Deep Brain Stimulation Conditions Research Articles

The effect of deep brain stimulation on lower extremity dexterity in people with Parkinson’s disease

Purpose To examine the effect of deep brain stimulation (DBS) on lower extremity dexterity in people with Parkinson’s disease (PwPD) and to investigate the relationship between this effect and the effect of DBS on measures of different walking characteristics, and other features of Parkinson’s disease. Materials and methods Thirty-six PwPD were included. Assessment was performed twice with DBS “on” and DBS “off” state. Results The LEDT scores of both extremities, the Unified Parkinson Disease Rating Scale-motor section (UPDRS-III), the 10-Meter Walk Test (TMWT), the Timed Up and Go Test (TUG), the Figure-of-Eight Walk Test (FEWT), and the Three-Meter Backward Walk Test (TMBWT) scores were significantly better in “on” DBS condition than “off” DBS condition. The effect of DBS on lower extremity dexterity is related to age and levodopa equivalent daily dosage (LEDD). The effect of DBS on lower extremity dexterity and the effect of DBS on the bradykinesia, TUG, the FEWT, and the TMBWT were also related. Conclusions DBS has a positive effect on lower extremity dexterity. Clinical characteristics such as age and LEDD and the effect of DBS on bradykinesia, walking with turning, curved walking, and backward walking is related with the effect of DBS on lower extremity dexterity.

Impacts of Deep Brain Stimulation of the Globus Pallidus Internus on Swallowing: A Retrospective, Cross-Sectional Study.

Deep brain stimulation (DBS) is a common treatment for motor symptoms of Parkinson disease (PD), a condition associated with increased risk of dysphagia. The effect of DBS on swallowing function has not been comprehensively evaluated using gold-standard imaging techniques, particularly for globus pallidus internus (GPi) DBS. The objective of this retrospective, cross-sectional study was to identify differences in swallowing safety and timing kinematics among PD subjects with and without GPi DBS. We investigated the effects of unilateral and bilateral GPi DBS as well as the relationship between swallowing safety and DBS stimulation parameters, using retrospective analysis of videofluoroscopy recordings (71 recordings from 36 subjects) from electronic medical records. Outcomes were analyzed by surgical status (pre-surgical, unilateral DBS, bilateral DBS). The primary outcome was percent of thin-liquid bolus trials rated as unsafe, with Penetration-Aspiration Scale scores of 3 or higher. Secondary analyses included swallowing timing measures, relationships between swallowing safety and DBS stimulation parameters, and Dynamic Imaging Grade of Swallowing Toxicity ratings. Most subjects swallowed all boluses safely (19/29 in the pre-surgical, 16/26 in the unilateral DBS, and 10/16 in the bilateral DBS conditions). Swallowing safety impairment did not differ among stimulation groups. There was no main effect of stimulation condition on timing metrics, though main effects were found for sex and bolus type. Stimulation parameters were not correlated with swallowing safety. Swallowing efficiency and overall impairment did not differ among conditions. These results provide evidence that GPi DBS does not affect pharyngeal swallowing function. Further, prospective, investigations are needed.

Effects of deep brain stimulation on quantitative sleep electroencephalogram during non-rapid eye movement in Parkinson's disease.

Sleep dysfunction is frequently experienced by people with Parkinson's disease (PD) and negatively influences quality of life. Although subthalamic nucleus (STN) deep brain stimulation (DBS) can improve sleep in PD, sleep microstructural features such as sleep spindles provide additional insights about healthy sleep. For example, sleep spindles are important for better cognitive performance and for sleep consolidation in healthy adults. We hypothesized that conventional STN DBS settings would yield a greater enhancement in spindle density compared to OFF and low frequency DBS. In a previous within-subject, cross-sectional study, we evaluated effects of low (60 Hz) and conventional high (≥130 Hz) frequency STN DBS settings on sleep macroarchitectural features in individuals with PD. In this post hoc, exploratory analysis, we conducted polysomnography (PSG)-derived quantitative electroencephalography (qEEG) assessments in a cohort of 15 individuals with PD who had undergone STN DBS treatment a median 13.5 months prior to study participation. Fourteen participants had unilateral DBS and 1 had bilateral DBS. During three nonconsecutive nights of PSG, the participants were assessed under three different DBS conditions: DBS OFF, DBS LOW frequency (60 Hz), and DBS HIGH frequency (≥130 Hz). The primary objective of this study was to investigate the changes in sleep spindle density across the three DBS conditions using repeated-measures analysis of variance. Additionally, we examined various secondary outcomes related to sleep qEEG features. For all participants, PSG-derived EEG data underwent meticulous manual inspection, with the exclusion of any segments affected by movement artifact. Following artifact rejection, sleep qEEG analysis was conducted on frontal and central leads. The measures included slow wave (SW) and spindle density and morphological characteristics, SW-spindle phase-amplitude coupling, and spectral power analysis during non-rapid eye movement (NREM) sleep. The analysis revealed that spindle density was significantly higher in the DBS HIGH condition compared to the DBS LOW condition. Surprisingly, we found that SW amplitude during NREM was significantly higher in the DBS LOW condition compared to DBS OFF and DBS HIGH conditions. However, no significant differences were observed in the other sleep qEEG features during sleep at different DBS conditions. This study presents preliminary evidence suggesting that conventional HIGH frequency DBS settings enhance sleep spindle density in PD. Conversely, LOW frequency settings may have beneficial effects on increasing slow wave amplitude during sleep. These findings may inform mechanisms underlying subjective improvements in sleep quality reported in association with DBS. Moreover, this work supports the need for additional research on the influence of surgical interventions on sleep disorders, which are prevalent and debilitating non-motor symptoms in PD.

Postural Instability and Risk of Falls in Patients with Parkinson's Disease Treated with Deep Brain Stimulation: A Stabilometric Platform Study.

Postural instability (PI) in Parkinson's disease (PD) exposes patients to an increased risk of falls (RF). While dopaminergic therapy and deep brain stimulation (DBS) improve motor performance in advanced PD patients, their effects on PI and RF remain elusive. PI and RF were assessed using a stabilometric platform in six advanced PD patients. Patients were evaluated in OFF and ON dopaminergic medication and under four DBS settings: with DBS off, DBS bilateral, and unilateral DBS of the more- or less-affected side. Our findings indicate that dopaminergic medication by itself exacerbated PI and RF, and DBS alone led to a decline in RF. No combination of medication and DBS yielded a superior improvement in postural control compared to the baseline combination of OFF medication and the DBS-off condition. Yet, for ON medication, DBS significantly improved both PI and RF. Among DBS conditions, DBS bilateral provided the most favorable outcomes, improving PI and RF in the ON medication state and presenting the smallest setbacks in the OFF state. Conversely, the more-affected side DBS was less beneficial. These preliminary results could inform therapeutic strategies for advanced PD patients experiencing postural disorders.

Complex network measures reveal optimal targets for deep brain stimulation and identify clusters of collective brain dynamics

An important question in computational neuroscience is how to improve the efficacy of deep brain stimulation by extracting information from the underlying connectivity structure. Recent studies also highlight the relation of structural and functional connectivity in disorders such as Parkinson’s disease. Exploiting the structural properties of the network, we identify nodes of strong influence, which are potential targets for Deep Brain Stimulation (DBS). Simulating the volume of the tissue activated, we confirm that the proposed targets are reported as optimal targets (sweet spots) to be beneficial for the improvement of motor symptoms. Furthermore, based on a modularity algorithm, network communities are detected as set of nodes with high-interconnectivity. This allows to localise the neural activity, directly from the underlying structural topology. For this purpose, we build a large scale computational model that consists of the following elements of the basal ganglia network: subthalamic nucleus (STN), globus pallidus (external and internal parts) (GPe-GPi), extended with the striatum, thalamus and motor cortex (MC) areas, integrating connectivity from multimodal imaging data. We analyse the network dynamics under Healthy, Parkinsonian and DBS conditions with the aim to improve DBS treatment. The dynamics of the communities define a new functional partition (or segregation) of the brain, characterising Healthy, Parkinsonian and DBS treatment conditions.

Pedunculopontine and Cuneiform Nuclei Deep Brain Stimulation for Severe Gait and Balance Disorders in Parkinson's Disease: Interim Results from a Randomized Double-Blind Clinical Trial.

Dopa-resistant freezing of gait (FOG) and falls represent the dominant motor disabilities in advanced Parkinson's disease (PD). We investigate the effects of deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), comprised of the pedunculopontine (PPN) and cuneiform (CuN) nuclei, for treating gait and balance disorders, in a randomized double-blind cross-over trial. Six PD patients with dopa-resistant FOG and/or falls were operated for MLR-DBS. Patients received three DBS conditions, PPN, CuN, or Sham, in a randomized order for 2-months each, followed by an open-label phase. The primary outcome was the change in anteroposterior anticipatory-postural-adjustments (APAs) during gait initiation on a force platformResults:The anteroposterior APAs were not significantly different between the DBS conditions (median displacement [1st-3rd quartile] of 3.07 [3.12-4.62] cm with sham-DBS, 1.95 [2.29-3.85] cm with PPN-DBS and 2.78 [1.66-4.04] cm with CuN-DBS; p = 0.25). Step length and velocity were significantly higher with CuN-DBS vs. both sham-DBS and PPN-DBS. Conversely, step length and velocity were lower with PPN-DBS vs. sham-DBS, with greater double stance and gait initiation durations. One year after surgery, step length was significantly lower with PPN-DBS vs. inclusion. We did not find any significant change in clinical scales between DBS conditions or one year after surgery. Two months of PPN-DBS or CuN-DBS does not effectively improve clinically dopa-resistant gait and balance disorders in PD patients.

Subthalamic nucleus conditioning reduces premotor-motor interaction in Parkinson's disease

BackgroundDeep brain stimulation of the subthalamic nucleus is effective to alleviate motor symptoms in advanced Parkinson's disease. Using a novel conditioning paradigm, it has been shown that deep brain stimulation pulses from electrodes in the subthalamic nucleus modulate corticospinal excitability as determined with transcranial magnetic stimulation applied to the motor cortex. The mechanism of action is unclear. ObjectiveTo investigate the effects of subthalamic nucleus and dorsal premotor cortex conditioning on corticospinal excitability as a function of interstimulus intervals between target areas and deep brain stimulation frequencies. MethodsIn 19 patients with Parkinson's disease with subthalamic nucleus deep brain stimulation, the premotor-motor interaction was investigated in four different deep brain stimulation conditions (off, clinically used settings, 3 Hz, 20 Hz). Transcranial magnetic pulses were applied to the premotor and motor cortex and paired at certain intervals with deep brain stimulation pulses. The volume of tissue activated by deep brain stimulation was correlated with neurophysiological findings. ResultsThere was distinct motor cortex inhibition by premotor cortex conditioning at an interstimulus interval of 1 ms before the motor cortex stimulation. Subthalamic nucleus conditioning with deep brain stimulation frequencies of 3 and 20 Hz at an interstimulus interval of 10 ms between subthalamic nucleus and primary motor cortex reduced premotor-motor inhibition. The volume of tissue activated by deep brain stimulation correlated positively with this effect. Corticospinal excitability was not affected by subthalamic nucleus conditioning as used here. ConclusionsPremotor-motor inhibition is modulated by subthalamic nucleus conditioning, presumably through the monosynaptic hyperdirect pathway.

Kinematic Metrics from a Wireless Stylus Quantify Tremor and Bradykinesia in Parkinson's Disease.

A fundamental challenge in the clinical care of Parkinson disease (PD) is the current dependence on subjective evaluations of tremor and bradykinesia. New technologies offer the ability to evaluate motor deficits using purely objective measures. The aim of this study was to develop and evaluate the efficacy of a wireless stylus (Cleveland Clinic Stylus) with an embedded motion sensor to quantitatively assess tremor and bradykinesia in patients with PD with subthalamic nucleus (STN) deep brain stimulation (DBS). Twenty-one subjects were tested in various on and off DBS conditions while holding the Cleveland Clinic Stylus while at rest, maintaining a postural hold, and during a movement task. Kinematic metrics were calculated from the motion sensor data, including 3D angular velocity and 3D acceleration data, and were compared between the on and off conditions. Generalized estimating equations (GEEs) were used to determine the relationship between kinematic metrics and MDS-Unified Parkinson's Disease Rating Scale Motor III (UPDRS-III) subscores. Kinematic metrics from the rest and postural tasks were significantly related to the UPDRS-III subscores of tremor (p < 0.001 for all metrics), and kinematic metrics from the movement task were significantly related to the UPDRS-III subscore of bradykinesia (p < 0.001 for 3/7 metrics). Kinematic metrics (7/9) showed a significant effect of stimulation setting (range: p < 0.03– < 0.0001) across the three tasks, indicating significant improvements from DBS in these measures. The Cleveland Clinic Stylus provided quantitative kinematic measures of tremor and bradykinesia severity and detected significant improvements in these measures from medication and DBS therapy. This low-cost, easy-to-use tool can provide objective measures that will improve clinical care of PD patients by providing a more reliable and objective evaluation of movement symptoms, disease progression, and effects of therapy in and outside the clinical setting.

A palm-worn device to quantify rigidity in Parkinson’s disease

BackgroundParkinsonian rigidity is identified on clinical examination as resistance to passive movement. Measurement of rigidity commonly relies on ordinal rating scales (MDS-UPDRS), however instrumented objective measures may provide greater mechanistic insight. New methodWe present a palm-worn instrument to objectively quantify rigidity on a continuous scale. The device employs a miniature motor to flex the third digit of the hand about the metacarpophalangeal joint whilst transducers record flexion/extension forces. We aim to determine congruence with the MDS-UPDRS, investigate sensitivity to the impact of deep brain stimulation (DBS) and contralateral movement, and make comparisons with healthy individuals. Eight participants with Parkinson’s disease underwent evaluation during conditions: on and off DBS, and with and without contralateral limb movement to activate rigidity. During each DBS condition, wash-in/out effects were tracked using both our instrument and two blinded clinical raters. Sixteen healthy volunteers (age-matched/young) served as controls. ResultsRigidity measured using our instrument had moderate agreement with the MDS-UPDRS and showed differences between therapeutic state, activation conditions, and disease/healthy cohorts. Rigidity gradually worsened over a one-hour period after DBS cessation, but improved more rapidly with DBS resumption. Comparison with existing methodsPrevious attempts to quantify rigidity include manual approaches where a clinician is required to manipulate limbs while sensors passively gather information, or large automated instruments to move the wrist or elbow. ConclusionGiven its ability to track changes in rigidity due to therapeutic intervention, our technique could have applications where continuous measurement is required or where a suitably qualified rater is absent.

Mapping movement, mood, motivation and mentation in the subthalamic nucleus.

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) contributes to the variability of motor and non-motor responses across patients with Parkinson's disease (PD). We previously tested the hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patient's clinically optimized DBS settings and active contact. Here, we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral borders of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of three unilateral DBS conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Ventral STN DBS induced greater improvement in rigidity and anxiety than dorsal STN DBS. In the 3D analysis, contact location was significant for body hypokinesia, rigidity and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. The 3D results provide new, direct functional evidence for the anatomically derived model of STN, in which motor function is best represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, because locations that induced improvements in motor function and mood overlapped substantially.

F151. Sensorimotor cortex plasticity correlates with effectiveness of pallidal stimulation in dystonia

Introduction Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective symptomatic treatment of farmacoresistant dystonic syndromes. The sensorimotor cortex of dystonia patients exhibits an exaggerated responsiveness to the TMS (transcranial magnetic stimulation) in conditioning protocols. The aim of our study was to analyse the excitability of the primary motor cortex (MI) in relation to modulation of input from the primary somatosensory cortex (SI) in dystonia patients treated by GPi DBS. Methods We examined 21 patients (mean age 51 ± (SD)17 years) with dystonia treated by GPi DBS. The SI was modulated in DBS ON and OFF conditions by a 2-min series of paired associative stimulation (PAS) with 5 Hz frequency, consisting of electrical stimulation of the median nerve followed by 20 ms of subthreshold TMS pulse. The excitability of the MI was tested by motor evoked potentials (MEP) applied before and after the PAS. The clinical effect (CE) was expressed as a change in the dystonic score between DBS ON condition and the preoperative state. Results The SI PAS caused a decrease of the MEP amplitude in dystonia patients with the GPi DBS ON state in comparison with GPi DBS OFF state ( p p N = 8, p p N = 13, >25% CE) had the MEP amplitude unchanged after the SI PAS in both of the GPi DBS conditions. Conclusion The SI PAS intervention applied over SI cortex affected motor cortex excitability in dystonia patients but not in healthy controls. The GPi DBS reduced the sensorimotor cortex plasticity of dystonia patients under level seen in the GPi DBS off state and even under the level seen in healthy controls. Surprisingly, only poor responders to GPi DBS therapy showed a loss of an inhibitory effect of the SI on the MI immediately after switching stimulation off in comparison with good responders and healthy controls. This may suggest, that the GPi DBS normalizes the excitability of MI through strengthening of the sensorimotor interaction and causes long lasting cortical plasticity changes in good responders which may contribute to better suppression of the dystonic symptoms. Supported by the grants GACR 16-13323S, PROGRES Q27/LF1 and MJFF11362.

Square biphasic pulse deep brain stimulation for essential tremor: The BiP tremor study

BackgroundConventional deep brain stimulation (DBS) utilizes regular, high frequency pulses to treat medication-refractory symptoms in essential tremor (ET). Modifications of DBS pulse shape to achieve improved effectiveness is a promising approach. ObjectivesThe current study assessed the safety, tolerability and effectiveness of square biphasic pulse shaping as an alternative to conventional ET DBS. MethodsThis pilot study compared biphasic pulses (BiP) versus conventional DBS pulses (ClinDBS). Eleven ET subjects with clinically optimized ventralis intermedius nucleus DBS were enrolled. Objective measures were obtained over 3 h while ON BiP stimulation. ResultsThere was observed benefit in the Fahn-Tolosa Tremor Rating Scale (TRS) for BiP conditions when compared to the DBS off condition and to ClinDBS setting. Total TRS scores during the DBS OFF condition (28.5 IQR = 24.5–35.25) were significantly higher than the other time points. Following active DBS, TRS improved to (20 IQR = 13.8–24.3) at ClinDBS setting and to (16.5 IQR = 12–20.75) at the 3 h period ON BiP stimulation (p = 0.001). Accelerometer recordings revealed improvement in tremor at rest (χ2 = 16.1, p = 0.006), posture (χ2 = 15.9, p = 0.007) and with action (χ2 = 32.1, p=<0.001) when comparing median total scores at ClinDBS and OFF DBS conditions to 3 h ON BiP stimulation. There were no adverse effects and gait was not impacted. ConclusionBiP was safe, tolerable and effective on the tremor symptoms when tested up to 3 h. This study demonstrated the feasibility of applying a novel DBS waveform in the clinic setting. Larger prospective studies with longer clinical follow-up will be required.

V40. Deep brain recordings using an implanted pulse generator in Parkinson’s disease

Introduction Deep brain stimulation (DBS) in the subthalamic nucleus (STN) for Parkinson’s disease (PD) has been shown to be a safe and effective treatment. Recent studies suggest that oscillatory beta activity could be used as a biomarker in patients with PD for subthalamic closed-loop stimulation leading to improved clinical benefit and reduced energy consumption. The aim of the present study was to evaluate the feasibility of local field potential (LFP) recordings for closed-loop stimulation using a new generation of implantable stimulators that also can record LFPs. Materials and methods Eight patients with PD (2 female, mean age 66.1 ± [SEM] 1.5 years; disease duration 10.5 ± 1.4 years) who underwent bilateral implantation of DBS electrodes in the STN were included in the study. LFP recordings were conducted at rest ON and OFF subthalamic high frequency stimulation (140 Hz) via DBS electrodes using the new stimulator device (bipolar recordings from contact pair 0–2, monopolar stimulation at contact 1). FFT based power spectra were calculated ON and OFF DBS, normalized to total power and compared between conditions. Results We recorded subthalamic oscillatory activity from 15 out of 16 DBS electrodes using the stimulator’s sensing function. We found discrete peaks in the beta band in 12 out of 15 electrodes (mean peak frequency 17 Hz). A significant reduction in averaged beta band power (13–30 Hz) of 14% was found ON compared to OFF DBS condition ( p = 0.002). No difference was found in the alpha band (7–13 Hz; p > 0.05). Direct comparison of beta peak frequency aligned power spectra across the group revealed a significant DBS related beta power reduction in a frequency range from −1.4 Hz to +5.8 Hz ( p ⩽ 0.03, FWE corrected) surrounding the individual peaks. Discussion We demonstrate for the first time recordings of human deep brain activity from a new generation of fully implantable pulse generators with sensing function. Discrete peaks in beta activity were obtained from the subthalamic area from 12 out of 15 electrodes when patients were OFF medication, moreover the new device could identify a significant suppression of beta band activity during DBS. The present results give further evidence for beta band activity being a useful biomarker in PD patients that can be followed with implantable systems.

Characteristics of the induced voltage between deep brain stimulation (DBS) device electrodes by a transcranial magnetic stimulation (TMS) device

The combination of deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) is expected to provide additional insights into the pathophysiology of some brain diseases. However, when using TMS in patients with DBS implants, the induced voltage between DBS electrodes presents the greatest risk of brain damage. This paper describes the characteristics of the induced DBS electrode voltage due to TMS. We first examined the TMS stimulus signal and the DBS output impedance characteristics, and then experimentally investigated the induced DBS electrode voltage for various DBS and TMS conditions. The results show that many factors impact the induced electrode voltage. The induced electrode voltage with DBS device working in the unipolar mode is greater than that with DBS device working in the bipolar mode. No matter DBS device is turned on or turned off, the induced electrode voltage is almost the same, but it can provide a significant addition to the original stimulus waveform. There are no significant differences in the induced DBS electrode voltage when the DBS system is working at different stimulus intensities. Lowering the TMS stimulus intensity could effectively reduce the induced DBS electrode voltage. The induced electrode voltage is also strongly related to the position of the TMS coil relative to the DBS lead. This study provides further information about the characteristics of the induced DBS electrode voltage in TMS applications and a reference for the combined use of DBS and TMS.

Low-frequency stimulation of STN-DBS reduces aspiration and freezing of gait in patients with PD.

To study whether 60-Hz stimulation, compared with routine 130 Hz, improves swallowing function and freezing of gait (FOG) in patients with Parkinson disease (PD) who undergo bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). We studied 7 patients with PD who experienced FOG that persisted despite routine 130-Hz stimulation and dopaminergic medication. Each patient received 3 modified barium swallow (MBS) studies in a single day under 3 DBS conditions in the medication-on state: 130 Hz, 60 Hz, or DBS off, in a randomized double-blind manner. The laryngeal penetration and aspiration events were cautiously assessed, and a swallowing questionnaire was completed. The Unified Parkinson's Disease Rating Scale, Part III motor score, axial subscore, tremor subscore, and FOG by a questionnaire and stand-walk-sit test were also assessed. The best DBS condition (60 Hz here) producing the least FOG was maintained for 3 to 8 weeks, and patients were assessed again. Changes in measurements between the 60 Hz and 130 Hz were analyzed using paired t test, with swallowing function as primary and the remainder as secondary outcomes. Changes between other DBS conditions were further explored with Bonferroni correction. Compared with the routine 130 Hz, 60-Hz stimulation significantly reduced aspiration frequency by 57% on MBS study and perceived swallowing difficulty by 80% on questionnaire. It also significantly reduced FOG, and axial and parkinsonian symptoms. The benefits at 60-Hz stimulation persisted over the average 6-week assessment. Compared with the routine 130 Hz, the 60-Hz stimulation significantly improved swallowing function, FOG, and axial and parkinsonian symptoms in patients with PD treated with bilateral STN-DBS, which persisted over the 6-week study period. This study provides Class IV evidence that for patients with PD who experience FOG, STN-DBS at 60 Hz decreases aspiration events observed during MBS compared with DBS at 130 Hz.

Stimulation of subthalamic nuclei restores a near normal planning strategy in Parkinson's patients.

A fundamental function of the motor system is to gather key information from the environment in order to implement behavioral strategies appropriate to the context. Although several lines of evidence indicate that Parkinson’s disease affects the ability to modify behavior according to task requirements, it is currently unknown whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects context-related planning. To explore this issue, we asked 12 Parkinson’s patients with bilateral STN DBS and 13 healthy subjects to execute similar arm reaching movements in two different paradigms: go-only and countermanding tasks. In the former task patients had to perform speeded reaching movements to a peripheral target. In contrast, in the countermanding task participants had to perform the same reaches unless an infrequent and unpredictable stop-signal was shown during the reaction time (RT) indicating that they should withhold the ongoing action. We compared the performance of Parkinson’s patients in different DBS conditions. We found that patients with both DBS-ON behaved similarly to healthy subjects, in that RTs of no-stop trial increased while movement times (MTs) decreased with respect to those of go-only-trials. However, when both DBS were off, both RTs and MTs were longer in no-stop trials than in go-only trials. These findings indicate that bilateral DBS of STN can partially restore the appropriate motor strategy according to the given cognitive contexts.

Deep Brain Stimulation of Pedunculopontine Tegmental Nucleus: Role in Sleep Modulation in Advanced Parkinson Disease Patients—One-Year Follow-Up

Sleep disorders are frequent non-motor symptoms in Parkinson disease (PD), probably due to multifactorial pathogeneses including disease progression, dopaminergic drugs, or concomitant illness. In recent years, the pedunculopontine tegmental (PPTg) nucleus has been considered a surgical target for deep brain stimulation (DBS) in advanced PD patients. As it is involved in controlling the sleep-wake cycle, we investigated the long-lasting effects of PPTg-DBS on the sleep of five PD patients implanted in both the PPTg and the subthalamic nucleus (STN) by rating two subjective clinical scales for sleep: the Parkinson's Disease Sleep Scale (PDSS), and the Epworth Sleepiness Scale (ESS). Sleep scales were administered a week before surgery (T0), three months after DBS (T1), and one year later (T2). In this study, STN-DBS was kept constantly in ON, and three different patterns of PPTg-DBS were investigated: STN-ON (PPTg switched off); PPTg-ON (PPTg stimulated 24 h/day); PPTg-cycle (PPTg stimulated only at night). In post-surgery follow-up, PD patients reported a marked improvement of sleep quality in all DBS conditions. In particular, stimulation of the PPTg nucleus produced not only a remarkable long-term improvement of nighttime sleep, but unlike STN-DBS, also produced significant amelioration of daytime sleepiness. Our study suggests that PPTg-DBS plays an important role in reorganizing regular sleep in PD patients.

Mapping Brain Regions in Which Deep Brain Stimulation Affects Schizophrenia-Like Behavior in Two Rat Models of Schizophrenia

Background and ObjectivesThe development of more efficient treatment remains a major unmet need in the realm of schizophrenia disease. Using the maternal immune stimulation and the pubertal cannabinoid administration rat model of schizophrenia, the present study aimed at testing the hypothesis that deep brain stimulation (DBS) serves as a novel therapeutic technique for this disorder. MethodsAdult offspring of dams, treated with the immune activating agent poly I:C (4 mg/kg, n = 50) or saline (n = 50), underwent bilateral stereotactic electrode implantation into one of the following brain regions: subthalamic nucleus (STN, n = 12/10), entopeduncularis nucleus (EP, n = 10/11), globus pallidus (GP, n = 10/10), medial prefrontal cortex (mPFC, n = 8/8), or dorsomedial thalamus (DM, n = 10/11). Adult rats treated with the CB1 receptor agonist WIN 55,212-2 (WIN, n = 16) or saline (n = 12) during puberty were bilaterally implanted with electrodes into either the mPFC (n = 8/6) or the DM (n = 8/6). After a post-operative recovery period of one week, all rats were tested on a well-established cross-species phenomenon that is disrupted in schizophrenia, the pre-pulse inhibition (PPI) of the acoustic startle reflex (ASR) under different DBS conditions. ResultsPoly I:C induced deficits in PPI of the ASR were normalized upon DBS. DBS effects depended on both stimulation target and stimulation parameters. Most prominent effects were found under DBS at high frequencies in the mPFC and DM. These effects were replicated in the pubertal WIN administration rat model of schizophrenia. ConclusionsBrain regions, in which DBS normalized PPI deficits, might be of therapeutic relevance to the treatment of schizophrenia. Results imply that DBS could be considered a plausible therapeutic technique in the realm of schizophrenia disease.

Selective Left, Right and Bilateral Stimulation of Subthalamic Nuclei in Parkinson's Disease: Differential Effects on Motor, Speech and Language Function

Deep brain stimulation (DBS) of the subthalamic nucleus improves the motor symptoms of Parkinson's disease, but may produce a worsening of speech and language performance at rates and amplitudes typically selected in clinical practice. The possibility that these dissociated effects might be modulated by selective stimulation of left and right STN has never been systematically investigated. To address this issue, we analyzed motor, speech and language functions of 12 patients implanted with bilateral stimulators configured for optimal motor responses. Behavioral responses were quantified under four stimulator conditions: bilateral DBS, right-only DBS, left-only DBS and no DBS. Under bilateral and left-only DBS conditions, our results exhibited a significant improvement in motor symptoms but worsening of speech and language. These findings contribute to the growing body of literature demonstrating that bilateral STN DBS compromises speech and language function and suggests that these negative effects may be principally due to left-sided stimulation. These findings may have practical clinical consequences, suggesting that clinicians might optimize motor, speech and language functions by carefully adjusting left- and right-sided stimulation parameters.

High frequency stimulation of the subthalamic nucleus acutely rescues motor deficits and neocortical movement representations following 6-hydroxydopamine administration in rats

Loss of frontal neocortical activation is one of the main neurophysiological abnormalities of Parkinson's disease (PD) and can be observed in rodent models of nigrostriatal degeneration. High-frequency deep brain stimulation (DBS) of the subthalamic nucleus improves motor deficits in PD. However, it is unknown whether this general therapeutic effect is associated with a restoration of frontal output function. To address this question, chronic stimulating electrodes were implanted bilaterally into the subthalamic nuclei of adult rats that received either bilateral intrastriatal 6-hydroxydopamine (6-OHDA) or vehicle infusion to induce nigrostriatal degeneration. Forelimb use and locomotor activity were assessed based on the cylinder and open field tests in intact, post-lesion + sham DBS, and post-lesion + DBS conditions. Intracortical microstimulation was then used to probe frontal output function of forelimb motor areas. DBS was found to improve motor deficits arising from 6-OHDA lesions, increase forelimb map area, and decrease movement thresholds relative to baseline. These effects were significantly greater in 6-OHDA lesion rats compared to vehicle controls. Results indicate that changes in motor map expression can take place during subthalamic DBS following dopamine depletion in a rodent model of PD.