Eileen M. Joyce

FRONTAL-LOBE FUNCTION IN KORSAKOFF AND NON-KORSAKOFF ALCOHOLICS - PLANNING AND SPATIAL WORKING MEMORY

Groups of Korsakoff (KS) and non-Korsakoff alcoholics (ALC) and a group of normal volunteers, matched for age and verbal IQ, were tested on traditional neuropsychological tests of frontal lobe function and on computerized tests of planning (the Tower of London task) and spatial working memory. KS demonstrated deficits on the planning task which could not be explained by abnormalities of memory, including spatial span, or by visuoperceptive disturbances. KS were also impaired on the spatial working memory task, in part because of the failure to adopt an organized strategy. ALC exhibited fewer impairments which could not be attributed to deficits in either planning or spatial working memory. On Nelsons modified Wisconsin Card Sorting Task, KS and ALC achieved fewer categories than controls but only KS made perseverative errors. The data suggest that in the alcoholic Korsakoffs syndrome there is a specific disturbance of frontal-lobe function in addition to amnesia. The impairment seen in chronic alcoholics without Korsakoffs syndrome, on the other hand, do not reflect specific frontal dysfunction.

Do patients with schizophrenia exhibit aberrant salience

Background It has been suggested that some psychotic symptoms reflect ‘aberrant salience’, related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulus–reinforcement associations in the presence of distracting task-irrelevant cues. Method We tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, participants made a speeded response to earn money in the presence of conditioned stimuli (CSs). Each CS comprised two visual dimensions, colour and form. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Measures of adaptive and aberrant motivational salience were calculated on the basis of latency and subjective reinforcement probability rating differences over the task-relevant and task-irrelevant dimensions respectively. Results Participants rated reinforcement significantly more likely and responded significantly faster on high-probability-reinforced relative to low-probability-reinforced trials, representing adaptive motivational salience. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. In the controls, aberrant salience correlated significantly with ‘introvertive anhedonia’ schizotypy. Conclusions These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. The relationship between aberrant salience and psychotic symptoms warrants further investigation in unmedicated patients.

Discrimination Learning, Reversal, and Set-Shifting in First-Episode Schizophrenia: Stability Over Six Years and Specific Associations with Medication Type and Disorganization Syndrome

Background The intradimensional/extradimensional (IDED) task assesses different forms of learning from feedback. Limited evidence suggests that attentional set-shifting deteriorates over time in schizophrenia. We tested this hypothesis and examined the specificity of learning impairments identified by this task. Method Two hundred sixty-two first-episode patients and 76 healthy control subjects, matched for age and premorbid IQ, were tested; 104 patients and 25 control subjects were reassessed 1 and 3 years later, and 31 patients were reassessed additionally 6 years later. Results Patients showed impaired set-shifting that correlated with current IQ and working memory, but there were no impairments when subgroups were matched on current IQ. In contrast, patients showed marked impairments in rule reversal learning that survived correction for IQ, were present in the context of intact rule abstraction, and correlated with disorganization symptoms. Patients prescribed second-generation antipsychotics were worse on set-shifting compared with first-generation, a finding not explained by demographic data, illness characteristics, or IQ. Patients and control subjects showed stable IDED performance over the first 6 years of illness, although set-shifting was inconsistent over the first year. Those with residual negative symptoms were more likely to fail the set-shifting stage at follow-up. Conclusions First-episode schizophrenia patients can learn and generalize rules but are inflexible when rules change, reflecting reduced responsiveness to negative feedback and difficulty in switching attention. Rule-reversal is a promising target for translational studies, because it is specific, clinically relevant, and might reflect orbitofrontal dysfunction. Set-shifting is related to poor function more generally but might be sensitive to medication effects and valuable for clinical trials.

Intact reward learning but elevated delay discounting in Parkinson's disease patients with impulsive-compulsive spectrum behaviors.

It has been postulated that impulsive-compulsive spectrum behaviors (ICBs) in Parkinsons disease (PD) reflect overvaluation of rewards, resulting from excessive dopaminergic transmission in the ventral striatum. However, as the ventral striatum is also strongly implicated in delay discounting, an alternative explanation would be that, similar to stimulant-dependent individuals, PD patients with ICBs impulsively discount future rewards. To test these hypotheses, we investigated whether 36 medicated PD patients with and without ICBs differed from controls on measures of stimulus-reinforcement learning and delay discounting. There was a clear double dissociation between reward learning and impulsivity in PD patients with and without ICBs. Although PD patients without ICBs were impaired at learning stimulus–reward associations for high-probability stimuli, PD patients with ICBs were able to learn such associations equally as well as controls. By contrast, PD patients with ICBs showed highly elevated delay discounting, whereas PD patients without ICBs did not differ from controls on this measure. These results contradict the hypothesis that ICBs in PD result from overvaluation of rewards. Instead, our data are more consistent with a model in which excessive dopaminergic transmission induces a strong preference for immediate over future rewards, driving maladaptive behavior in PD patients with ICBs.

The Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL) Development and validation

Background: Gilles de la Tourette syndrome (GTS) is a chronic neuropsychiatric disorder which has a significant detrimental impact on the health-related quality of life (HR-QOL) of patients. However, no patient-reported HR-QOL measures have been developed for this population. Objective: The development and validation of a new scale for the quantitative assessment of HR-QOL in patients with GTS. Methods: In stage 1 (item generation), a pool of 40 potential scale items was generated based on interviews with 133 GTS outpatients, literature review, and consultation with experts. In stage 2 (scale development), these items were administered to a sample of 192 GTS outpatients. Standard statistical methods were used to develop a rating scale satisfying criteria for acceptability, reliability, and validity. In stage 3 (scale evaluation), the psychometric properties of the resulting scale were tested in a second sample of 136 subjects recruited through the UK-Tourette Syndrome Association. Results: Response data analysis and item reduction methods led to a final 27-item GTS-specific HR-QOL scale (GTS-QOL) with four subscales (psychological, physical, obsessional, and cognitive). The GTS-QOL demonstrated satisfactory scaling assumptions and acceptability; both internal consistency reliability and test-retest reliability were high (Cronbach alpha ≥0.8 and intraclass correlation coefficient ≥0.8); validity was supported by interscale correlations (range 0.5–0.7), confirmatory factor analysis, and correlation patterns with other rating scales and clinical variables. Conclusions: The Gilles de la Tourette syndrome (GTS)–specific health-related quality of life (HR-QOL) scale (GTS-QOL) is proposed as a new disease-specific patient-reported scale for the measurement of HR-QOL in patients with GTS, taking into account the complexity of the clinical picture of GTS.

Abnormal brain connectivity in first-episode psychosis: A diffusion MRI tractography study of the corpus callosum

A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the clinical manifestations of schizophrenia. Recently, diffusion imaging tractography has made it possible to study white matter pathways in detail and we present here a study of patients with first-episode psychosis using this technique. We selected the corpus callosum for this study because there is evidence that it is abnormal in schizophrenia. In addition, the topographical organization of its fibers makes it possible to relate focal abnormalities to specific cortical regions. Eighteen patients with first-episode psychosis and 21 healthy subjects took part in the study. A probabilistic tractography algorithm (PICo) was used to study fractional anisotropy (FA). Seed regions were placed in the genu and splenium to track fiber tracts traversing these regions, and a multi-threshold approach to study the probability of connection was used. Multiple linear regressions were used to explore group differences. FA, a measure of tract coherence, was reduced in tracts crossing the genu, and to a lesser degree the splenium, in patients compared with controls. FA was also lower in the genu in females across both groups, but there was no gender-by-group interaction. The FA reduction in patients may be due to aberrant myelination or axonal abnormalities, but the similar tract volumes in the two groups suggest that severe axonal loss is unlikely at this stage of the illness.

White matter tracts in first-episode psychosis: A DTI tractography study of the uncinate fasciculus

A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the symptoms and cognitive abnormalities of schizophrenia. Recently, diffusion imaging tractography has made it possible to study white matter pathways in detail, and we present here a study of patients with first-episode psychosis using this technique. We studied the uncinate fasciculus (UF), the largest white matter tract that connects the frontal and temporal lobes, two brain regions significantly implicated in schizophrenia. Nineteen patients with first-episode schizophrenia and 23 controls were studied using a probabilistic tractography algorithm (PICo). Fractional anisotropy (FA) and probability of connection were obtained for every voxel in the tract, and the group means and distributions of these variables were compared. The spread of the FA distribution in the upper tail, as measured by the squared coefficient of variance (SCV), was reduced in the left UF in the patient group, indicating that the number of voxels with high FA values was reduced in the core of the tract and suggesting the presence of changes in fibre alignment and tract coherence in the patient group. The SCV of FA was lower in females across both groups and there was no correlation between the SCV of FA and clinical ratings.

Duration of untreated psychosis and social function: 1-year follow-up study of first-episode schizophrenia

Background In first-episode schizophrenia, longer duration of untreated psychosis (DUP) predicts poorer outcomes. Aims To address whether the relationship between DUP and outcome is a direct causal one or the result of association between symptoms and/or cognitive functioning and social functioning at the same time point. Method Symptoms, social function and cognitive function were assessed in 98 patients with first-episode schizphrenia at presentation and 1 year later. Results There was no significant clinical difference between participants with short and long DUP at presentation. Linear regression analyses revealed that longer DUP significantly predicted more severe positive and negative symptoms and poorer social function at 1 year, independent of scores at presentation. Path analyses revealed independent direct relationships between DUP and social function, core negative symptoms and positive symptoms. There was no significant association between DUP and cognition. Conclusions Longer DUP predicts poor social function independently of symptoms. The findings underline the importance of taking account of the phenomenological overlap between measures of negative symptoms and social function when investigating the effects of DUP.

Neural and Behavioral Correlates of Aberrant Salience in Individuals at Risk for Psychosis

The “aberrant salience” model proposes that psychotic symptoms first emerge when chaotic brain dopamine transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant. This is thought to occur during the prodromal phase of psychotic disorders, but this prediction has not been tested previously. In the present study, we tested this model in 18 healthy volunteers and 18 unmedicated individuals at ultra-high risk of psychosis. Subjects performed the Salience Attribution Test, which provides behavioral measures of adaptive and aberrant motivational salience, during functional magnetic resonance imaging to assess neural responses to relevant and irrelevant stimulus features. On a separate occasion, the same subjects were also studied with [18F]fluorodopa positron emission tomography to measure dopamine synthesis capacity. Individuals at ultra-high risk of psychosis were more likely to attribute motivational salience to irrelevant stimulus features (t(26.7) = 2.8, P = .008), and this bias was related to the severity of their delusion-like symptoms (r = .62, P = .008). Ventral striatal responses to irrelevant stimulus features were also correlated with delusion-like symptoms in the ultra-high risk group (r = .59, P = .017). Striatal dopamine synthesis capacity correlated negatively with hippocampal responses to irrelevant stimulus features in ultra-high risk individuals, but this relationship was positive in controls. These data are consistent with the hypothesis that aberrant salience processing underlies psychotic symptoms and involves functional alterations in the striatum, hippocampus, and the subcortical dopamine system.

Cognitive heterogeneity in schizophrenia

Purpose Further clarification of the nature of cognitive heterogeneity in schizophrenia is needed to aid the endophenotype approach to the understanding of the genetic basis of the disorder. This review summarizes recent neuropsychological studies of schizophrenia, aimed at establishing whether there are valid forms of cognitive impairment that can be defined with the use of neuropsychological measures in patients with schizophrenia, and studies that have attempted to relate specific neuropsychological findings to genetic polymorphisms. Recent findings There is good evidence for significant cognitive heterogeneity in schizophrenia. It is not yet clear, however, whether this heterogeneity is better accounted for by a general loss of function, varying in degree between different patients, or by impairment in specific cognitive abilities, for example working memory. Molecular genetic studies have provided evidence for associations of single nucleotide polymorphisms with both specific and general impairments, with some additional support for a working memory deficit from neuroimaging studies. Summary Larger, better controlled studies are needed before the genetic sources of cognitive heterogeneity in schizophrenia can be accurately characterized. This will be aided with the development and use of more specific neuropsychological tasks that can accurately discriminate between different cognitive domains.