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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.
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.
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.
Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia.
fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object–location paired-associate memory task, with experimental manipulation of mnemonic load.
In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS.
Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.
Cognitive models suggest that auditory verbal hallucinations arise through defective self-monitoring and the external attribution of inner speech. We used a paradigm that engages verbal self-monitoring (VSM) to examine whether this process is impaired in people experiencing prodromal symptoms, who have a very high risk of developing psychosis.
We tested 31 individuals with an At-Risk Mental State (ARMS) and 31 healthy volunteers. Participants read single adjectives aloud while the source and pitch of the online auditory verbal feedback was manipulated, then immediately identified the source of the speech they heard (Self/Other/Unsure). Response choice and reaction time were recorded.
When reading aloud with distorted feedback of their own voice, ARMS participants made more errors than controls (misidentifications and unsure responses). ARMS participants misidentified the source of their speech as ‘Other’ when the level of acoustic distortion was severe, and misidentification errors were inversely related to reaction times.
Impaired VSM is evident in people with an ARMS, although the deficit seems to be less marked than in patients with schizophrenia. Follow-up of these participants may clarify the extent to which the severity of this impairment predicts the subsequent onset of psychosis and development of positive symptoms.
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.
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.
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.
This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.
Cognitive models propose that faulty appraisal of anomalous experiences
is critical in developing psychosis, particularly delusions. A data
gathering bias may be fundamental to abnormal appraisal
To examine whether there is a data gathering bias in people at high risk
of developing psychosis
Individuals with an at-risk mental state (n=35) were
compared with a matched group of healthy volunteers
(n=23). Participants were tested using a modified
version of the ‘beads’ reasoning task with different levels of task
When task demands were high, the at-risk group made judgements on the
basis of less information than the control group (P <
0.05). Within both groups, jumping to conclusions was directly correlated
with the severity of abnormal beliefs and intolerance of uncertainty
(P<0.05). In the at-risk group it was also
associated with impaired working memory (P<0.05),
whereas in the control group poor working memory was associated with a
more conservative response style (P<0.05)
People with an at-risk mental state display a jumping to conclusions
reasoning style, associated with impaired working memory and intolerance
of uncertainty. This may underlie a tendency to develop abnormal beliefs
and a vulnerability to psychosis
Cognitive models of psychosis suggest that whether anomalous experiences
lead to clinically relevant psychotic symptoms depends on how they are
appraised, the context in which they occur and the individual's emotional
To develop and validate a semi-structured interview (the Appraisals of
Anomalous Experiences Interview; AANEX) to assess (a) anomalous
experiences and (b) appraisal, contextual and response variables
Following initial piloting, construct validity was tested via
cross-sectional comparison of data from clinical and non-clinical samples
with anomalous experiences. Interrater reliability was also assessed
Scores from AANEX measuring appraisals, responses and social support
differentiated the clinical and nonclinical groups. Interrater
reliability was satisfactory for 65 of the 71 items. Six items were
The AANEX is avalid multidimensional instrument that provides a detailed
assessment of psychotic-like experiences and subjective variables
relevant to the development of a need for clinical care
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