Apathy is commonly defined as a loss of motivation leading to a reduction in goal-directed behaviors. This multidimensional syndrome, which includes cognitive, emotional and behavioral components, is one of the most prevalent neuropsychiatric features of Parkinson’s disease (PD). It has been established that the prevalence of apathy increases as PD progresses. However, the pathophysiology and anatomic substrate of this syndrome remain unclear. Apathy seems to be underpinned by impaired anatomical structures that link the prefrontal cortex with the limbic system. It can be encountered in the prodromal stage of the disease and in fluctuating PD patients receiving bilateral chronic subthalamic nucleus stimulation. In these stages, apathy may be considered as a disorder of motivation that embodies amotivational behavioral syndrome, is underpinned by combined dopaminergic and serotonergic denervation and is dopa-responsive. In contrast, in advanced PD patients, apathy may be considered as cognitive apathy that announces cognitive decline and PD dementia, is underpinned by diffuse neurotransmitter system dysfunction and Lewy pathology spreading and is no longer dopa-responsive. In this review, we discuss the clinical patterns of apathy and their treatment, the neurobiological basis of apathy, the potential role of the anatomical structures involved and the pathways in motivational and cognitive apathy.

Presence hallucination in Parkinson’s disease (PD) is shown to arise from errors in sensorimotor integration and frontotemporal disconnection.

Postoperative apathy is a frequent symptom in Parkinson’s disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering and ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and one-year postoperative apathy in Parkinson’s disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with one-year postoperative apathy considering: i) preoperative clinical phenotype, ii) dopaminergic drug management and iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and one year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive, and behavioral signs. We modelled the volume of tissue activated in 161 patients using Lead DBS toolbox and analyzed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited one-year postoperative apathy: 67 (18.2%) with “de novo apathy” and 27 (7.4%) with “sustained apathy”. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having “reversed apathy”. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having “no apathy”. We identified preoperative apathy score (OR 1.16, IC95% [1.10 ; 1.22], p<0.001), preoperative episodic memory free recall score (OR 0.93, IC95% [0.88 ; 0.97], p=0.003), and one-year postoperative motor responsiveness (OR 0.98, IC95% [0.96 ; 0.99], p=0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with “sustained apathy” had poorer preoperative fronto-striatal cognitive status and higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (p=0.023), suggesting cognitive dopa-resistant apathy. Patients with “reversed apathy” benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left STN (p=0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage post-operative apathy.