Motor cortex transcranial direct current stimulation improves non-motor symptoms in early-onset Parkinson's disease: a pilot study.

Early-onset Parkinson's Disease (EOPD) demands tailored treatments. The younger age of patients might account for a higher sensitivity to transcranial direct current stimulation (tDCS) based non-invasive neuromodulation, which may raise as an integrative therapy in the field. Accordingly, here we assessed the safety and efficacy of the primary left motor cortex (M1) anodal tDCS in EOPD. Ten idiopathic EOPD patients received tDCS at 2.0 mA per 20 min for 10 days within a crossover, double-blind, sham-controlled pilot study. The outcome was evaluated by measuring changes in MDS-UPDRS part III, Non-Motor Symptoms Scale (NMSS), PD-cognitive rating scale, and PD Quality of Life Questionnaire-39 scores. We showed that anodal but not sham tDCS significantly reduced the NMSS total and "item 2" (sleep/fatigue) scores. Other parameters were not modified. No adverse events occurred. M1 anodal tDCS might thus evoke plasticity changes in cortical-subcortical circuits involved in non-motor functions, supporting the value as a therapeutic option in EOPD.

Enhanced suppression of otoacoustic emissions by contralateral stimulation in Parkinson's disease.

Dopamine depletion affects several aspects of hearing function. Previous work [Wu, Yi, Manca, Javaid, Lauer, and Glowatzki, eLife 9, e52419 (2020)] demonstrated the role of dopamine in reducing the firing rates of inner ear cells, which is thought to decrease synaptic excitotoxicity. Thus, a lack of dopamine could indirectly increase acoustic stimulation of medial olivocochlear efferents. To investigate that, here we studied contralateral suppression of distortion product otoacoustic emissions in a population of Parkinsonian patients, compared to an age-matched control group, both audiometrically tested. To rule out activation of the acoustic reflex, middle ear impedance was monitored during testing. The results show significantly stronger contralateral suppression in the patient group.

Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature.

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinson's disease and 22 control subjects underwent 3-T magnetic resonance imaging with T2*-weighted, whole-brain T1-weighted and diffusion tensor imaging scans. The mean R2* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinson's disease and control subjects. Comparisons were also performed using voxel-based analysis of R2*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinson's disease displayed significantly higher R2* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinson's disease from controls. The markers comprising discriminating combinations were R2* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinson's physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R2*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinson's disease and, possibly, of other subcortical pathologies.

Effect of Vigabatrin on motor responses to transcranial magnetic stimulation: an effective tool to investigate in vivo GABAergic cortical inhibition in humans.

In this study, transcranial magnetic stimulation (TMS) of the hand primary motor area was used to test possible excitability changes induced by the administration of Vigabatrin (Gamma-Vinyl-gamma-aminobutryic acid;4-amino-hex-5-enoic acid; GVG), a selective GABAergic drug, on cortical inhibitory mechanisms in healthy subjects. In a group of 15 healthy volunteers, the level of motor cortical excitability was studied by means of paired-pulse TMS (p-TMS) protocols exploring the early (1-6 ms of interstimulus intervals, ISI) and the late cortical inhibition (20-250 ms ISI), and by evaluating the cortical silent period (CSP) duration obtained in response to single pulse stimulation of cortical motor area. In all participants TMS procedures were carried out before and after administering GVG for three consecutive days at a daily dosage of 50 mg/kg. Three months later, a third TMS recording session was repeated to investigate possible long-lasting GVG effects on cortical excitability. GVG induces relevant changes of cortical excitability consisting in an increase of late cortical inhibition in response to the long ISI p-TMS and in a prolonged duration of the CSP. No significant change in the early cortical inhibition was observed in response to the short ISI p-TMS. The analysis of peripheral motor excitability was also assessed, with no effects. The present electrophysiological data show that GVG is able to induce a significant increase of the late cortical inhibition, whereas it does not affect the early cortical inhibition. These data suggest that the great availability of synaptic GABA differently acts on the inhibitory circuitries controlled by different GABA-receptor subtypes.

Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease.

OBJECT: The authors compared the effects of deep brain stimulation (DBS) in the globus pallidus internus (GPi) with those in the subthalamic nucleus (STN) in patients with Parkinson disease (PD) in whom electrodes had been bilaterally implanted in both targets. METHODS: Eight of 14 patients with advanced PD in whom electrodes had been implanted bilaterally in both the GPi and STN for DBS were selected on the basis of optimal DBS effects and were studied 2 months postsurgery in off- and on-stimulus conditions and after at least 1 month of pharmacological withdrawal. Subcutaneous administration of an apomorphine test dose (0.04 mg/kg) was also performed in both conditions. Compared with the off status, the results showed less reduction in the Unified PD Rating Scale Section III scores during DBS in the GPi (43.1%) than during DBS of the STN (54.5%) or DBS of both the STN and GPi (57.1%). The difference between the effects of DBS in the GPi compared with that in the STN or simultaneous DBS was statistically significant (p < 0.01). In contrast, no statistical difference was found between DBS in the STN and simultaneous DBS in the STN and GPi (p < 0.9). The improvement induced by adding apomorphine administration to DBS was similar in all three stimulus modalities. The abnormal involuntary movements (AIMs) induced by apomorphine were almost abolished by DBS of the GPi, but were not affected by stimulation of the STN. The simultaneous stimulation of STN and GPi produced both antiparkinsonian and anti-AIM effects. CONCLUSIONS: The improvement of parkinsonian symptoms during stimulation of the GPi, STN, and both nuclei simultaneously may indicate a similar DBS mechanism for both nuclei in inducing antiparkinsonian effects, although STN is more effective. The antidyskinetic effects produced only by DBS of the GPi, with or without STN, may indicate different mechanisms for the antidyskinetic and antiparkinsonian activity related to DBS of the GPi or an additional mechanism in the GPi. These findings indicate that implantation of double electrodes for DBS should not be proposed as a routine procedure, but could be considered as a possible subsequent choice if electrode implantation for DBS of the STN does not control AIMs.