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Altered neurocognitive function in schizophrenia could reflect both genetic and illness-specific effects.
To use functional magnetic resonance imaging to discriminate between the influences of the genetic risk for schizophrenia and environmental factors on the neural substrate of verbal fluency, a candidate schizophrenia endophenotype using a case control twin design.
We studied 23 monozygotic twin pairs: 13 pairs discordant for schizophrenia and 10 pairs of healthy volunteer twins. Groups were matched for age, gender, handedness, level of education, parental socio-economic status, and ethnicity. Behavioural performance and regional brain activation during a phonological verbal fluency task were assessed.
Relative to healthy control twins, both patients and their non-psychotic co-twins produced fewer correct responses and showed less activation in the medial temporal region and inferior frontal gyrus. Twins with schizophrenia showed greater activation than both their non-psychotic co-twins and controls in right lateral temporal cortex, reflecting reduced deactivation during word generation while their non-psychotic co-twins showed greater activation in the left temporal cortex.
Both genetic vulnerability to schizophrenia and schizophrenia were associated with impaired verbal fluency performance, reduced engagement of the medial temporal region and dorsal inferior frontal gyrus. Schizophrenia was specifically associated with an additional reduction in deactivation in the right temporal cortex.
DTI studies in schizophrenia have consistently reported decreased fractional anisotropy (FA, an index of white matter microstructure) in patients. There is little evidence as to the genetic or environmental determinants of this difference however. Studies of twins with schizophrenia allow us to estimate these influences. We report a cross-sectional case control study of twins with and without schizophrenia.
We recruited mono- and di-zygotic twins concordant and discordant for DSM schizophrenia from across the United Kingdom, referred by their treating psychiatrists. We recruited healthy control twins from the Institute of Psychiatry Volunteer Twin Register and by national media advertisements. Clinical diagnoses were confirmed using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Spitzer and Endicott, 1978). Zygosity was confirmed by DNA analysis. Eleven pairs of monozygotic twins concordant for schizophrenia, 10 pairs of monozygotic and seven pairs of dizygotic twins discordant for schizophrenia, 24 pairs of healthy monozygotic twins and 20 pairs of healthy dizygotic twins were recruited.
Subjects were scanned with an optimized DTI sequence at 1.5T. Scans were warp-corrected, masked, and FA calculated at each voxel. FA maps were then co-registered to a study-specific FA template using SPM2 and group differences calculated on segmented white-matter FA maps using non-parametric XBAM_v3.4.
Results are presented of analyses comparing twins with schizophrenia with their well co-twin, linear trend analyses comparing healthy controls with well di and mono-zygotic co-twins, and a heritability analysis of the healthy controls.
Cannabis is the world's most commonly used illicit substance. Whilst its effects on perception are well documented, little is known about the neural basis of these effects and how they are modulated by two of cannabis sativa's most abundant active ingredients, Delta-9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD).
We used fMRI to assess the effects of THC and CBD on brain activation during a simple visual and auditory stimulation paradigm in healthy volunteers.
Fourteen right handed male subjects were scanned on 3 occasions. Identical 10mg THC, 600mg CBD and placebo capsules were allocated in a balanced double blinded pseudorandomised crossover design.
Ingestion of THC and CBD led to reliable increases in plasma levels of each substance and for THC concomitant increases in anxiety, intoxication and positive psychotic symptoms; CBD and placebo caused no significant symptoms. Visual and auditory stimulation led to robust activations in occipital and temporal cortices respectively under placebo conditions. Administration of THC led to decreased activation in primary sensory cortices relative to placebo whilst CBD led to an increase in activation in right temporal regions during auditory stimulation and right striate cortex activation during visual stimulation. THC mediated reduction of activation in this area during auditory stimulation correlated with a concomitant rise in psychotic symptoms.
These data indicate that the different psychoactive constituents of cannabis have dissociable effects on sensory processing, often in opposite directions
Recent studies have identified DAAO as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders.
The present investigation examined the impact of DAAO genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers.
We tested the hypotheses that the high-risk variant of DAAO would be associated with altered prefrontal function and functional connectivity in schizophrenic and bipolar patients.
We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 121 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 48 healthy volunteers. We then used statistical parametric mapping (SPM) and psycho-physiological interaction (PPI) analyses to estimate the main effects of diagnostic group, the main effect of genotype and their interaction on brain activation and functional connectivity.
In schizophrenic patients relative to bipolar patients and controls, the high-risk variant of DAAO was associated with lower deactivation in the left precuneus and greater activation in the right calcarine and posterior cingulate gyrus during task performance. In addiction, these areas expressed altered functional connectivity with the rest of the brain in schizophrenic patients relative to bipolar patients and controls.
Our results suggest that genetic variation in DAAO has a significant impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in specific brain regions.
Cannabis is the world's most widely used illicit drug. It can impair verbal learning and induce psychosis, both acutely and possibly following long term use. But, where cannabis acts in the brain to impair verbal learning and induce psychotic symptoms is unclear. The aim of this study was to clarify how one of the main psychoactive ingredients of cannabis, delta-9-tetrahydrocannabinol (THC) acts on the brain to impair verbal learning and induce psychotic symptoms.
15 healthy males with minimal exposure to cannabis, were studied on 2 occasions approximately 1 month apart, following oral administration of 10mg of THC or placebo 1 hour prior to scanning, in a double-blind design. MR images were acquired on a 1.5T GE camera while subjects performed a Verbal paired associates task with separate encoding followed by retrieval conditions, with the conditions repeated in the same sequence 4 times. We examined the main effects of drug, task and drug- task interactions.
Administration of THC abolished the normal linear decrement in parahippocampal activation across successive encoding blocks and was associated with a trend for impaired word recall. Administration of THC also altered the normal time-dependent change in ventral striatal activation during retrieval of word pairs which was directly correlated with concurrently induced psychotic symptoms.
These results suggest that impairment in learning and verbal memory associated with cannabis use may be mediated through its action in the medial temporal cortex while psychotic symptoms may be induced through its action in the ventral striatum.
Neuroimaging is one of the most promissing avenues for exploring psychiatric disorders in general and schizophrenia in particular both in terms of aetiology but also pathophysiology and treatment response.The aim of this workshop is to discuss possible avenues for Europe-wide collaborative research in neuroimaging and the implications it has for training and general infrastructure
The workshop leaders with discuss at their individual presentations the current vision for more uniform approach to neuroimaging across Europe, steps already taken towards it and plans for the future.
The organisers of the workshop hope that a consensus view will emerge to move neuroimaging research in schizophrenia into a Europe wide platform.
The future rests is collaborative large scale multicentre research.
Executive and mnemonic impairments have been well documented in the high-risk states for development of psychosis and have been pinpointed as a possible core neuropsychological dysfunction. However, their neurofunctional correlates are still not clear.
fMRI was used in 17 patients at risk for developing psychosis (ARMS, “at risk mental state”), 10 patients with a first episode of psychosis (FEP) and 15 age-matched healthy comparison subjects to examine neural responses to increasing difficulty of mnemonic engagement in an object–location paired associate memory task. Groups were matched in terms of age, IQ, gender, and psychopathology ratings. Accuracy and reaction time were recorded during the scan.
As the mnemonic load increased, response latency increased and response accuracy decreased in an approximately linear fashion. No main effect for group was observed. However, a trend towards decreased accuracy in FEP subjects, as compared with controls, was evident. As the task difficulty increased, increased brain activity was observed in the medial frontal cortex and in the medial posterior parietal cortex. Between-groups differences in activation were observed in a cluster spanning the MFG, SFG and SMA and in the right precuneus. However, these neurofunctional abnormalities were more evident in the most demanding level of the task than in the easy level, with the ARMS groups showing less activation than controls and higher activation than FEP.
Abnormal neural activity in medial frontal cortex and posterior parietal cortex during paired associate learning task may represent a neurofunctional substrates of vulnerability to psychosis.
Object working memory performance is abnormal in the early stages of schizophrenia. Such tasks recruit frontal and temporal cortices, possible sites of progressive change over the early illness course. We wanted to clarify if functional changes can be detected in the early stages of schizophrenia, to identify their anatomical location and their relationship to the stage of illness using a functional object working memory task in which the length of memory delay was manipulated.
40 subjects contributed: 10 first episode psychosis (FEp) patients, 16 with an at risk mental state (ARMS) and 14 healthy controls. We collected functional MRI data while the subjects performed a version of the delayed matching to sample (DMTS) task from the Cambridge Automated Neuropsychological Test Battery (CANTAB).
Behaviourally there was a trend to a group by delay interaction, the two patient groups making more errors at longer memory delays. At successful recognition a main effect of group was detected in the medial temporal lobe bilaterally, while a main effect of delay was detected in the left medial temporal lobe. At each length of memory delay the patient groups showed consistently greater activation of medial temporal regions when performing the task accurately.
Both ARMS & FEp groups showed greater activation than controls in the medial temporal cortex across all lengths of memory delay. These differences were not related to poorer task performance, but suggest an inefficiency mechanism that may correlate with the vulnerability to psychosis rather than pychosis per se.
There is considerable interest in the therapeutic potential of Cannabidiol (CBD), the second most abundant component of Cannabis. While delta-9-THC, the main psychoactive ingredient of cannabis, impairs memory and induces anxiety and psychotic symptoms acutely and increases the risk of psychotic disorders in regular cannabis users, CBD does not impair memory, may have anxiolytic and possibly antipsychotic effects. Hence, we compared directly the acute neural effects of these two active ingredients of cannabis, by combining pharmacological challenge with fMRI. Using a double-blind, repeated measures design and oral challenge with 10mg of delta-9-THC, 600mg of CBD or placebo in 15 healthy volunteers, we examined whether delta-9-THC and CBD have opposing effects on the neural substrates of verbal memory and fear processing and whether they also have opposing effects on the neural substrates of anxiety and psychotic symptoms induced by delta-9-THC. Delta-9-THC induced anxiety and psychotic symptoms acutely while there was a trend for a reduction in anxiety but no change in psychotic symptoms with CBD. During the memory task, delta-9-THC attenuated and CBD increased activation in the striatum bilaterally. Effect of delta-9-THC on striatal activation was inversely correlated with the psychotic symptoms induced by it concomitantly. During the processing of fearful faces, delta-9-THC increased and CBD attenuated activation in the amygdala and these effects correlated with their anxiogenic and anxiolytic effects respectively. These opposing effects of CBD on the key neural substrates for psychotic symptoms and anxiety induced by delta-9-THC may suggest its possible therapeutic role in countering these conditions.
The complex sulco-gyral pattern results from fetal and early childhood processes that shape the cortex anatomy from a smooth lissencephalic structure to a highly convoluted surface. Abnormal brain maturation has been suggested as risk factor for schizophrenia. Thus, measures of the cortical folding pattern could provide cues for the neurodevelopmental aspects of pathopsychology.
Brain morphometry softwares providing 3D sulci descriptors (e.g. surface) from MRI (Mangin, 2004 ; Cachia, 2007). This automatized method avoids biases inherent to image normalisation and partial volume effect. Therefore, statistics on sulcal measurements should generalize across patients. T1 MRI datasets were studied in at-risk subjects, adolescent onset schizophrenia, and patients with treatment-resistant depression and auditory hallucinations.
Decreased in sulci surface were detected in whole brain sulcal indices and in regional sulcal indices. Decreases in global sulcal indices were detected in most patient groups, except in at risk subjects. Decreases in local sulcal indices were detected in langage-related areas in resistant hallucinators (Cachia 2007), and confined to left temporal regions in adolescent schizophrenia (Pentilla, submitted). In patients with treatment-resistant depression, sulci descriptors differed in right hemisphere sulci adjacent to limbic regions (Pentilla, submitted).
The potential of the gyrification pattern for the inference of neuroimage-based developmental biomarkers will be further examined using multivariate classification approaches (Duchesnay 2006).
. Mangin et al., Neuroimage 2004 - Cachia et al., Neuroimage 2007 – Duchesnay et al., Neuroimage 2006
Individuals at Ultra High Risk (UHR) for psychosis typically present with attenuated psychotic symptoms. However it is difficult to predict which individuals will later develop frank psychosis when their mental state is rated in terms of individual symptoms.
The objective of the study was to examine the phenomenological structure of the UHR mental state and identify symptom profiles that predict later transition to psychosis.
Psychopathological data from a large sample of UHR subjects were analysed using latent class cluster analysis.
A total of 318 individuals with a UHR for psychosis. Data were collected from two specialised community mental health services for people at UHR for psychosis: OASIS in London and PACE, in Melbourne.
Latent class cluster analysis produced 4 classes: Class 1 - Mild was characterized by lower scores on all the CAARMS items. Subjects in Class 2 - Moderate scored moderately on all CAARMS items and was more likely to be in employment. Those in Class 3 - Moderate-Severe scored moderately-severe on negative symptoms, social isolation and impaired role functioning. Class 4 - Severe was the smallest group and was associated with the most impairment: subjects in this class scored highest on all items of the CAARMS, had the lowest GAF score and were more likely to be unemployed. This group was also characterized by the highest transition rate (41%).
Different constellations of symptomatology are associates with varying levels of risk to of transition to psychosis.
Stress is a key feature of many aetiological models of psychosis and there is considerable empirical evidence implicating stress in the development of psychosis. This paper investigates the role of psychosocial stress in the onset of psychosis by examining the relationship between current and lifetime exposure to traumatic experiences and psychosocial stressors, HPA axis function, and psychopathology in people at high risk of developing psychosis.
Sixty ‘high risk’ (HR) participants were compared with 50 healthy control (HC) participants on measures of exposure to psychosocial stressors. Subgroups of HR and HC participants which provided saliva samples were compared regarding measures of HPA axis function.
HR participants were exposed to greater levels of psychosocial stress than HC participants. Specifically, HR participants were more likely to have been separated from their parents (p = .003), report severe parental antipathy (p = .011), and have been bullied while growing up (p = .024). HR participants experienced greater levels of perceived stress than HC participants (p = .001) and were more likely to have had a negative life event in the previous 6 months (p < .001). Positive correlations were found between current stress and number of life events and attenuated psychotic symptoms (r = .585, p < .001, and r = .384, p = < .001, respectively) in the HR participants.
This study shows that people at high risk of developing psychosis experience greater levels of psychosocial stress than matched healthy control participants throughout the lifetime, from early childhood to the present day, and that current stress is strongly associated with psychotic symptomatology.
People with ‘prodromal’ symptoms have a very high risk of developing psychosis. We used functional MRI to examine the neurocognitive basis of this vulnerability.
Cross-sectional comparison of subjects with an ARMS (n=17), first episode schizophreniform psychosis (n=10) and healthy volunteers (n=15). Subjects were studied using functional MRI while they performed an overt verbal fluency task, a random movement generation paradigm and an N-Back working memory task.
During an N-Back task the ARMS group engaged inferior frontal and posterior parietal cortex less than controls but more than the first episode group. During a motor generation task, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than the first episode group. During verbal fluency using ‘Easy’ letters, the ARMS group demonstrated intermediate activation in the left inferior frontal cortex, with first episode groups showing least, and controls most, activation. When processing ‘Hard’ letters, differential activation was evident in two left inferior frontal regions. In its dorsolateral portion, the ARMS group showed less activation than controls but more than the first episode group, while in the opercular part of the left inferior frontal gyrus / anterior insula activation was greatest in the first episode group, weakest in controls and intermediate in the ARMS group.
The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have just developed psychosis but less severe.
To examine the effect of a polymorphism in the Dopamine Transporter (DAT) gene on brain activation during executive function and, for the first time:
1. determine the extent to which this is altered in schizophrenia and
2. use a verbal fluency paradigm.
This is relevant since:
1. DAT plays a key role in the regulation of dopamine, which modulates cortical activation during cognitive tasks and
2. a disruption of dopamine function is a fundamental pathophysiological feature of schizophrenia.
Functional magnetic resonance imaging was used to measure whole-brain responses during overt verbal fluency in 85 subjects: 44 healthy volunteers and 41 DSM-IV schizophrenia patients. Main effects of genotype and diagnostic group on activation and their interaction were estimated using an ANOVA in SPM5.
The 10-repeat allele of the 3'UTR VNTR was associated with greater activation than the 9-repeat allele in the left (Z=4.8; FWEp=0.005) and right (Z=4.2; FWEp=0.057) anterior insula and with decreased activation in the rostral anterior cingulate (Z=4.3 FWEp=0.04) during word generation (versus baseline). These effects were irrespective of diagnostic group but generally more marked in patients. There were also strong trends for groupxgenotype interactions in the left middle frontal gyrus and the left nucleus accumbens. Analysis was controlled for task performance, IQ, antipsychotic medication, psychopathology and demographics.
Cortical function during executive tasks is normally modulated by variation in the DAT gene, effect which is dependent on the brain region. DAT's effect may be altered in schizophrenia patients, which may reflect altered central dopamine function.
The most striking, yet poorly understood morphological features of the human cerebral cortex are the complex arrangements of its foldings: the sulci and gyri. Cortical gyrification is formed during fetal age and childhood. Thus, indices measuring the folding pattern could provide cues for the neurodevelopmental pathopsychology.
A fully-automated method was applied to T1 magnetic resonance images to extract, label and measure the sulcus area in the whole cortex. Gyrification was assessed using both global and local sulcal indices, defined respectively as the ratio between the total sulcal area, or the area of each labeled sulcus, and the outer cortex area.
As a validation, MRI datasets in controls showed that handedness modify the folding of the motor area in dominant hemisphere (Mangin 2004), and differences in left and right superior temporal sulci which may stem from language-based asymmetries (Ochiai 2004). In a sample of schizophrenia patients with treatment-resistant auditory hallucination, global sulcal surface index was decreased, and local sulci surface indices differed in language-related regions. Further analyses are performed in samples from various MR datasets. Statistics on such measurements should generalize across patients and hospitals.
The potential of the gyrification pattern for the neuroimage-based inference of developmental deviation will be examined.
There is increasing evidence that changes in connections linking brain regions, as well as grey matter volumetric abnormalities are important in schizophrenia. The extent to which these are related to being at risk of psychosis as opposed to having a psychotic disorder is unclear. We will review the diffusion tensor imaging (DTI) findings which inform us about white matter integrity and organization, and relate it to our own work which compares grey matter volumes and white matter integrity in people at high risk of psychosis, patients with first episode psychosis, and healthy volunteers. We will also discuss the relationship of these findings to clinical symptoms and outcome.
30 subjects with an ‘at risk mental state’ (PACE criteria), 15 first psychotic episode patients and 30 controls were studied using an SPGR sequence and DTI.
Both the volumetric and DTI datasets were analysed using voxel based techniques in standard space. There were frontal and temporal grey matter reductions in the first episode group and more modest temporo-parietal volume reductions in the ‘at risk’ group. The first episode group had reduced fractional anisotropy in the superior longitudinal fasciculus bilaterally, left anterior corpus callosal and right superior fronto-occiptal tracts relative to controls, with qualitatively similar but less severe reductions in the ‘at risk’ subjects.
Abnormalities in the frontal and temporal grey matter and the tracts connecting them were evident in patients with first episode schizophrenia, with similar but less marked abnormalities in subjects with an ‘at risk’ mental state.
Early Intervention (EI) services aim to reduce progression to chronic illness for patients with schizophrenia. The Lambeth Early Onset study (2002) demonstrated reduced hospitalisation at 18 months for patients exposed to EI services. This study assesses the durability of these benefits at 5 years.
Hospital use in the LEO cohort was assessed by case note review.
There was no statistically significant difference in terms of ever being admitted at 5 years (OR 1.42; 95% CI 0.550 - 3.68; p=0.468)). Although the mean number of admissions was lower in the EI group: 1.65 (SD = 0.86) versus 1.83 (SD= 0.92), this difference was not significant (coefficient = 0.096; 95% CI -0.550 - 0.742; p=0.770). At 5 years patients assigned to EI used 42.25 days (SD 112.8 days) versus 51.41 days (SD 125 days); coefficient = 6.344; 95% CI -46 - 58.7; p= 0.810. The primary outcome was robust to potentially extreme admission rates for missing subjects on sensitivity analysis.
There is no evidence from these data that EI services statistically significantly reduce hospital use at 5 years follow-up (vis a vis care as usual) despite some interim benefits at 18 months. We only considered a limited number of outcomes and more work needs to be done in this area.