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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.

A 29 year old woman underwent a planned Caesarean delivery. She denied any pre-existing medical conditions. 72-hours later she developed multiple generalised tonic-clonic seizures requiring sedation and intubation. Brain imaging revealed long standing enlargement of the ventricles. Urinary protein and blood pressure were normal. She continued to have frequent seizures confirmed on EEG despite treatment with multiple anti-epileptics.Collateral history from family revealed seizures as an infant but none since aged 6 months and that she was not taking anticonvulsants. Further inquiries confirmed a regular prescription for Vitamin B6 (Pyridoxine) which she had stopped during pregnancy. In the context of refractory seizures and the imaging findings, the possibility of Pyridoxine-dependent epilepsy was raised. Pyridoxine 100 mg twice daily was started. After the first dose, the patient’s seizures stopped and she was extubated, anticonvulsants were stopped and she had no further seizures.Pyridoxine dependent epilepsy is an autosomal recessive condition. Clinical features include refractory seizures in the first few months of life. It is caused by mutations in the ALDH7A1 gene which codes for α-aminoadipic semialdehyde dehydrogenase (α-AASA, Antiquitin), an enzyme involved in the breakdown of lysine within the brain resulting in raised levels. Diagnosis involves genetic testing and elevated plasma and urine levels of α-AASA. Treatment is lifelong daily pyridoxine supplementation.Pabrinex containing Pyridoxine should be considered in all patients who have ongoing seizures not responding to multiple anti-epileptic medication.

Apathy is recognized to be a common, disabling syndrome that occurs across a range of psychiatric and neurological conditions, including Parkinson’s disease. It can have a significant impact on quality of life, both for people affected and those around them. Currently, there are no established, evidence‐based treatments for this debilitating syndrome. Assessment and treatment have been complicated by overlaps with depression and anhedonia, as well as a lack of understanding of the underlying mechanisms. Emerging lines of evidence conceptualize apathy as a reduction of motivation associated with disordered effort‐based decision‐making and dysfunction of distinct neural circuitry between the basal ganglia and medial prefrontal cortex. Here, we introduce a novel cognitive‐behavioral framework that can inform a clinician’s conceptualization and treatment of apathy, using cognitive‐behavioral therapy (CBT) techniques. We focus on people with Parkinson’s disease in our model, but our approach is transdiagnostic and can be applied to other conditions. It considers both individual targets for therapy as well as maintenance and intervention at a systemic level. The generalizability and parsimony of the framework provides a structured assessment and formulation of apathy, while also allowing clinicians to remain sensitive to other neuropsychiatric symptoms that can occur alongside apathy, such as depression and anxiety.

Apathy is a common syndrome observed in many neurological conditions, including in up to 70% of patients with Parkinson's disease. Mechanisms underlying apathy are poorly understood and clinically we lack robust, objective detection methods. We aimed to address this using novel objective measures of motivation and reward sensitivity in relation to apathy in patients with Parkinson's disease. Saccadic velocity and pupil modulation by reward were used as objective metrics of motivation in patients with Parkinson's disease. In addition, differences in reward sensitivity in patients off medication were compared with those on medication, and assessed in relation to apathy. 20 patients with idiopathic Parkinson's disease and 21 healthy participants were recruited. Patients were tested in counterbalanced sessions, on and off dopaminergic medication. Participants were asked to make saccadic eye movements for different monetary rewards, with eye position, velocity, and pupil diameter monitored with an infrared eye tracker. Faster initiation of saccades received a greater proportion of rewards. Apathy was indexed by Lille Apathy Rating Scale (LARS) scores. Healthy controls and patients on medication demonstrated an increase in saccadic peak velocity as reward magnitude increased (an increase by 41 deg/s [SE 20] p<0·0001, and 22·5 [4·7] p<0·0001, respectively). This reward sensitivity was lost in patients off medication (5·2 [3·2], p=0·117). In all groups, pupil diameter dilated more with larger rewards (p<0·05). In Parkinson's diease, pupil reward sensitivity was greater in patients on medication than off medication, but not statistically so (p=0·06). A median split of patients on medication into high motivated and low motivated groups based on LARS scores revealed a significant interaction between motivation level and rewards for saccadic peak velocity (F2,18=5·153, p=0·049), with the apathetic (low motivation) group exhibiting less reward sensitivity in saccadic peak velocity. These findings demonstrate that saccadic velocity and pupil diameter are affected by reward magnitude and that the degree of modulation varies with motivation levels across individuals. These indices provide a novel behavioural measure for probing disorders of motivation in neurological disorders such as Parkinson's disease. Dopaminergic medication might be an effective treatment for apathy by increasing reward sensitivity, independent of effects on motor control. Wellcome Trust.

In an age of modern technology and an increasing movement towards a 24-h working culture, life for many is becoming more stressful and demanding. To help juggle these work commitments and an active social life, nootropic medication, (the so-called ‘smart pills’) have become a growing part of some people’s lives. Users claim that these drugs allow them to reach their maximal potential by becoming more efficient, smarter and requiring less sleep. The use of these medications and the role of health professionals in their distribution raises many ethical questions.

Apathy is a common, debilitating syndrome characterized by lack of motivation and inactivity, which significantly reduces quality of life across a range of brain disorders. We investigated whether hypersensitivity to effort or insensitivity to rewards might underlie the apathetic state when people make effort-based decisions.Using a novel task that manipulated reward and effort independently, participants (N=72, 24 each apathetic patients, non-apathetic patients, healthy controls) decided whether to engage with offers of monetary reward for physical effort. Patients included individuals with a range of diagnoses: cerebral small vessel disease and CADASIL, Parkinsonian conditions and limbic encephalitis. Apathy was defined using the Lille apathy rating scale.Apathetic patients accepted significantly fewer offers than non-apathetic patients, who did not differ from controls. This difference in behaviour was mainly driven by insensitivity to rewards rather than hypersensitivity to effort, confirmed using computational modelling, and with effects similar across diagnoses. Further investigation in the CADASIL group revealed reward insensitivity was associated with blunted autonomic (pupillary) responses to incentives.These findings demonstrate effort-based decision-making is disrupted in patients with apathy. They provide a plausible mechanism for the reduced goal-directed behaviour and state of inactivity that characterises the syndrome, and identify a potential therapeutic avenue.

Apathy or lack of motivation is increasingly recognized to be a major factor affecting quality of life and prognosis in many neurological conditions. It is particularly prevalent in Parkinson's disease, impacting on every disease stage, including de novo cases, and has been reported to affect up to 70% of cases. Despite the pervasiveness of apathy, challenges remain in its detection, clinical assessment and treatment. Several lines of evidence have implicated fronto-striatal reward related neural pathways in the genesis of apathy but the precise processes remain to be fully explained. This thesis examines the potential mechanisms of apathy using Parkinson's disease as a model to study the condition. Novel oculomotor tasks that used eye movement and pupillary responses were developed to help assess if insensitivity to incentives could be an underlying component of apathy. This was examined in healthy young and elderly participants as well as in patients with Parkinson's disease. Patients were tested both ON and OFF their normal dopaminergic medication so that the effect of dopamine could be assessed and the association with apathy determined. This was also performed in a pharmacological study in young participants with the use of Haloperidol, a dopaminergic D2-selective antagonist. Insensitivity to rewards modulated by dopamine was regarded to be a contributory mechanism of apathy in Parkinson's disease and also applicable to general mechanisms of motivation in healthy populations.

Apathy is increasingly appreciated to be a major problem in Parkinson's disease (PD), with up to 70% of cases affected. The mechanisms underlying the condition are poorly understood and objective detection methods are lacking. We used eye movement and pupil modulation in response to rewards as metrics of motivation to assess the relation of reward sensitivity to apathy and influence of dopaminergic medication.30 patients with idiopathic PD, tested ON and OFF medication, and healthy age-matched participants made saccades for different monetary rewards. Saccadic peak velocity and pupil diameter were measured using an infrared eye-tracker, while apathy was indexed by Lille Apathy Rating Scale scores.PD patients ON demonstrated increased saccadic velocity and pupil diameter as reward magnitude increased, just like controls. This reward sensitivity was blunted in PD patients OFF dopaminergic medication. Crucially, apathetic PD patients exhibited significantly less pupillary reward sensitivity than more motivated PD cases.Saccadic velocity and pupil diameter are influenced by reward magnitude, with the degree of modulation varying with motivation levels across individuals. These indices provide novel, objective behavioural measures for assessing clinical apathy in PD. Dopaminergic medication may also be an effective treatment for apathy by increasing reward sensitivity, independent of effects on motor control.

Apathy, a syndrome characterized by lack of motivation, is common across neurodegenerative conditions. Although it is now established to be associated with poor quality of life, mechanisms underlying the condition are poorly understood.Here we used two novel incentivised oculomotor paradigms to measure reward sensitivity in 30 Parkinson's disease (PD) patients, both ON and OFF dopaminergic medication, comparing them to age-matched controls. To distinguish between pupillary response to anticipated reward vs. response associated with motor preparation, a Go/NoGo version was performed in a further 20 PD cases.Reward sensitivity, indexed by pupillary dilation for reward, was greater in controls and PD ON compared to OFF (p<0.01). There was a significant correlation between pupil reward sensitivity and clinical apathy in PD (p<0.001), with apathetic individuals displaying less reward sensitivity. Pupillary reward sensitivity was observed regardless of whether a saccade was required. On diffusion-weighted MR imaging, reward sensitivity correlated with fractional anisotropy in the caudal cingulate zone of controls (p<0.05), an area previously implicated in motivation.Reward insensitivity may underlie lack of motivation in PD and is quantifiable using pupillary responses to rewards, independent of motor preparation. Dopaminergic medication can increase reward sensitivity and may be effective therapy for apathy, independent of motor control.