A circuit-based approach to modulate hypersexuality in Parkinson's disease.

AIM: Impulse-control disorder is a common neuropsychiatric complication in Parkinson's disease (PD) under dopamine replacement therapy. Prior studies tested the balance between enhanced desire towards reward and cognitive control deficits, hypothesized to be biased towards the former in impulse control disorders. We provide evidence for this hypothesis by measuring behavioral and neural patterns behind the influence of sexual desire over response inhibition and tools towards functional restoration using repetitive transcranial stimulation in patients with hypersexuality as predominant impulsive disorder. METHODS: The effect of sexual cues on inhibition was measured with a novel erotic stop-signal task under on and off dopaminergic medication. Task-related functional and anatomical connectivity models were estimated in 16 hypersexual and 17 nonhypersexual patients with PD as well as in 17 healthy controls. Additionally, excitatory neuromodulation using intermittent theta-burst stimulation (sham-controlled) was applied over the pre-supplementary motor area in 20 additional hypersexual patients with PD aiming to improve response inhibition. RESULTS: Compared with their nonhypersexual peers, patients with hypersexuality recruited caudate, pre-supplementary motor area, ventral tegmental area, and anterior cingulate cortex while on medication. Reduced connectivity was found between pre-supplementary motor area and caudate nucleus in hypersexual compared with nonhypersexual patients (while medicated), a result paralleled by compensatory enhanced anatomical connectivity. Furthermore, stimulation over the pre-supplementary motor area improved response inhibition in hypersexual patients with PD when exposed to sexual cues. CONCLUSION: This study, therefore, has identified a specific fronto-striatal and mesolimbic circuitry underlying uncontrolled sexual responses in medicated patients with PD where cortical neuromodulation halts its expression.

Cortical disinhibition in Parkinson's disease.

In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease.

Transcranial static magnetic field stimulation of the supplementary motor area decreases corticospinal excitability in the motor cortex: a pilot study.

Transcranial static magnetic field stimulation (tSMS) is a non-invasive brain stimulation technique that is portable and easy to use. Long-term, home-based treatments with tSMS of the supplementary motor area (SMA) are promising for movement disorders and other brain diseases. The aim of the present work was to investigate the potential of SMA-tSMS for reducing corticospinal excitability. We completed an open pilot study in which twenty right-handed healthy subjects (8 females; age: 31.3 ± 5.4 years) completed two 30-min sessions (at least one week apart) of SMA-tSMS. We assessed corticospinal excitability by applying transcranial magnetic stimulation (TMS) over the primary motor cortex, recording 30 motor evoked potentials (MEPs) from either the left or right first dorsal interosseous (FDI, 'hotspot' muscle) and extensor carpi radialis (ECR, 'offspot' muscle) in each session before and after (up to 30 min) tSMS. We observed moderate-to-extreme level of Bayesian evidence for a reduction of MEP amplitude after 30 min of tSMS over SMA compared to baseline. Thus, tSMS applied over SMA may reduce corticospinal excitability. These findings, if confirmed with double-blind, placebo-controlled experiments, support the potential of targeting the SMA for neuromodulating a large motor network in future therapeutic applications of tSMS.