Kinan Muhammed

Fasting biases brain reward systems towards high-calorie foods.

Nutritional state (e.g. fasted vs. fed) and different food stimuli (e.g. high‐calorie vs. low‐calorie, or appetizing vs. bland foods) are both recognized to change activity in brain reward systems. Using functional magnetic resonance imaging, we have studied the interaction between nutritional state and different food stimuli on brain food reward systems. We examined how blood oxygen level‐dependent activity within a priori regions of interest varied while viewing pictures of high‐calorie and low‐calorie foods. Pictures of non‐food household objects were included as control stimuli. During scanning, subjects rated the appeal of each picture. Twenty non‐obese healthy adults [body mass index 22.1 ± 0.5 kg/m2 (mean ± SEM), age range 19–35 years, 10 male] were scanned on two separate mornings between 11:00 and 12:00 h, once after eating a filling breakfast (‘fed’: 1.6 ± 0.1 h since breakfast), and once after an overnight fast but skipping breakfast (‘fasted’: 15.9 ± 0.3 h since supper) in a randomized cross‐over design. Fasting selectively increased activation to pictures of high‐calorie over low‐calorie foods in the ventral striatum, amygdala, anterior insula, and medial and lateral orbitofrontal cortex (OFC). Furthermore, fasting enhanced the subjective appeal of high‐calorie more than low‐calorie foods, and the change in appeal bias towards high‐calorie foods was positively correlated with medial and lateral OFC activation. These results demonstrate an interaction between homeostatic and hedonic aspects of feeding behaviour, with fasting biasing brain reward systems towards high‐calorie foods.

Distinct Subtypes of Apathy Revealed by the Apathy Motivation Index

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.

Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson’s disease

Apathy is extremely common in neurodegenerative disorders such as Parkinson’s disease. Muhammed et al. report that lack of sensitivity to rewards may underlie apathy, with dopamine playing a modulatory role. The study provides a basis for objective clinical markers of motivation and treatment efficacy in neurodegenerative conditions.

Apathy in rapid eye movement sleep behaviour disorder is common and under-recognized.

Apathy is an important neuropsychiatric feature of Parkinsons disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population.

Fractionating the Neurocognitive Mechanisms Underlying Working Memory: Independent Effects of Dopamine and Parkinson's Disease.

Abstract Deficits in working memory (WM) in Parkinsons disease (PD) are often considered to be secondary to dopaminergic depletion. However, the neurocognitive mechanisms by which dopamine causes these deficits remain highly contested, and PD is now also known to be associated with nondopaminergic pathology. Here, we examined how PD and dopaminergic medication modulate three components of WM: maintenance over time, updating contents with new information and making memories distracter‐resistant. Compared with controls, patients were disproportionately impaired when retaining information for longer durations. By applying a probabilistic model, we were able to reveal that the source of this error was selectively due to precision of memory representations degrading over time. By contrast, replenishing dopamine levels in PD improved executive control over both the ability to ignore and update, but did not affect maintenance of information across time. This was due to a decrease in guess responses, consistent with the view that dopamine serves to prevent WM representations being corrupted by irrelevant information, but has no impact on information decay. Cumulatively, these results reveal a dissociation in the neural mechanisms underlying poor WM: whereas dopamine reduces interference, nondopaminergic systems in PD appear to modulate processes that prevent information decaying more quickly over time.

Dysfunctional effort-based decision-making underlies apathy in genetic cerebral small vessel disease

Le Heron et al. demonstrate, using behavioural, physiological and imaging techniques, converging evidence that reduced reward sensitivity underlies apathy in patients with a monogenic form of cerebral small vessel disease. This specific change in effort-based decision making points to potential treatment avenues for apathy.

Multiple sclerosis causing a partial sixth nerve palsy

A 27-year-old man with no significant medical history, presented with right foot weakness and difficulty with balance. MRI of his brain, cervical and thoracic spinal cord showed multiple white matter lesions consistent with demyelination. His cerebrospinal fluid had a white cell count of 27 mononuclear cells and was positive for oligoclonal bands. He was treated with a 3-day course of intravenous methylprednisolone (1 g) with good resolution of his symptoms. An extensive screen for infective causes was negative and a definitive diagnosis at this time …

Apathy in rapid eye movement sleep behaviour disorder is associated with serotonin depletion in the dorsal raphe nucleus

Apathy is a common and debilitating condition that often emerges during prodromal Parkinsons disease. Using neuroimaging in patients with REM sleep behaviour disorder, Barber et al. show that apathy in this prodromal population is related to serotonin depletion in the dorsal raphe nucleus, suggesting a mechanism for its expression and a potential target for therapeutic intervention.

PUPILLARY REWARD SENSITIVITY IS A MARKER OF APATHY IN PARKINSON'S DISEASE

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 Parkinsons 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.

A COMMON MECHANISM UNDERLYING APATHY ACROSS NEUROLOGICAL DISORDERS

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.