Altered nucleus accumbens functional connectivity precedes apathy in Parkinson’s disease

Abstract

Work in animal and human neuroscience has identified neural regions forming a network involved in the production of motivated, goal-directed behaviour. In particular, the nucleus accumbens and anterior cingulate cortex are recognized as key network nodes underlying decisions of whether to exert effort for reward, to drive behaviour. Previous work has convincingly shown that this cognitive mechanism, known as effort-based decision making, is altered in people with Parkinson’s disease with a syndrome of reduced goal-directed behaviour - apathy. Building on this work, we investigated whether the neural regions implementing effort-based decision-making were associated with apathy in Parkinson’s disease, and more importantly, whether changes to these regions were evident prior to apathy development. We performed a large, multimodal neuroimaging analysis in a cohort of people with Parkinson’s disease (n = 199) with and without apathy at baseline. All participants had ∼ 2 year follow-up apathy scores, enabling examination of brain structure and function specifically in those with normal motivation who converted to apathy by ∼ 2 year follow-up. In addition, of the people with normal motivation, a subset (n = 56) had follow-up neuroimaging data, allowing for examination of the rate of change in key nodes over time in those who did, and did not, convert to apathy. Healthy control (n = 54) data was also included to aid interpretation of findings. Functional connectivity between the nucleus accumbens and dorsal anterior cingulate cortex was higher in people with normal motivation who later converted to apathy compared to those who did not, whereas no structural differences were evident between these groups. In contrast, grey matter volume in these regions was reduced in the group with existing apathy. Furthermore, of those with normal motivation who had undergone longitudinal neuroimaging, converters to apathy showed a higher rate of change in grey matter volume within the nucleus accumbens. Overall, we show that changes in functional connectivity between nucleus accumbens and anterior cingulate cortex precedes apathy in people with Parkinson’s disease, with conversion to apathy associated with higher rate of grey matter volume loss in nucleus accumbens, despite no baseline differences. These findings significantly add to an accumulating body of transdiagnostic evidence that apathy arises from disruption to key nodes within a network in which normal goal-directed behaviour is instantiated, and raise the possibility of identifying those at risk for developing apathy before overt motivational deficits have arisen.

Depression in Parkinson’s disease is associated with dopamine unresponsive reduced reward sensitivity during effort-based decision making

“…42 In PD patients, reduced functional connectivity and striatal neurodegeneration precede the emergence of motivational symptoms. 16,17 This suggests that disruption to frontostriatal circuit synchrony may impair reward valuation and lead to the emergence of motivational and mood symptoms. Different subregions of the ventral striatum have been shown to have dissociable contributions to the motivational versus hedonic components of the affective processing of reward.…”

“…15 Loss of pre-synaptic dopaminergic projections to the striatum and reduced functional connectivity in this region are associated with increased apathy and anhedonia in PD. 16,17 This may explain why mood changes in PD are frequently associated with motor fluctuations, or “ON/OFF” dopamine states 18 , and suggests depression in PD could be related to dopaminergic deficits which mediate specific neurocognitive processes.…”

Impaired value-based decision-making in Parkinson’s disease apathy

“… 42 As serotonin promotes choice persistence, 32 upregulation of serotonergic systems could be an explanation for how our non-apathy group could continue to exploit, despite impaired encoding of a decision outcomes. A ‘double-hit’ phenomenon would be consistent with recent longitudinal imaging by Morris et al ., 99 where loss of functional connectivity between dACC and ventral striatum in non-apathetic PD patients preceeded the clinical expression of a demotivated state.…”

Mild Behavioral Impairment in Parkinson’s Disease: An Updated Review on the Clinical, Genetic, Neuroanatomical, and Pathophysiological Aspects

“…It has been indicated that PD patients with apathy display a widespread decrease in the extra-striatal uptake of dopamine transporters compared to those without apathy, as well as a lower longitudinal dopamine transporter uptake [22]. Abnormal functional connectivity between the anterior cingulate cortex and nucleus accumbens has been demonstrated to precede apathy in patients with PD [23], and apathy has been shown to be 2.6 more common in non-PD individuals carrying GBA mutations compared to healthy controls [24]. Visual hallucinations in patients with PD have also been associated with specific dopamine receptor single-nucleotide polymorphisms (SNPs) [25].…”