Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Limbic Stimulation Drives Mania in STN-DBS in Parkinson Disease: A Prospective Study.

In this one-year prospective study, Parkinson's disease (PD) patients with or without mania following STN-DBS were compared to investigate risk and etiological factors, clinical management and consequences. Eighteen (16.2%) out of 111 consecutive PD patients developed mania, of whom 17 were males. No preoperative risk factor was identified. Postoperative mania was related to ventral limbic subthalamic stimulation in 15 (83%) patients, and resolved as stimulation was relocated to the sensorimotor STN, besides discontinuation or reduction of dopamine agonists and use of low-dose clozapine in 12 patients, while motor and nonmotor outcomes were similar. These findings underpin the prominent role of limbic subthalamic stimulation in postoperative mania. ANN NEUROL 2022;92:411-417.

Comparison of clinical outcomes and accuracy of electrode placement between robot-assisted and conventional deep brain stimulation of the subthalamic nucleus: a single-center study.

BACKGROUND: Several surgical methods are used for deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD). This study aimed to compare clinical outcomes and electrode placement accuracy after robot-assisted (RAS) versus frame-based stereotactic (FSS) STN DBS in Parkinson's disease. METHODS: In this single-center open-label study, we prospectively collected data from 48 consecutive PD patients who underwent RAS (Neuromate®; n = 20) or FSS (n = 28) STN DBS with the same MRI-based STN targeting between October 2016 and December 2018 in the university neurological hospital of Lyon, France. Clinical variables were assessed before and 1 year after surgery. The number of electrode contacts within the STN was determined by merging post-operative CT and pre-operative MRI using Brainlab® GUIDE™XT software. RESULTS: One year after surgery, the improvement of motor manifestations (p = 0.18), motor complications (p = 0.80), and quality of life (p= 0.30) and the reduction of dopaminergic treatment (p = 0.94) and the rate of complications (p = 0.99) were similar in the two groups. Surgery duration was longer in the RAS group (p = 0.0001). There was no difference in the number of electrode contacts within the STN. CONCLUSION: This study demonstrates that RAS and FSS STN DBS for PD provide similar clinical outcomes and accuracy of electrode placement.

Toe dystonia in Parkinson's disease: Impact of subthalamic nucleus deep brain stimulation.

BACKGROUND: Off state toe dystonia (TD) is a symptom frequently encountered in Parkinson's disease (PD), but little is known about its evolution after subthalamic nucleus deep brain stimulation (STN-DBS). OBJECTIVE: To analyze the prevalence and the evolution of TD in PD patients candidate to STN-DBS. METHODS: Individual data of consecutive 130 PD patients who underwent STN-DBS between 2010 and 2015 were collected. RESULTS: Data were successfully collected in 95 patients. TD affect 45.3% of the patients in our cohort. TD was present in 32.7% of patients before surgery and was alleviated by STN-DBS in 48% of the cases. Motor improvement provided by STN-DBS, levodopa-equivalent treatment diminution after surgery, disease duration or age at the time of surgery were not predictive of TD evolution. A younger age at PD diagnosis was significantly associated with TD resolution. CONCLUSION: STN-DBS is partially efficient for TD but its evolution seems independent of significant predictive factors.

Interaction of noradrenergic pharmacological manipulation and subthalamic stimulation on movement initiation control in Parkinson's disease.

BACKGROUND: Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic). OBJECTIVE: To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity. METHODS: Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (∝2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 µg oral dose of clonidine (ON- or OFF-DBS). RESULTS: In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state. CONCLUSIONS: Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency.

A phantom and animal study of temperature changes during fMRI with intracerebral depth electrodes.

BACKGROUND: MRI is routinely used in patients undergoing intracerebral electroencephalography (icEEG) in order to precisely locate the position of intracerebral electrodes. In contrast, fMRI has been considered unsafe due to suspected greater risk of radiofrequency-induced (RF) tissue heating at the vicinity of intracerebral electrodes. We determined the possible temperature change at the tip of such electrodes during fMRI sessions in phantom and animals. METHODS: A human-shaped torso phantom and MRI-compatible intracerebral electrodes approved for icEEG in humans were used to mimic a patient with four intracerebral electrodes (one parasagittal and three coronal). Six rabbits were implanted with one or two coronal electrodes. MRI-induced temperature changes at the tip of electrodes were measured using a fibre-optic thermometer. All experiments were performed on Siemens Sonata 1.5T scanner. RESULTS: For coronally implanted electrodes with wires pulled posteriorly to the magnetic bore, temperature increase recorded during EPI sequences reached a maximum of 0.6°C and 0.9°C in phantom and animals, respectively. These maximal figures were decreased to 0.2°C and 0.5°C, when electrode wires were connected to cables and amplifier. When electrode wires were pulled anteriorly to the magnetic bore, temperature increased up to 1.3°C in both phantom and animals. Greater temperature increases were recorded for the single electrode implanted parasagitally in the phantom. CONCLUSION: Variation of the temperature depends on the electrode and wire position relative to the transmit body coil and orientation of the constant magnetic field (B0). EPI sequence with intracerebral electrodes appears as safe as standard T1 and T2 sequence for implanted electrodes placed perpendicular to the z-axis of the magnetic bore, using a 1.5T MRI system, with the free-end wires moving posteriorly, in phantom and animals.

Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours.

Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinson's disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinson's disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinson's disease may be considered as new indications for subthalamic stimulation.

Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation.

Apathy has been reported to occur after subthalamic nucleus stimulation, a treatment of motor complications in advanced Parkinson's disease. We carried out a prospective study of the occurrence of apathy and associated symptoms, predictors and mechanisms in the year following subthalamic stimulation. Dopamine agonist drugs were discontinued immediately after surgery and levodopa was markedly reduced within 2 weeks. Apathy and depression were assessed monthly, using the Starkstein apathy scale and the Beck Depression Inventory. Dopamine agonists were re-introduced if patients developed apathy or depression. Preoperative non-motor fluctuations were evaluated using the Ardouin Scale. Depression, apathy and anxiety were evaluated both on and off levodopa. Analysis of predictors of apathy was performed using a Cox proportional hazard model. Twelve patients who developed apathy and a control group of 13 patients who did not underwent [11C]-raclopride positron emission tomography scanning before and after oral intake of methylphenidate. In 63 patients with Parkinson's disease treated with subthalamic stimulation, dopaminergic treatment was decreased by 82% after surgery. Apathy occurred after a mean of 4.7 (3.3-8.2) months in 34 patients and was reversible in half of these by the 12-month follow-up. Seventeen patients developed transient depression after 5.7 (4.7-9.3) months and these fell into the apathy group with one single exception. At baseline, fluctuations in depression, apathy and anxiety scores were greater in the group with apathy. Fluctuations in apathy, depression and anxiety ratings during a baseline levodopa challenge were also significant predictors of postoperative apathy in univariate analysis, but not motor and cognitive states or the level of reduction of dopaminergic medication. The multivariate model identified non-motor fluctuations in everyday life and anxiety score during the baseline levodopa challenge as two independent significant predictors of postoperative apathy. Without methylphenidate, [11C]-raclopride binding potential values were greater in apathetic patients bilaterally in the orbitofrontal, dorsolateral prefrontal, posterior cingulate and temporal cortices, left striatum and right amygdala, reflecting greater dopamine D2/D3 receptor density and/or reduced synaptic dopamine level in these areas. The variations of [11C]-raclopride binding potential values induced by methylphenidate were greater in non-apathetic patients in the left orbitofrontal cortex, dorsolateral prefrontal cortex, thalamus and internal globus pallidus and bilaterally in the anterior and posterior cingulate cortices, consistent with a more important capacity to release dopamine. Non-motor fluctuations are related to mesolimbic dopaminergic denervation. Apathy, depression and anxiety can occur after surgery as a delayed dopamine withdrawal syndrome. A varying extent of mesolimbic dopaminergic denervation and differences in dopaminergic treatment largely determine mood, anxiety and motivation in patients with Parkinson's disease, contributing to different non-motor phenotypes.

Do the effects measured by intraoperative and postoperative STN macrostimulation in Parkinson's disease match?

The aim of our study was to compare the results obtained by intraoperative and postoperative subthalamic nucleus (STN) macrostimulation in Parkinson's disease (PD). One hundred three PD patients implanted with bilateral STN stimulation were included. The thresholds for efficacy and side effects (motor contraction; paresthesias; oculomotor signs) observed on the same trajectory and at the same depth during the intraoperative evaluation and the first postoperative setting of STN stimulation parameters were collected. The level of improvement was divided into four categories depending on the degree of rigidity reduction: 0: no effect, A (mediocre efficacy): 20-50%, B (good efficacy): 60-100%, LL: lesion-like effect (disappearance of rigidity after implantation). Efficacy of STN stimulation was analyzed in 83 patients for a total of 664 contacts. For the best effects (B, LL), the results obtained in the operative room were concordant with those of the postoperative evaluation for 81% of the contacts. For the mediocre effects (A) and absence of efficacy, the results were only concordant in 20%. Side effects were analyzed in 103 patients for a total of 824 contacts. In 35% of the tested contacts paresthesias that were absent during surgery were observed postoperatively. This discrepancy was of 17% for the motor and of 10% for oculomotor side effects. Differences between the type of electrodes used, the stimulation parameters employed and the conditions of the assessment could explain these discrepancies.

Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: five year follow-up.

OBJECTIVE: To assess the long-term efficacy and safety of bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson's disease (PD). METHODS: 42 consecutive patients with idiopathic PD treated with bilateral STN stimulation were enrolled. Parkinsonian status, medication intake and neuropsychological evaluation were assessed preoperatively and at 1 and 5 years postoperatively in on and off medication/on and off stimulation conditions. RESULTS: 23 patients could be followed-up 5 years after surgery. In the remaining cases, 5 died, 1 could not be assessed because of device removal for infection, 1 decided not to be stimulated, and 11 were lost of follow-up (one because of a liver carcinoma and the others because they refused the formal four conditions of assessment). STN stimulation reduced the UPDRS motor score by 55 % compared to baseline in the off-medication conditions. Tremor, rigidity, bradykinesia, postural stability, and gait improved by 74 %, 66 %, 59 %, 17 % and 37 %, respectively. UPDRS part II scores were reduced by 38 %. The dopaminergic treatment daily dose was reduced by 54.4 % after surgery. Axial dopa-unresponsive signs worsened in some patients. Among the 42 initial patients we observed the following: 2 brain hemorrhages, 3 infections of the device, 2 phlebitis and 1 pulmonary embolism. In addition, 2 patients needed a repositioning of the electrode. Among the 23 patients followed at 5 years, long lasting side effects consisted in dysarthria (56 %), depression (39 %), eyelid opening apraxia (30.4 %) and apathy (4.3 %). CONCLUSIONS: Our data confirm that bilateral STN stimulation is beneficial in the long-term for PD patients but does not prevent disease progression and the occurence of axial levodopa unresponsive signs in some patients.

Patterns of bidirectional communication between cortex and basal ganglia during movement in patients with Parkinson disease.

Cortico-basal ganglia networks are considered to comprise several parallel and mostly segregated loops, where segregation is achieved in space through topographic connectivity. Recently, it has been suggested that functional segregation may also be achieved in the frequency domain, by selective coupling of related activities at different frequencies. So far, however, any coupling across frequency in the human has only been modeled in terms of unidirectional influences, a misplaced assumption given the looped architecture of the basal ganglia, and has been considered in static terms. Here, we investigate the pattern of bidirectional coupling between mesial and lateral cortical areas and the subthalamic nucleus (STN) at rest and during movement, with and without pharmacological dopaminergic input, in patients with Parkinson's disease. We simultaneously recorded scalp electroencephalographic activity and local field potentials from depth electrodes and deduced patterns of directed coherence between cortical and STN levels across three frequency bands [sub-beta (3-13 Hz), beta (14-35 Hz), gamma (65-90 Hz)] in the different states. Our results show (1) asymmetric bidirectional coupling between STN and both mesial and lateral cortical areas with greater drives from cortex to STN at frequencies <35 Hz, (2) a drop of beta band coupling driven from mesial cortex to STN during movement, and (3) an increase in symmetrical bidirectional drives between STN and mesial cortex and in lateral cortical drive to STN in the gamma band after dopaminergic therapy. The results confirm a bidirectional pattern of cortico-basal ganglia communication that is differentially patterned across frequency bands and changes with movement and dopaminergic input.

Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: three years follow-up.

OBJECTIVE: To assess the long-term efficacy and safety of chronic bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced Parkinson's disease (PD). METHODS: 36 consecutive patients with idiopathic Parkinson's disease treated with bilateral stimulation of the STN were studied. Parkinsonian status was assessed preoperatively and at 1 and 3 years postoperatively using the Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological evaluation in on and off-medication / on and off stimulation conditions. RESULTS: At 3 years follow-up, STN stimulation reduced the UPDRS motor score by 54.2 % compared to baseline in the off-medication conditions. Tremor, rigidity, bradykinesia, postural stability, and gait improved by 72.2 %, 62.4 %, 56.8 %, 40.5 % and 45.3 %, respectively. UPDRS part II scores were reduced by 41.4 %. The overall dopaminergic drugs dose was reduced by 48.6 % after surgery and four patients were no longer taking antiparkinsonian medication at three years. However, axial dopa-unresponsive signs worsened in some patients. The most frequent transient adverse event consisted in mood disorders in 23 patients. CONCLUSIONS: Our data demonstrate that: 1) bilateral STN stimulation is relatively safe, improves the motor symptoms and drug-related motor complications of PD, and reduces the daily dosage of medication; 2) this benefit is sustained over time despite the occurrence of axial doparesistant signs in some patients.

Chorea induced by globus pallidus externus stimulation in a dystonic patient.

Bilateral high-frequency stimulation of the internal part of the pallidum has proven its efficacy in improving motor symptoms of dystonia. In Parkinson's disease, the stimulation of the external pallidum (GPe) can induce dyskinesias. This has never been described in dystonia. We report here a case of abnormal movements induced by the stimulation of GPe in a dystonic patient and discuss the pathophysiological mechanisms.

Brainstem auditory evoked potential monitoring during microvascular decompression for hemifacial spasm: intraoperative brainstem auditory evoked potential changes and warning values to prevent hearing loss--prospective study in a consecutive series of 84 patients.

OBJECTIVE: The nerve function of Cranial Nerve VIII is at risk during microvascular decompression for hemifacial spasm. Intraoperative monitoring of brainstem auditory evoked potentials (BAEPs) can be a useful tool to decrease the danger of hearing loss. The aim of this study was 1) to assess the side effects of surgery on hearing and describe the main intraoperative BAEP changes observed in the authors' series, and 2) to define warning values beyond which the probability of hearing impairment rises significantly. These values were calculated by correlating the (possible) postoperative hearing disturbances evaluated in terms of pure tone average with intraoperative BAEP changes (especially delay in Wave V latency). METHODS: This series included 84 consecutive patients affected with hemifacial spasm who underwent microvascular decompression during which BAEPs were monitored. During surgery, Wave I, I to V interpeak interval, latency, and amplitude of Wave V were recorded and measured. Auditory function was studied before and after surgery and expressed as a pure tone average in all patients. Then, correlations were made between hearing impairment after surgery and intraoperative BAEP changes in an attempt to define warning values. RESULTS: Seventy-four patients (88%) had no hearing loss after surgery (Group 1). Eight patients (9.5%) had hearing impairment with a decrease in pure tone average of more than 20 dB (Group 2). Two patients (2.3%) experienced a definitive and complete hearing loss on the side operated on (Group 3). Among intraoperative BAEP changes, latency of Peak V was the most frequently observed and the most significant phenomenon, especially during cerebellar retraction and the decompression step of the microvascular decompression procedure. In the group of patients without hearing loss (Group 1), the mean delay in latency of Peak V was 0.61 millisecond (standard deviation, +/-0.36 ms); in the group with hearing decrease (Group 2), the mean delay was 1.05 milliseconds (standard deviation, +/-0.64 ms); and in the group with deafness (Group 3), Wave V was abolished. CONCLUSION: From a practical standpoint, three warning values, based on delay in latency of Peak V, were established for use during surgery: an initial one at 0.4 millisecond ("watching" signal) at the safety limit; a second one at 0.6 millisecond (risk "warning" signal), which is the mean value corresponding to the group of patients without postoperative hearing loss; and an ultimate one at 1 millisecond ("critical" warning), before irreversibility. These warnings should help the surgeon to avoid or correct maneuvers that are dangerous for hearing function, which is mandatory in functional surgery.

Evidencias de compromiso cerebral en el estadio crónico de la enfermedad de Chagas obtenidas por medio del potencial P300 y de electroencefalografía cuantificada / P300 event related potentials and qEEG evidenced a cerebral dysfunction in human chronic Chagas disease

Es reconocido el compromiso del sistema nervioso periférico en la etapa crónica de la enfermedad de Chagas, incorporándose últimamente evidencias tomográficas y neuropsicológicas de compromiso cerebral. Con el objetivo de evaluar dicho compromiso por medio del potencial P 300 y la electroencefalografía cuantificada (EEGc) se estudiaron 35 pacientes (26 a 55 años), comparados con un grupo control de similar número y edad (29 a 55 años). Se observó: latencia de la onda P 3 mayor en el grupo en estudio (331,24 +/- 24,02 contra 318,86 +/- 23,18) (p=0,01716). El EEGc mostró diferencias en la potencia relativa de la banda Beta 1, menor en los pacientes (p=1,62834E5) y en la frecuencia dominante, 1 Hz menor en los chagasicos (p=0,01077). El análisis multivariado discrimina tres subpoblaciones: una normal, una de enfermos con incremento alfa y otra de enfermos con decremento alfa e incremento delta y theta (p=0,00004). La proporción de resultados patológicos fue del 20 por ciento en los EEGc y el 11,43 por ciento en los potenciales cognitivos. No se correlacionó el compromiso neurológico y el cardíaco. Se concluye que existen francos indicadores electrofisiológicos de compromiso cerebral en el estadio crónico de la enfermedad de Chagas, hallazgo que refuerza a los obtenidos por otros métodos.