder, and the potential functional consequences that these disturbances entail.

Regional brain abnormalities associated with long-term heavy cannabis use.

CONTEXT Cannabis is the most widely used illicit drug in the developed world. Despite this, there is a paucity of research examining its long-term effect on the human brain. OBJECTIVE To determine whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor-rich regions of the brain, the hippocampus and the amygdala. DESIGN Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging. SETTING Participants were recruited from the general community and underwent imaging at a hospital research facility. PARTICIPANTS Fifteen carefully selected long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched nonusing control subjects (mean age, 36.4 years). MAIN OUTCOME MEASURES Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured. RESULTS Cannabis users had bilaterally reduced hippocampal and amygdala volumes (P = .001), with a relatively (and significantly [P = .02]) greater magnitude of reduction in the former (12.0% vs 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years (P = .01) and subthreshold positive psychotic symptoms (P < .001). Positive symptom scores were also associated with cumulative exposure to cannabis (P = .048). Although cannabis users performed significantly worse than controls on verbal learning (P < .001), this did not correlate with regional brain volumes in either group. CONCLUSIONS These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users and corroborate similar findings in the animal literature. These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.

Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children.

BACKGROUND Executive function deficits have been reported repeatedly in children with Attention Deficit Hyperactivity Disorder (ADHD). Stimulant medication has been shown to be effective in improving cognitive performance on most executive function tasks, but neuropsychological tests of executive function in this population have yielded inconsistent results. Methodological limitations may explain these inconsistencies. This study aimed to measure executive function in medicated and non-medicated children with ADHD by using a computerized battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), which is sensitive to executive function deficits in older patients with frontostriatal neurological impairments. METHODS Executive function was assessed in 30 children with ADHD: 15 were stimulant medication naive and 15 were treated with stimulant medication. These two groups were compared to 15 age, sex and IQ matched controls. RESULTS The unmedicated children with ADHD displayed specific cognitive impairments on executive function tasks of spatial short-term memory, spatial working memory, set-shifting ability and planning ability. Impairments were also seen on spatial recognition memory and delayed matching to sample, while pattern recognition memory remained intact. The medicated children with ADHD were not impaired on any of the above executive function tasks except for deficits in spatial recognition memory. CONCLUSIONS ADHD is associated with deficits in executive function. Stimulant medication is associated with better executive function performance. Prospective follow-up studies are required to examine these effects.

Disrupted Axonal Fiber Connectivity in Schizophrenia

BACKGROUND Schizophrenia is believed to result from abnormal functional integration of neural processes thought to arise from aberrant brain connectivity. However, evidence for anatomical dysconnectivity has been equivocal, and few studies have examined axonal fiber connectivity in schizophrenia at the level of whole-brain networks. METHODS Cortico-cortical anatomical connectivity at the scale of axonal fiber bundles was modeled as a network. Eighty-two network nodes demarcated functionally specific cortical regions. Sixty-four direction diffusion tensor-imaging coupled with whole-brain tractography was performed to map the architecture via which network nodes were interconnected in each of 74 patients with schizophrenia and 32 age- and gender-matched control subjects. Testing was performed to identify pairs of nodes between which connectivity was impaired in the patient group. The connectional architecture of patients was tested for changes in five network attributes: nodal degree, small-worldness, efficiency, path length, and clustering. RESULTS Impaired connectivity in the patient group was found to involve a distributed network of nodes comprising medial frontal, parietal/occipital, and the left temporal lobe. Although small-world attributes were conserved in schizophrenia, the cortex was interconnected more sparsely and up to 20% less efficiently in patients. Intellectual performance was found to be associated with brain efficiency in control subjects but not in patients. CONCLUSIONS This study presents evidence of widespread dysconnectivity in white-matter connectional architecture in a large sample of patients with schizophrenia. When considered from the perspective of recent evidence for impaired synaptic plasticity, this study points to a multifaceted pathophysiology in schizophrenia encompassing axonal as well as putative synaptic mechanisms.

Neuroanatomical abnormalities in schizophrenia: A multimodal voxelwise meta-analysis and meta-regression analysis

Despite an increasing number of published voxel based morphometry studies of schizophrenia, there has been no adequate attempt to examine gray (GM) and white matter (WM) abnormalities and the heterogeneity of published findings. In the current article, we used a coordinate based meta-analysis technique to simultaneously examine GM and WM abnormalities in schizophrenia and to assess the effects of gender, chronicity, negative symptoms and other clinical variables. 79 studies meeting our inclusion criteria were included in the meta-analysis. Schizophrenia was associated with GM reductions in the bilateral insula/inferior frontal cortex, superior temporal gyrus, anterior cingulate gyrus/medial frontal cortex, thalamus and left amygdala. In WM analyses of volumetric and diffusion-weighted images, schizophrenia was associated with decreased FA and/or WM in interhemispheric fibers, anterior thalamic radiation, inferior longitudinal fasciculi, inferior frontal occipital fasciculi, cingulum and fornix. Male gender, chronic illness and negative symptoms were associated with more severe GM abnormalities and illness chronicity was associated with more severe WM deficits. The meta-analyses revealed overlapping GM and WM structural findings in schizophrenia, characterized by bilateral anterior cortical, limbic and subcortical GM abnormalities, and WM changes in regions including tracts that connect these structures within and between hemispheres. However, the available findings are biased towards characteristics of schizophrenia samples with poor prognosis.

Mapping grey matter reductions in schizophrenia: an anatomical likelihood estimation analysis of voxel-based morphometry studies.

Voxel-based morphometry (VBM) is a popular tool for mapping neuroanatomical changes in schizophrenia patients. Several recent meta-analyses have identified the brain regions in which patients most consistently show grey matter reductions, although they have not examined whether such changes reflect differences in grey matter concentration (GMC) or grey matter volume (GMV). These measures assess different aspects of grey matter integrity, and may therefore reflect different pathological processes. In this study, we used the Anatomical Likelihood Estimation procedure to analyse significant differences reported in 37 VBM studies of schizophrenia patients, incorporating data from 1646 patients and 1690 controls, and compared the findings of studies using either GMC or GMV to index grey matter differences. Analysis of all studies combined indicated that grey matter reductions in a network of frontal, temporal, thalamic and striatal regions are among the most frequently reported in literature. GMC reductions were generally larger and more consistent than GMV reductions, and were more frequent in the insula, medial prefrontal, medial temporal and striatal regions. GMV reductions were more frequent in dorso-medial frontal cortex, and lateral and orbital frontal areas. These findings support the primacy of frontal, limbic, and subcortical dysfunction in the pathophysiology of schizophrenia, and suggest that the grey matter changes observed with MRI may not necessarily result from a unitary pathological process.