Mechanisms Underlying Motivational Dysfunction in Schizophrenia.

Negative symptoms are a debilitating feature of schizophrenia which are often resistant to pharmacological intervention. The mechanisms underlying them remain poorly understood, and diagnostic methods rely on phenotyping through validated questionnaires. Deeper endo-phenotyping is likely to be necessary in order to improve current understanding. In the last decade, valuable behavioural insights have been gained through the use of effort-based decision making (EBDM) tasks. These have highlighted impairments in reward-related processing in schizophrenia, particularly associated with negative symptom severity. Neuroimaging investigations have related these changes to dysfunction within specific brain networks including the ventral striatum (VS) and frontal brain regions. Here, we review the behavioural and neural evidence associated with negative symptoms, shedding light on potential underlying mechanisms and future therapeutic possibilities. Findings in the literature suggest that schizophrenia is characterised by impaired reward based learning and action selection, despite preserved hedonic responses. Associations between amotivation and reward-processing deficits have not always been clear, and may be mediated by factors including cognitive dysfunction or dysfunctional or self-defeatist beliefs. Successful endo-phenotyping of negative symptoms as a function of objective behavioural and neural measurements is crucial in advancing our understanding of this complex syndrome. Additionally, transdiagnostic research-leveraging findings from other brain disorders, including neurological ones-can shed valuable light on the possible common origins of motivation disorders across diseases and has important implications for future treatment development

The influence of negative and affective symptoms on anhedonia self-report in schizophrenia.

BACKGROUND: Anhedonia, a symptom prevalent in schizophrenia patients, is thought to arise either within negative symptomatology or from secondary sources, such as depression. The common co-occurrence of these diseases complicates the assessment of anhedonia in schizophrenia. METHOD: In a sample of 40 outpatients with chronic schizophrenia, we explored both the validity of the Snaith-Hamilton Pleasure Scale (SHAPS) self-report for anhedonia assessment and those factors influenced its scoring. We assessed negative symptoms using the Brief Negative Symptom Scale (BNSS), depression symptoms using the Calgary Depression Scale for Schizophrenia (CDSS) and cognitive impairment using the Brief Assessment of Cognition in Schizophrenia (BACS), before exploring associations between these scales. RESULTS: The SHAPS was validated for use in schizophrenia. SHAPS scores were not associated with negative symptoms or cognitive impairment, but were linked to a single Depression symptom: Hopelessness (r = 0.52, p < 0.001). CONCLUSIONS: SHAPS scores, therefore, appear to only reflect anticipatory anhedonia arising from the affective domain. We advocate the development of multi-faceted self-report measures to more holistically assess anhedonia in schizophrenia.M.H is funded by a Wellcome Trust Principal Research Fellowship and by the NIHR BRC at Oxford. E.F.E and the research database were supported by intramural funding from CPFT and the UK National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre (BRC)

Dopamine and reward hypersensitivity in Parkinson's disease with impulse control disorder.

Impulse control disorders in Parkinson's disease are common neuropsychiatric complications associated with dopamine replacement therapy. Some patients treated with dopamine agonists develop pathological behaviours, such as gambling, compulsive eating, shopping, or disinhibited sexual behaviours, which can have a severe impact on their lives and that of their families. In this study we investigated whether hypersensitivity to reward might contribute to these pathological behaviours and how this is influenced by dopaminergic medication. We asked participants to shift their gaze to a visual target as quickly as possible, in order to obtain reward. Critically, the reward incentive on offer varied over trials. Motivational effects were indexed by pupillometry and saccadic velocity, and patients were tested ON and OFF dopaminergic medication, allowing us to measure the effect of dopaminergic medication changes on reward sensitivity. Twenty-three Parkinson's disease patients with a history of impulse control disorders were compared to 26 patients without such behaviours, and 31 elderly healthy controls. Intriguingly, behavioural apathy was reported alongside impulsivity in the majority of patients with impulse control disorders. Individuals with impulse control disorders also exhibited heightened sensitivity to exogenous monetary rewards cues both ON and OFF (overnight withdrawal) dopamine medication, as indexed by pupillary dilation in anticipation of reward. Being OFF dopaminergic medication overnight did not modulate pupillary reward sensitivity in impulse control disorder patients, whereas in control patients reward sensitivity was significantly reduced when OFF dopamine. These effects were independent of cognitive impairment or total levodopa equivalent dose. Although dopamine agonist dose did modulate pupillary responses to reward, the pattern of results was replicated even when patients with impulse control disorders on dopamine agonists were excluded from the analysis. The findings suggest that hypersensitivity to rewards might be a contributing factor to the development of impulse control disorders in Parkinson's disease. However, there was no difference in reward sensitivity between patient groups when ON dopamine medication, suggesting that impulse control disorders may not emerge simply because of a direct effect of dopaminergic drug level on reward sensitivity. The pupillary reward sensitivity measure described here provides a means to differentiate, using a physiological measure, Parkinson's disease patients with impulse control disorder from those who do not experience such symptoms. Moreover, follow-up of control patients indicated that increased pupillary modulation by reward can be predictive of the risk of future emergence of impulse control disorders and may thereby provide the potential for early identification of patients who are more likely to develop these symptoms

Brain mechanisms in clinical apathy

Clinical apathy is a debilitating disorder of motivation that is increasingly recognised across neurological and psychiatric disorders. Current challenges remain in understanding the underlying mechanisms of the syndrome, and the lack of licensed treatment. Some evidence has associated apathy with reduced incentivisation by reward, possibly secondary to distinct brain changes in a well defined fronto-striatal network. However, it remains unclear exactly whether the behavioural and anatomical correlates of apathy are consistent across brain disorders. This thesis attempts to clarify these questions by considering apathy as a behavioural disorder, which can be examined using effort-based decision making tasks. Behavioural and anatomical studies were performed across several conditions, including cerebrovascular small vessel disease, schizophrenia, stroke, and healthy people. Two decision making paradigms were used, one which probes how people evaluate costs and benefits of actions, and another which characterises how motivated behaviour dynamically varies over time in the face of unexpected setbacks or uplifts. An association between apathy, reward insensitivity, and fronto-striatal pathology was found in small vessel disease. Behavioural phenotypes of amotivation varied across conditions depending on associated factors such as level of cognitive function in schizophrenia, and concurrent depression in patients with focal stroke. Finally, dopaminergic treatment may serve as a therapeutic option for some apathetic patients with subcortical lesions

The Effects of Motivational Reward on the Pathological Attentional Blink following Right Hemisphere Stroke

Recent work has shown that attentional deficits following stroke can be modulated by motivational stimulation, particularly anticipated monetary reward. Here we examined the effects of anticipated reward on the pathological attentional blink (AB), an index of temporal selective attention, which is prolonged in patients with right hemisphere damage and a history of left neglect. We specifically compared the effects of reward versus feedback-without-reward on the AB in 17 patients. We found that the patients all manifested impaired performance compared to healthy controls and that reward modulated the pathological blink in the patient group, but only in the second experimental session. When the performance of patients whose neglect had recovered was compared with that of patients who had ongoing or persistent neglect, reward appeared to only influence the AB in the former. These results have implications for our understanding of motivation-attention interactions following right hemisphere stroke, and how they may impact upon recovery from spatial neglect