Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson’s disease
Authors: Béreau Matthieu , Kibleur Astrid , Servant Mathieu , Clément Gautier , Dujardin Kathy , Rolland Anne-Sophie , Wirth Thomas , Lagha-Boukbiza Ouhaid , Voirin Jimmy , Santin Marie des Neiges , Hainque Elodie , Grabli David , Comte Alexandre , Drapier Sophie , Durif Franck , Marques Ana , Eusebio Alexandre , Azulay Jean-Philippe , Giordana Caroline , Houeto Jean-Luc , Jarraya Béchir , Maltete David , Rascol Olivier , Rouaud Tiphaine , Tir Mélissa , Moreau Caroline , Danaila Teodor , Prange Stéphane , Tatu Laurent , Tranchant Christine , Corvol Jean-Christophe , Devos David , Thobois Stephane , Desmarets Maxime , Anheim Mathieu 
Published: October 2023

Abstract
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 1-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 1-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 1 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 behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-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 [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P &lt; 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 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 a 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 subthalamic nucleus (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 postoperative apathy.