Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Apathy in Parkinson's Disease

Apathy is a syndrome characterized by a primary lack of motivation and it manifests in three domains: behavioral (lack of effort and productivity, dependence on others for structuring daily activities), cognitive (loss of interest in new experiences, lack of concern for one's problems) and affective (flattened affect and lack of response to positive or negative events). Apathy has been consistently attributed to functional disturbance of neural systems involving mesial frontal and the anterior cingulate cortex (ACC), an area with reciprocal connections with limbic, frontal cortices and the basal ganglia.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive tool used to manipulate activity in specific brain neural circuits through the skull and, in turn, induce short-term (milliseconds) and long-term (minutes to hours) changes in behavior. The duration of effect depends on the stimulation mode. Several studies have now demonstrated that rTMS may facilitate or modulate behavior beyond the actual stimulation. rTMS of the mid-dorsolateral frontal cortex (MDLFC) has been used to treat depression presumably because of its modulatory effect on the fronto-cingulate system (MDLFC and the ACC circuitry). Studies have shown that rTMS of the left MDLFC modulates the blood flow response in the ACC. We therefore hypothesize that high-frequency rTMS of the left MDLFC will also improve apathy in PD.

Inclusion criteria

• diagnosis of "probable" PD, defined by the presence of at least 2 out of 3 cardinal motor features of PD (resting tremor, rigidity, and bradykinesia, plus a sustained and significant response to dopaminergic treatment);
• age 30 or over; and
• on stable medications for at least 30 days.

Exclusion criteria

• features suggestive of other causes of parkinsonism/ parkinson-plus syndromes;
• history of deep brain stimulation or ablation surgery, significant headaches, epilepsy or seizure disorder, mass brain lesions, or major head trauma leading to loss of consciousness of any length;
• family (1st degree relatives) history of epilepsy;
• evidence for dementia;
• presence of contraindications for functional magnetic resonance imaging (fMRI);
• history of schizophrenia, schizoaffective disorder, other psychosis, rapid-cycling bipolar illness, alcohol/drug abuse within the past year;
• need for rapid clinical response due to conditions such as initiation, psychosis, or suicidality;
• unstable medical condition such as diabetes, cardiac disease, hypertension;
• pregnancy; and
• colorblindness.