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Objective: To assess apathy in patients with Parkinson’s disease and its relation to disability, mood, personality, and cognition. Methods: Levels of apathy in 45 patients with Parkinson’s disease were compared with a group of 17 similarly disabled patients with osteoarthritis. Additional neuropsychiatric data were collected concerning levels of depression, anxiety, and hedonic tone. Personality was assessed with the tridimensional personality questionnaire. Cognitive testing included the mini-mental state examination, the Cambridge examination of cognition in the elderly, and specific tests of executive functioning. Results: Patients with Parkinson’s disease had significantly higher levels of apathy than equally disabled osteoarthritic patients. Furthermore, within the Parkinson sample, levels of apathy appear to be unrelated to disease progression. The patients with Parkinson’s disease with the highest levels of apathy where not more likely to be depressed or anxious than those with the lowest levels of apathy, though they did show reduced hedonic tone. No differences in personality traits were detected in comparisons between patients with Parkinson’s disease and osteoarthritis, or between patients in the Parkinson group with high or low levels of apathy. As a group, the patients with Parkinson’s disease tended not to differ significantly from the osteoarthritic group in terms of cognitive skills. However, within the Parkinson’s disease sample, the high apathy patients performed significantly below the level of the low apathy patients. This was particularly evident on tests of executive functioning. Conclusions: Apathy in Parkinson’s disease is more likely to be a direct consequence of disease related physiological changes than a psychological reaction or adaptation to disability. Apathy in Parkinson’s disease can be distinguished from other psychiatric symptoms and personality features that are associated with the disease, and it is closely associated with cognitive impairment. These findings point to a possible role of cognitive mechanisms in the expression of apathy.

Abstract Background Negative symptoms are a core feature of schizophrenia and also found in healthy individuals in subclinical forms. According to the current literature the two negative symptom domains, apathy and diminished expression may have different underlying neural mechanisms. Previous observations suggest that striatal dysfunction is associated with apathy in schizophrenia. However, it is unclear whether apathy is specifically related to ventral or dorsal striatal alterations. Here, we investigated striatal dysfunction in patients with schizophrenia and a non-clinical population, to determine whether it is a relevant neural correlate for apathy. Methods Chronic schizophrenia patients (n= 16) and healthy controls (n=23) underwent an event- related functional MRI, while performing a variant of the Monetary Incentive Delay Task. The two negative symptom domains were assessed in both groups using the Brief Negative Symptoms Scale. Results In schizophrenia patients, we saw a strong negative correlation between apathy and ventral and dorsal striatal activation during reward anticipation. In contrast, there was no correlation with diminished expression. In healthy controls, global negative symptoms were correlated with decreased dorsal striatal activity. Discussion This study replicates our previous findings of a correlation between ventral striatal activity and apathy but not diminished expression in chronic schizophrenia patients. The association between apathy and reduced dorsal striatal activity suggests that impaired action-outcome selection is involved in the pathophysiology of motivational deficits. Finally, our findings in healthy controls support the idea that striatal alterations are a plausible neural correlate for negative symptoms in both a clinical and a subclinical context.

Abstract Background Negative symptoms and depression have in many studies been found to be moderately associated, and when present, it reflects negative symptoms of a secondary nature. Primary negative symptoms are thought to be intrinsic to schizophrenia, while secondary to be caused by depression, positive symptoms and medication side effects. Instability in above associations over time is also considered to reflect a secondary origin. Despite the clinical importance of secondary negative symptoms little research has focused on what is their underlying nature. Especially apathy and depression have common clinical features and are often found to correlate. Apathy and depression are self-perceived states and self-reports could add to our understanding. Studying the underlying themes of associations between apathy and depression as well as stability over time could therefore add to the current understanding of the primary or secondary nature of negative symptoms. Methods Eighty-four first episode psychosis patients from TOP/NORMENT study in Oslo, Norway were assessed at baseline and 1-year follow-up with the Calgary Depression Scale (CDSS), Apathy Evaluation Scale (AES), both self-report (AES-S) and clinician (AES-C), and the Positive and Negative Symptoms Scale (PANSS). Correlation with total scale, individual scale items and linear regression was used to study associations and explained variance over time. Results were repeated controlling for positive symptoms and excluding those with high level of depression. Results CDSS and AES correlated at the 0.4 to 0.5 levels at both baseline and follow up, regardless of AES-S or AES-C. Hopelessness and feeling of depression were the CDSS items with stable and concurrent correlation strength to AES-S and AES-C. For CDSS, we found correlation of equal strength and stability to the AES-S- and AES-C items of getting things done during the day, spending time on interests, getting excited and taking initiative. Same significant correlations to CDSS were found for PANSS amotivation factor, but not for PANSS expressive factor. Controlling for PANSS positive symptoms did not change results, and excluding those with high levels of depression only mildly changed results. Discussion This study shows a significant correlation between apathy and depression that is stable over time for the full scale and also at the item level, regardless of self-reporting or clinician assessed apathy. Underlying themes of the concurrent correlation reflect lack of initiative and hopelessness and are in line with the defeatist beliefs found to correlate with negative symptoms, mediate between motivation and reduced effort and have recently been a target for cognitive remediation therapy. This study does not give an answer to a primary or secondary origin of apathy, but the stability points more to an underlying common nature than one being the cause of the other.

Apathy is a debilitating but poorly understood disorder characterized by a reduction in motivation. As well as being associated with several brain disorders, apathy is also prevalent in varying degrees in healthy people. Whilst many tools have been developed to assess levels of apathy in clinical disorders, surprisingly there are no measures of apathy suitable for healthy people. Moreover, although apathy is commonly comorbid with symptoms of depression, anhedonia and fatigue, how and why these symptoms are associated is unclear. Here we developed the Apathy-Motivation Index (AMI), a brief self-report index of apathy and motivation. Using exploratory factor analysis (in a sample of 505 people), and then confirmatory analysis (in a different set of 479 individuals), we identified subtypes of apathy in behavioural, social and emotional domains. Latent profile analyses showed four different profiles of apathy that were associated with varying levels of depression, anhedonia and fatigue. The AMI is a novel and reliable measure of individual differences in apathy and might provide a useful means of probing different mechanisms underlying sub-clinical lack of motivation in otherwise healthy individuals. Moreover, associations between apathy and comorbid states may be reflective of problems in different emotional, social and behavioural domains.

BackgroundApathy is a core symptom of Huntington’s Disease (HD), appearing up to 10 years before the onset of motor symptoms and worsening alongside disease progression. Research into the disease needs greater focus on this symptom, but to date, limited tools exist for measuring apathy in HD.AimsThis study aimed to evaluate the longitudinal validity and sensitivity of two novel computer tasks that were designed to measure apathy in HD, to assess their potential for future use in clinical trials.MethodA total of 83 individuals with HD and 54 controls underwent extensive testing on a battery of existing and novel tasks that measured a range of deficits in HD. Included in this battery were the two novel tasks, the Persistence task and the Maze task, as well as the current gold-standard measures: the Problem Behaviours Assessment Scale of apathy (PBA-apathy) and the Composite Unified Huntington’s Disease Rating scale (cUHDRS). Participants were tested on the entire battery at baseline and at 12-month follow up.ResultsBoth the Maze and Persistence tasks were able to distinguish gene positive participants from controls, but only the Maze task was found to be sensitive to change between baseline and follow up. Moreover, it appeared to be more sensitive than the cUHDRS, which did not show significant change over 12 months in this population. However, the Maze task did not show association with PBA-apathy scores, suggesting it does not measure core elements of apathy as defined by the PBA. The Persistence task was associated with PBA-apathy at baseline, but this association did not persist to follow up, suggesting that the task lacks longitudinal validity.ConclusionThis study highlights the potential utility of objective computer tasks in HD research, reducing the field’s reliance on subjective self-report measures. Excitingly the findings also suggest that the Maze task could become a new objective measure of disease progression, superior to existing tools.

Disorders of motivation are common across brain disorders. Clinicians frequently encounter pathological apathy across a range of conditions, including many neurodegenerative conditions such as small cerebrovascular disease, Parkinsons and Alzheimers disease. It is now becoming understood that apathy has a poor prognosis for long-term functional and cognitive outcome. Unfortunately, we understand very little about the mechanisms underlying the syndrome.In this talk, I shall put forward a conceptual framework with which we can begin to understand apathy by considering the processes that normally underlie motivated, goal- directed behavior. In particular Ill focus on the ability to generate options for behavior and effort-based decision making for rewards. Recent studies of the latter have been particularly revealing in both healthy people and neurological patient populations.Several lines of evidence suggest that when we make decisions about how much effort we might invest in actions, we weigh up the costs involved for the potential rewards to be obtained. Functional imaging in healthy people reveals both medial frontal and basal ganglia involvement when individuals make such decisions. In patients with apathy, this evaluation is altered. Apathetic patients show blunted sensitivity to rewards and less inclination to invest effort for low rewards than healthy individuals. Some evidence shows that these factors can be improved by dopaminergic medication. The findings support the view that it might be possible to provide a mechanistic account of the syndrome of apathy which might lead to treatments for the disorder.

Apathy and anhedonia are common syndromes of motivation that are associated with a wide range of brain disorders and have no established therapies. Research using animal models suggests that a useful framework for understanding motivated behaviour lies in effort-based decision making for reward. The neurobiological mechanisms underpinning such decisions have now begun to be determined in individuals with apathy or anhedonia, providing an important foundation for developing new treatments. The findings suggest that there might be some shared mechanisms between both syndromes. A transdiagnostic approach that cuts across traditional disease boundaries provides a potentially useful means for understanding these conditions.

A recent conceptual development in schizophrenia is to view its manifestations as interactive networks rather than individual symptoms. Negative symptoms, which are associated with poor functional outcome and reduced rates of recovery, represent a critical need in schizophrenia therapeutics. MIN101 (roluperidone), a compound in development, demonstrated efficacy in the treatment of negative symptoms in schizophrenia. However, it is unclear how the drug achieved its effect from a network perspective. The current study evaluated the efficacy of roluperidone from a network perspective. In this randomized clinical trial, participants with schizophrenia and moderate to severe negative symptoms were randomly assigned to roluperidone 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). Macroscopic network properties were evaluated to determine whether roluperidone altered the overall density of the interconnections among symptoms. Microscopic properties were evaluated to examine which individual symptoms were most influential (ie, interconnected) on other symptoms in the network and are responsible for successful treatment effects. Participants receiving roluperidone did not differ from those randomized to placebo on macroscopic properties. However, microscopic properties (degree and closeness centrality) indicated that avolition was highly central in patients receiving placebo and that roluperidone reduced this level of centrality. These findings suggest that decoupling the influence of motivational processes from other negative symptom domains is essential for producing global improvements. The search for pathophysiological mechanisms and targeted treatment development should be focused on avolition, with the expectation of improvement in the entire constellation of negative symptoms if avolition is effectively treated.