Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease

Abstract

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.

Subthalamic Nucleus Lesions Enhance the Psychomotor-Activating, Incentive Motivational, and Neurobiological Effects of Cocaine

“…For example, Baunez and colleagues reported that bilateral STN lesions enhance motivation for food, as measured by progressive ratio performance and conditioned place preference (Baunez et al, 2002(Baunez et al, , 2005. Furthermore, HFS of the STN, which is thought to mimic ablation of the STN by inducing depolarization block (Benazzouz et al, 1993(Benazzouz et al, , 1995(Benazzouz et al, , 2000Lozano et al, 2002) (but see Garcia et al, 2005), enhances motivation and decreases apathy and also increases the therapeutic potency of the dopamine-enhancing drug L-3,4-dihydroxyphenylalanine (L-DOPA) in patients with Parkinson's disease (Limousin et al, 1998;Houeto et al, 2002;Funkiewiez et al, 2003;Ashkan et al, 2004).…”

“…However, recently, it has been shown that amphetamine and cocaine induce robust c-fos expression in the STN (Uslaner et al, 2001a), which sensitizes as a result of repeated drug administration (Uslaner et al, 2003b) and that bilateral lesions of the STN increase responding for food rewards (Baunez et al, 2002). Furthermore, high-frequency electrical stimulation (HFS) of the STN, which is used to treat symptoms of Parkinson's disease, also enhances motivation and other limbic system-related processes in these patients (Funkiewiez et al, 2003;Takeshita et al, 2005). These studies suggest, therefore, that in addition to its involvement in motor control, the STN may play a role in motivational processes and the behavioral response to drugs of abuse.…”

Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment

“…STN-DBS itself has a positive eff ect on offperiod apathy, contributing to improvement of off -period cognitive and emotional aspects in apathy. 92,[104][105][106] However, with regard to the on-period motivational aspects of the antiparkinsonian drugs, a slowly progressive desensitisation of the psychotropic eff ects of dopaminergic treatment after drug decrease 107 explains why the hypodopaminergic withdrawal syndrome in patients on chronic STN-DBS typically occurs with a substantial delay of several months after surgery 83,92 (unlike the much more acute withdrawal syndrome after cessation of dopamine agonists in patients not receiving chronic STN-DBS). 93 The potential to reverse postoperative apathy after D2 or D3 receptor stimulation with oral dopamine receptor agonists 108,109 clearly suggests a Parkinson's disease-related symptom that has been unmasked by a decrease in drug treatment.…”

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…Worsening of dyskinesia or dystonia can appear during initial DBS programming sessions, but these symptoms decline after several hours of continuous stimulation. 160 Deep brain stimulation can generate cognitive side effects as well, including mood changes, 161 depression, 162 decreased working memory performance, 163,164 impulsivity, 165 and hallucinations. 166 One explanation for the emergence of such cognitive side effects is that suprathreshold currents spread into nonmotor regions within the basal ganglia and thalamocortical networks.…”