James Woolley

Progressive increase of frontostriatal brain activation from childhood to adulthood during event-related tasks of cognitive control

Higher cognitive inhibitory and attention functions have been shown to develop throughout adolescence, presumably concurrent with anatomical brain maturational changes. The relatively scarce developmental functional imaging literature on cognitive control, however, has been inconsistent with respect to the neurofunctional substrates of this cognitive development, finding either increased or decreased executive prefrontal function in the progression from childhood to adulthood. Such inconsistencies may be due to small subject numbers or confounds from age‐related performance differences in block design functional MRI (fMRI). In this study, rapid, randomized, mixed‐trial event‐related fMRI was used to investigate developmental differences of the neural networks mediating a range of motor and cognitive inhibition functions in a sizeable number of adolescents and adults. Functional brain activation was compared between adolescents and adults during three different executive tasks measuring selective motor response inhibition (Go/no‐go task), cognitive interference inhibition (Simon task), and attentional set shifting (Switch task). Adults compared with children showed increased brain activation in task‐specific frontostriatal networks, including right orbital and mesial prefrontal cortex and caudate during the Go/no‐go task, right mesial and inferior prefrontal cortex, parietal lobe, and putamen during the Switch task and left dorsolateral and inferior frontotemporoparietal regions and putamen during the Simon task. Whole‐brain regression analyses with age across all subjects showed progressive age‐related changes in similar and extended clusters of task‐specific frontostriatal, frontotemporal, and frontoparietal networks. The findings suggest progressive maturation of task‐specific frontostriatal and frontocortical networks for cognitive control functions in the transition from childhood to mid‐adulthood. Hum Brain Mapp, 2006.

Neuroanatomical Abnormalities That Predate the Onset of Psychosis: A Multicenter Study

CONTEXT People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent. OBJECTIVE To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites. DESIGN Case-control study. SETTING Multisite. PARTICIPANTS A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not. MAIN OUTCOME MEASURES Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry. RESULTS The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not. CONCLUSIONS Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder.

What causes the onset of psychosis

It has become increasingly clear that the simple neurodevelopmental model fails to explain many aspects of schizophrenia including the timing of the onset, and the nature of the abnormal perceptions. Furthermore, we do not know why some members of the general population have anomalous experiences but remain well, while others enter the prodrome of psychosis, and a minority progress to frank schizophrenia. We suggest that genes or developmental damage result in individuals vulnerable to dopamine deregulation. In contemporary society, this is often compounded by abuse of drugs such as amphetamines and cannabis, which then propel the individual into a state of dopamine-induced misinterpretation of the environment. Certain types of social adversity such as migration and social isolation, as well as affective change can also contribute to this. Thereafter, biased cognitive appraisal processes result in delusional interpretation of the abnormal perceptual experiences. Thus, a plausible model of the onset of psychosis needs to draw not only on neuroscience, but also on the insights of social psychiatry and cognitive psychology.

Disorder-specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention-deficit hyperactivity disorder compared to boys with obsessive-compulsive disorder

Inhibitory dysfunction is a key behavioral and cognitive phenotype of attention‐deficit hyperactivity disorder (ADHD) and obsessive–compulsive disorder (OCD). Both disorders show neuropsychological deficits and fronto‐striatal dysfunction during tasks of motor response inhibition and cognitive flexibility. This study investigates differences and commonalities in functional neural networks mediating inhibitory control between adolescents with ADHD and those with OCD to identify disorder‐specific neurofunctional markers that distinguish these two inhibitory disorders.

Alterations in White Matter Evident Before the Onset of Psychosis

Background Psychotic disorders are associated with widespread reductions in white matter (WM) integrity. However, the stage at which these abnormalities first appear and whether they are correlates of psychotic illness, as opposed to an increased vulnerability to psychosis, is unclear. We addressed these issues by using diffusion tensor imaging (DTI) to study subjects at ultra high risk (UHR) of psychosis before and after the onset of illness. Methods Thirty-two individuals at UHR for psychosis, 32 controls, and 15 patients with first-episode schizophrenia were studied using DTI. The UHR subjects and controls were re-scanned after 28 months. During this period, 8 UHR subjects had developed schizophrenia. Between-group differences in fractional anisotropy (FA) and diffusivity were evaluated cross sectionally and longitudinally using a nonparametric voxel-based analysis. Results At baseline, WM DTI properties were significantly different between the 3 groups (P < .001). Relative to controls, first-episode patients showed widespread reductions in FA and increases in diffusivity. DTI indices in the UHR group were intermediate relative to those in the other 2 groups. Longitudinal analysis revealed a significant group by time interaction in the left frontal WM (P < .001). In this region, there was a progressive reduction in FA in UHR subjects who developed psychosis that was not evident in UHR subjects who did not make a transition. Conclusions People at UHR for psychosis show alterations in WM qualitatively similar to, but less severe than, those in patients with schizophrenia. The onset of schizophrenia may be associated with a progressive reduction in the integrity of the frontal WM.

White matter microstructure in schizophrenia: effects of disorder, duration and medication

Background Diffusion tensor magnetic resonance imaging studies in schizophrenia to date have been largely inconsistent. This may reflect variation in methodology, and the use of small samples with differing illness duration and medication exposure. Aims To determine the extent and location of white matter microstructural changes in schizophrenia, using optimised diffusion tensor imaging in a large patient sample, and to consider the effects of illness duration and medication exposure. Method Scans from 76 patients with schizophrenia and 76 matched controls were used to compare fractional anisotropy, a measure of white matter microstructural integrity, between the groups. Results We found widespread clusters of reduced fractional anisotropy in patients, affecting most major white matter tracts. These reductions did not correlate with illness duration, and there was no difference between age-matched chronically and briefly medicated patients. Conclusions The finding of widespread fractional anisotropy reductions in our larger sample of patients with schizophrenia may explain some of the inconsistent findings of previous, smaller studies.

Economic impact of early intervention in people at high risk of psychosis

Background Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis. Method The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model. Results Over the initial 12 months from presentation, the costs of the OASIS intervention were £1872 higher than CAU. However, after 24 months they were £961 less than CAU. Conclusions This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.

Altered brain function directly related to structural abnormalities in people at ultra high risk of psychosis: Longitudinal VBM-fMRI study

BACKGROUND Several studies have indicated that people with prodromal signs of psychosis show alterations in the structure and function of the brain when they first present to clinical services. However, the longitudinal course of these abnormalities, and how they relate to subsequent clinical and functional outcome is relatively unclear. METHODS A cohort of subjects at ultra high risk of psychosis were studied using functional magnetic resonance imaging (fMRI) in conjunction with the N-Back task, and volumetric MRI at first clinical presentation and again after one year. Levels of psychopathology and global functioning were assessed at the same time points using the CAARMS, PANSS, and the GAF scale. RESULTS At baseline, the high risk group showed reduced activation during the task in the left middle frontal gyrus, supramarginal gyrus and inferior parietal lobule, and reduced gray matter volume in the left middle and medial frontal gyri, left insula and the right anterior cingulate gyrus. Within the high-risk group, there was a positive correlation between the magnitude of the functional and structural alterations in the left middle frontal gyrus. Between presentation and follow up, the severity of perceptual disorder and thought disorder (rated by the CAARMS), and of general psychopathology (rated by the PANSS general score) decreased, and the level of global functioning improved. This clinical and functional improvement was associated with a longitudinal increase in activation in the anterior cingulate and right parahippocampal gyrus. The change in anterior cingulate response was directly correlated with the improvement in the GAF score. CONCLUSIONS In subjects presenting with prodromal signs of psychosis, reduced prefrontal activation during a working memory task is associated with a reduction in gray matter volume in the same area. Changes in anterior cingulate activation were correlated with functional improvement in this group, consistent with the role of this region in multiple cognitive and social processes.

Disorder-Specific Dysfunctions in Patients With Attention-Deficit/Hyperactivity Disorder Compared to Patients With Obsessive-Compulsive Disorder During Interference Inhibition and Attention Allocation

Background: Abnormalities in inhibitory control and underlying fronto‐striatal networks is common to both attention deficit hyperactivity disorder (ADHD) and obsessive‐compulsive‐disorder (OCD). The aim of this study was to investigate disorder‐specific abnormalities in neural networks mediating interference inhibition and selective attention. Method: Event‐related functional magnetic resonance imaging (fMRI) was used to compare brain activation of boys with ADHD (18), with OCD (10), and healthy boys during (20) during a Simon task that measures interference inhibition and controls for and therefore comeasures attention allocation. Results: During interference inhibition, both patient groups shared mesial frontal dysfunction compared to controls. Disorder‐specific dysfunctions were observed in OCD patients in dorsolateral prefrontal cortex during the oddball condition and in ADHD patients in inferior parietal lobe during interference inhibition and in caudate and posterior cingulate during the simpler oddball condition. The decreased activation in caudate and cingulate in ADHD was furthermore negatively correlated with ADHD symptoms and positively with OCD behavioral traits. Conclusions: The study shows that ADHD and OCD patients have shared but also disorder‐specific brain dysfunctions during interference inhibition and attention allocation. Both disorders shared dysfunction in mesial frontal cortex. Disorder‐specific dysfunctions, however, were observed in dorsolateral prefrontal cortex in OCD patients and in caudate, cingulate, and parietal brain regions in ADHD patients. The disorder‐specific dissociation of striato‐cingulate activation that was increased in OCD compared to ADHD patients, was furthermore inversely related to the symptomatology of the two disorders, and may potentially reflect differential dopamine modulation of striatal brain regions. Hum Brain Mapp, 2011.

Effect of age at onset of schizophrenia on white matter abnormalities

BACKGROUND The pattern of brain morphological changes at the early stages of schizophrenia may depend on the age at onset of illness; in children and adolescents with schizophrenia, grey matter deficits are seen in the parietal lobe whereas in individuals with adult onset these are more widespread. AIMS To examine whether white matter is similarly affected. METHOD Diffusion tensor imaging was used to compare fractional anisotropy measures in individuals with adolescent-onset (n = 17) and adult-onset schizophrenia (n = 17) with those in age- and gender-matched controls. RESULTS Compared with their respective controls, individuals with adolescent-onset schizophrenia showed fractional anisotropy decrease in parietal regions; individuals with adult onset showed additional fractional anisotropy reductions in frontal, temporal and cerebellar regions. A differential effect of age at onset (adolescent v. adult) was noted bilaterally in medial prefrontal white matter. CONCLUSIONS White matter abnormalities in frontal regions in schizophrenia may depend on developmental stage at the time of illness onset.