Effects of upper limb vibratory stimulation training on motor symptoms in Parkinson's disease: an observational study.

OBJECTIVES: Parkinson's disease is characterized by motor and non-motor symptoms. Tremor is one of the motor symptoms that can affect manual skills and have an impact on daily activities. The aim of the current study is to investigate the effect of upper limb training provided by a specific vibratory device (Armshake®, Move It GmbH - Bochum, Germany) on tremor and motor functionality in patients with Parkinson's disease. Furthermore, the training effect on global cognitive functioning is assessed. DESIGN: An uncontrolled before-after clinical trial. PATIENTS: Individuals with diagnosis of Parkinson's disease, motor upper limbs deficits, and absence of dementia. METHODS: Participants underwent a 3-week programme (3 times a week) and was evaluated before, after, and at 1 month follow-up by motor (Fahn Tolosa Marin Tremor Rating Scale, Unified Parkinson's Disease Rating Scale - part III, Purdue Pegboard Test, Disability of the Arm, Shoulder and Hand Questionnaire) and cognitive (Montreal Cognitive Assessment) scales. RESULTS: Twenty subjects are included. After treatment a statistically significant improvement in tremor, manual dexterity and activities of daily living was found. The data indicated no effects on global cognitive functioning. CONCLUSION: These findings suggest positive effects of vibratory stimulation training on upper limb motor symptoms in Parkinson's disease.

Restless legs syndrome in the dominant Parkinson's side related to subthalamic deep-brain stimulation.

BACKGROUND: Restless legs syndrome (RLS) has an increased estimated prevalence in patients with Parkinson's disease (PS). RLS frequently mimics symptoms intrinsic to PD, such as motor restlessness, contributing to making its diagnosis challenging in this population. We report the case of a patient with new-onset RLS following subthalamic deep-brain stimulation (DBS-STN). We assessed symptoms using suggested immobilization test (SIT) with both DBS-STN activated and switched off. CASE DESCRIPTION: A 59-year-old man with idiopathic PD developed disabling RLS following DBS-STN at age 58, with PD onset at 50 manifesting as left arm tremor. Despite improved motor symptoms during the month following surgery, the patient experienced left leg discomfort at rest, transiently alleviated by movements due to an irrepressible urge to move, and worsened at night. Symptoms had no temporal relationship with oral dopa-therapy and disappeared when DBS-STN was deactivated. A 1 h SIT assessed motor behavior with irrepressible urge to move, as well as sensory symptoms by visual analog scale. After 30 m DBS-STN was switched off followed by the appearance of tremor in the left arm while both motor and sensory symptoms of RLS disappeared in the left leg. DISCUSSION: The mechanisms of DBS-STN's impact on RLS remain controversial. We hypothesize the DBS-STN to induce in our patient a hyperdopaminergic tone. DBS-induced and DBS-ameliorated RLS represent interesting conditions to further understand the pathophysiology of RLS. Moreover, the present observation suggests that SIT can be a valuable tool to assess RLS in PD patients before and after DBS-STN in future prospective studies.

Noninvasive modulation of essential tremor with focused ultrasonic waves.

Objective: Transcranial focused low-intensity ultrasound has the potential to noninvasively modulate confined regions deep inside the human brain, which could provide a new tool for causal interrogation of circuit function in humans. However, it has been unclear whether the approach is potent enough to modulate behavior.Approach: To test this, we applied low-intensity ultrasound to a deep brain thalamic target, the ventral intermediate nucleus, in three patients with essential tremor.Main results: Brief, 15 s stimulations of the target at 10% duty cycle with low-intensity ultrasound, repeated less than 30 times over a period of 90 min, nearly abolished tremor (98% and 97% tremor amplitude reduction) in 2 out of 3 patients. The effect was observed within seconds of the stimulation onset and increased with ultrasound exposure time. The effect gradually vanished following the stimulation, suggesting that the stimulation was safe with no harmful long-term consequences detected.Significance: This result demonstrates that low-intensity focused ultrasound can robustly modulate deep brain regions in humans with notable effects on overt motor behavior.

Insights from a model based study on optimizing non invasive brain electrical stimulation for Parkinson's disease.

Parkinson's Disease (PD) is a disorder in the central nervous system which includes symptoms such as tremor, rigidity, and Bradykinesia. Deep brain stimulation (DBS) is the most effective method to treat PD motor symptoms especially when the patient is not responsive to other treatments. However, its invasiveness and high risk, involving electrode implantation in the Basal Ganglia (BG), prompt recent research to emphasize non-invasive Transcranial Electrical Stimulation (TES). TES proves to be effective in treating some PD symptoms with inherent safety and no associated risks. This study explores the potential of using TES, to modify the firing pattern of cells in BG that are responsible for motor symptoms in PD. The research employs a mathematical model of the BG to examine the impact of applying TES to the brain. This is conducted using a realistic head model incorporating the Finite Element Method (FEM). According to our findings, the firing pattern associated with Parkinson's disease shifted towards a healthier firing pattern through the use of tACS. Employing an adaptive algorithm that continually monitored the behavior of BG cells (specifically, Globus Pallidus Pars externa (GPe)), we determined the optimal electrode number and placement to concentrate the current within the intended region. This resulted in a peak induced electric field of 1.9 v/m at the BG area. Our mathematical modeling together with precise finite element simulation of the brain and BG suggests that proposed method effectively mitigates Parkinsonian behavior in the BG cells. Furthermore, this approach ensures an improvement in the condition while adhering to all safety constraints associated with the current injection into the brain.

Dual target deep brain stimulation for complex essential and dystonic tremor - A 5-year follow up.

BACKGROUND: Essential tremor (ET) is characterized by action tremor of the upper limbs, head tremor and voice tremor. Dystonic tremor (DT) is produced by muscle contractions in a body affected by dystonia. Deep brain stimulation (DBS) of ventral intermediate nucleus of the thalamus (VIM) is the most well-known advanced treatment for medication-refractory tremor. However, decline in efficacy overtime has led to explore other targets. This study aimed to measure the efficacy of bilateral dual targeting ViM/caudal Zona Incerta (cZI) stimulation on tremor control. A secondary aim was to evaluate if there was a difference in the efficacy between ET and DT. METHODS: 36 patients were retrospectively recruited at the Walton NHS Foundation Trust, Liverpool, UK. Patients were assessed pre-operatively, and then at 1-year, 3-years, and 5-years post-operatively with the following scales: Fahn-Tolosa-Marin tremor rating (FTMTR) scale, EuroQol-5D, and Hospital Anxiety and Depression Scale. RESULTS: Bilateral ViM-cZI DBS significantly improved overall tremor score by 45.1% from baseline to 3-years post-operatively (p < 0.001). It continued to show improvement in overall FTMTR score by 30.7% at 5-years but this failed to meet significance. However, there was no significant improvement of mood or quality of life (QoL) scores. ET group on average showed a significant better clinical outcome compared to the DT group (p > 0.001). CONCLUSIONS: Our study found that bilateral ViM-cZI DBS treatment had a favourable effect on motor symptoms sustained over the 5-years in tremor patients, especially in ET group. There was limited effect on mood and QoL with similar trends in outcomes for both tremor types.

Amelioration of Parkinsonian tremor evoked by DBS: which role play cerebello-(sub)thalamic fiber tracts?

BACKGROUND: Current pathophysiological models of Parkinson's disease (PD) assume a malfunctioning network being adjusted by the DBS signal. As various authors showed a main involvement of the cerebellum within this network, cerebello-cerebral fiber tracts are gaining special interest regarding the mediation of DBS effects. OBJECTIVES: The crossing and non-decussating fibers of the dentato-rubro-thalamic tract (c-DRTT/nd-DRTT) and the subthalamo-ponto-cerebellar tract (SPCT) are thought to build up an integrated network enabling a bidimensional communication between the cerebellum and the basal ganglia. The aim of this study was to investigate the influence of these tracts on clinical control of Parkinsonian tremor evoked by DBS. METHODS: We analyzed 120 electrode contacts from a cohort of 14 patients with tremor-dominant or equivalence-type PD having received bilateral STN-DBS. Probabilistic tractography was performed to depict the c-DRTT, nd-DRTT, and SPCT. Distance maps were calculated for the tracts and correlated to clinical tremor control for each electrode pole. RESULTS: A significant difference between "effective" and "less-effective" contacts was only found for the c-DRTT (p = 0.039), but not for the SPCT, nor the nd-DRTT. In logistic and linear regressions, significant results were also found for the c-DRTT only (pmodel logistic = 0.035, ptract logistic = 0,044; plinear = 0.027). CONCLUSIONS: We found a significant correlation between the distance of the DBS electrode pole to the c-DRTT and the clinical efficacy regarding tremor reduction. The c-DRTT might therefore play a major role in the mechanisms of alleviation of Parkinsonian tremor and could eventually serve as a possible DBS target for tremor-dominant PD in future.

Consistency is key: influence of skull density ratio distribution on the formation of clinically effective lesions and long-term tremor suppression following treatment with MR-guided focused ultrasound.

OBJECTIVE: Skull density ratio (SDR) influences the permeability of the skull to the ultrasound waves used in magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of tremor. SDR values vary across the skull and the mean value is known to be predictive of sonication thermal increase. The aim of this investigation was to explore the effects of the SDR distribution on clinical outcomes following treatment with MRgFUS. METHODS: Data from 61 patients with essential or dystonic tremor treated with MRgFUS targeting the ventral intermediate nucleus (Vim) were retrospectively analyzed. Tremor suppression was assessed using the Clinical Rating Scale for Tremor (CRST) and hand tremor score (HTS). Vim ablation volume was measured on the T1-weighted MR image acquired both at 1 day and 12 months after treatment. The numerical distribution of SDR values measured for each element in the ultrasound transducer was quantified by calculating the mean, standard deviation, skewness, entropy, and kurtosis of the SDR histogram. The effect of the SDR metrics on change in CRST and HTS was examined using a linear mixed-effects model. Additionally, the effect of the regional distribution of SDR values was explored in an element-wise analysis between patients with above- and below-average tremor suppression. RESULTS: A significant positive effect was found between SDR kurtosis and improvement in CRST (ß = 0.33, p = 0.004) and HTS (ß = 0.38, p < 0.001). The effect was found to be significant at 1 month posttreatment (CRST: ß = 0.415, p = 0.008; HTS: ß = 0.369, p = 0.016), and at the most recent clinical follow-up (CRST: ß = 0.395, p < 0.001; HTS: ß = 0.386, p < 0.001). One hundred seventy-one significant elements were identified in the element-wise analysis. The mean percentage difference from the mean SDR in these elements was associated with improvement in CRST (ß = 0.27, p < 0.008) and HTS (ß = 0.27, p < 0.015). Higher SDR kurtosis was associated with increased lesion volume at 12 months (p = 0.040) and less reduction in volume relative to the day-1 lesion volume (p = 0.007). CONCLUSIONS: Greater SDR kurtosis was associated with larger, more stable lesions at 12 months posttreatment and increased tremor suppression at long-term follow-up. SDR kurtosis may provide a more meaningful prognostic factor than the mean SDR.

Successful magnetic resonance-guided focused ultrasound treatment of tremor in patients with a skull density ratio of 0.4 or less.

OBJECTIVE: The use of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of tremor-related disorders and other novel indications has been limited by guidelines advocating treatment of patients with a skull density ratio (SDR) above 0.45 ± 0.05 despite reports of successful outcomes in patients with a low SDR (LSDR). The authors' goal was to retrospectively analyze the sonication strategies, adverse effects, and clinical and imaging outcomes in patients with SDR ≤ 0.4 treated for tremor using MRgFUS. METHODS: Clinical outcomes and adverse effects were assessed at 3 and 12 months after MRgFUS. Outcomes and lesion location, volume, and shape characteristics (elongation and eccentricity) were compared between the SDR groups. RESULTS: A total of 102 consecutive patients were included in the analysis, of whom 39 had SDRs ≤ 0.4. No patient was excluded from treatment because of an LSDR, with the lowest being 0.22. Lesioning temperatures (> 52°C) and therapeutic ablations were achieved in all patients. There were no significant differences in clinical outcome, adverse effects, lesion location, and volume between the high SDR group and the LSDR group. SDR was significantly associated with total energy (rho = -0.459, p < 0.001), heating efficiency (rho = 0.605, p < 0.001), and peak temperature (rho = 0.222, p = 0.025). CONCLUSIONS: The authors' results show that treatment of tremor in patients with an LSDR using MRgFUS is technically possible, leading to a safe and lasting therapeutic effect. Limiting the number of sonications and adjusting the energy and duration to achieve the required temperature early during the treatment are suitable strategies in LSDR patients.

Deep brain stimulation with short versus conventional pulse width in Parkinson's disease and essential tremor: A systematic review and meta-analysis.

BACKGROUND: To maximize clinical benefit and minimize stimulation-induced side effects, optimising deep brain stimulation (DBS) parameters is paramount. Recent literature suggests a potential benefit of short pulse width DBS (spDBS; ≤40 µs) over conventional pulse width DBS (cDBS; ≥60 µs) in movement disorders. OBJECTIVE: To compare therapeutic window (TW), therapeutic and side effects and energy consumption of spDBS and cDBS in movement disorders. METHODS: We systematically searched Medline, Embase, Cochrane Library and Web of Science. Appropriate paired analyses were performed. RESULTS: Nine Parkinson's disease (PD) (143 patients), 4 essential tremor (ET) (26 patients) and no dystonia studies were included in the meta-analysis. TW defined as therapeutic amplitude range was larger with spDBS vs. cDBS in PD (standardized mean difference (SMD) = -1.04, p < 0.001) and ET (SMD = -0.71, p < 0.001), but the TW in terms of charge per pulse (CPP) did not differ. In PD, no differences were found in therapeutic and side effects (MDS-UPDRS-III, speech and gait, dyskinesia, non-motor symptoms and quality of life). In ET, Fahn-Tolosa-Marin Tremor Rating Scale was lower with spDBS vs. cDBS (SMD = 0.36, p < 0.001). A qualitative analysis suggested fewer stimulation-induced side effects with spDBS. CPP was lower with spDBS vs. cDBS in PD (SMD = 0.79, p < 0.001) and ET (MD = 46.46 nC, p < 0.001), but real-world data on battery longevity are lacking. CONCLUSION: Although spDBS enlarges the TW as a wider amplitude range in both PD and ET, it does not alter TW defined by CPP. The therapeutic efficacy of spDBS is not different from cDBS in PD, but spDBS apparently induces more tremor reduction in ET.

The history of deep brain stimulation.

Deep brain stimulation (DBS) surgery is an established and effective treatment for several movement disorders (tremor, Parkinson's disease, and dystonia), and is under investigation in numerous other neurological and psychiatric disorders. However, the origins and development of this neurofunctional technique are not always well understood and recognized. In this mini-review, we review the history of DBS, highlighting important milestones and the most remarkable protagonists (neurosurgeons, neurologists, and neurophysiologists) who pioneered and fostered this therapy throughout the 20th and early 21st century. Alongside DBS historical markers, we also briefly discuss newer developments in the field, and the future challenges which accompany such progress.

Hand and distal joint tremor are most coherent with the activity of elbow flexors and wrist extensors in persons with essential tremor.

Essential tremor (ET) affects millions of people. Although frontline treatment options (medication, deep brain stimulation, and focused ultrasound ablation) have provided significant relief, many patients are unsatisfied with the outcomes. Peripheral suppression techniques, such as injections of botulinum toxin or sensory electrical stimulation of muscles, are gaining popularity, but could be optimized if the muscles most responsible for a patient's tremor were identified. The purpose of this study was to quantify the relationship between the activity in various upper limb muscles and the resulting tremor in patients with ET. Surface electromyogram (sEMG) from the 15 major superficial muscles of the upper limb and displacement of the hand and upper limb joints were recorded from 22 persons with ET while they performed kinetic and postural tasks representative of activities of daily living. We calculated the peak coherence (frequency-dependent correlation) in the tremor band (4-8 Hz) between the sEMG of each muscle and the displacement in each major degree of freedom (DOF). Averaged across subjects with ET, the highest coherence was found between elbow flexors (particularly biceps brachii and brachioradialis) and the distal DOF (forearm, wrist, and hand motion), and between wrist extensors (extensor carpi radialis and ulnaris) and the same distal DOF. These coherence values represent the upper bound on the proportion of the tremor caused by each muscle. We conclude that, without further information, elbow flexors and wrist extensors should be among the first muscles considered for peripheral suppression techniques in persons with ET.NEW & NOTEWORTHY We characterized the relationships between activity in upper limb muscles and tremor in persons with essential tremor using coherence, which provides an upper bound on the proportion of the tremor due to each muscle. Averaged across subjects and various tasks, tremor in the hand and distal joints was most coherent with elbow flexors and wrist extensors. We conclude that, without further information, these muscle groups should be among the first considered for peripheral suppression techniques.

Development and Pilot Testing of the Tremor Retrainer Smartphone Application for the Treatment of Functional Tremor.

Background: Functional tremor is a common and disabling condition with limited treatment options. A prior proof-of-concept pilot study sought to translate entrainment, a key diagnostic feature of functional tremor, into a treatment strategy. Methods: The Tremor Retrainer smartphone application was developed though a collaboration between neurologists and a software engineer. It analyzes data from smartphone accelerometers to measure baseline tremor frequency, then provides auditory cues at a lower frequency for the patient to match with flexion-extension movements at the wrist. The application provides continuous biofeedback on performance via a visual gauge. Patients with functional tremor underwent a one-week treatment protocol with the Tremor Retrainer application and provided feedback on usability and acceptability to guide software programming. Results: Three pediatric patients completed the one-week protocol and their feedback was used to modify the software. All patients felt that the application was easy to use and could be effective in treating functional tremor. Discussion: The Tremor Retrainer smartphone application uses auditory cues and a visual gauge to provide a personalized and widely accessible entrainment-based intervention. Pilot testing in pediatric patients provided key feedback for application design. Highlights: The Tremor Retrainer smartphone application modulates functional tremor frequency by providing pulsed auditory cues for a patient to match with wrist flexion-extension movements while receiving continuous biofeedback via a visual gauge. This adaption of the diagnostic sign of entrainment has potential as an accessible treatment for patients with functional tremor.

Usefulness of thalamic beta activity for closed-loop therapy in essential tremor.

A partial loss of effectiveness of deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM) has been reported in some patients with essential tremor (ET), possibly due to habituation to permanent stimulation. This study focused on the evolution of VIM local-field potentials (LFPs) data over time to assess the long-term feasibility of closed-loop therapy based on thalamic activity. We performed recordings of thalamic LFPs in 10 patients with severe ET using the ACTIVA™ PC + S (Medtronic plc.) allowing both recordings and stimulation in the same region. Particular attention was paid to describing the evolution of LFPs over time from 3 to 24 months after surgery when the stimulation was Off. We demonstrated a significant decrease in high-beta LFPs amplitude during movements inducing tremor in comparison to the rest condition 3 months after surgery (1.91 ± 0.89 at rest vs. 1.27 ± 1.37 µV2/Hz during posture/action for N = 8/10 patients; p = 0.010), 12 months after surgery (2.92 ± 1.75 at rest vs. 2.12 ± 1.78 µV2/Hz during posture/action for N = 7/10 patients; p = 0.014) and 24 months after surgery (2.32 ± 0.35 at rest vs 0.75 ± 0.78 µV2/Hz during posture/action for 4/6 patients; p = 0.017). Among the patients who exhibited a significant decrease of high-beta LFP amplitude when stimulation was Off, this phenomenon was observed at least twice during the follow-up. Although the extent of this decrease in high-beta LFPs amplitude during movements inducing tremor may vary over time, this thalamic biomarker of movement could potentially be usable for closed-loop therapy in the long term.

[Observation on the efficacy of different targets low-frequency repetitive transcranial magnetic stimulation for the treatment of tremor-dominant subtypes of Parkinson's disease].

Objective: To analyze the efficacy of different targets low-frequency repetitive transcranial magnetic stimulation (rTMS) for the treatment of tremor Parkinson's disease(PD). Method: A total of 82 patients with primary PD who were admitted to the Department of Neurology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from April 1, 2020 to March 31, 2021 were prospectively collected. According to the clinical characteristics of major movement disorders, 82 patients with tremor type (TD) were selected to enroll.The patients were randomly divided into 3 groups at a 1∶1∶1 ratio according to the randomized coding sequence of the trial: the primary motor cortex (M1) group with 26 cases, the cerebellum group with 26 cases and the dual-site (M1, cerebellum) group with 30 cases. All patients were treated with 1 Hz low-frequency stimulation of the corresponding target once a day for 5 days a week for 2 weeks, a total of 10 times; The dosage remained unchanged during the treatment for all groups. Before and after 2 weeks' treatment, the patients were assessed with the Unified PD Rating Scale (UPDRS) and PD Quality of Life Questionnaire-39 (PDQ-39) without medication. Cortical excitability, namely transcranial magnetic stimulation motor evoked potential (TMS-MEP), [including resting motor threshold (rMT) and active motor threshold (aMT) examinations], timed up and go (TUG) and electromyographic tremor were conducted. Result: There were 82 patients, 39 males and 43 females, with an average age of (67±8) years. Before the treatment, there was no statistically significant difference in the evaluation indicators among the three groups (all P>0.05). After the treatment, the differences of the UPDRS-Ⅲ score [(38.9±2.5) vs (29.2±3.6) ], UPDRS tremor score [(23.7±2.1) vs (14.6±3.1) ], TUG time [(44.8±3.1) s vs (33.7±4.1) s], tremor amplitude [(480±126) µV vs (276±94) µV], PDQ-39 score [(51±13) vs (45±13) ], rMT [(36±17)% vs (43±13)%], and aMT [(26±16)% vs (31±12)%] were statistically significant (all P<0.01) from those before the treatment. There was no statistical difference in the above factors between the M1 group and cerebellum group (all P>0.05). There was no statistically significant difference in tremor peak frequency among the three groups before and after the treatment (all P>0.05). Conclusions: Dual-site low-frequency rTMS can improve PD tremor, while M1 or cerebellar low-frequency rTMS does not significantly improve PD tremor. Its mechanism may be to improve PD tremor symptoms by regulating cortical excitability.

Comparative Effectiveness of Transcutaneous Afferent Patterned Stimulation Therapy for Essential Tremor: A Randomized Pragmatic Clinical Trial.

Background: Transcutaneous afferent patterned stimulation (TAPS) is a wrist-worn, non-invasive therapy delivering calibrated stimulation to the median and radial nerves. Previous randomized controlled studies have demonstrated the efficacy and safety of TAPS therapy in some patients with essential tremor (ET), but evidence supporting therapeutic benefits of TAPS versus standard of care (SOC) is lacking. This randomized prospective study evaluated the clinical benefit of adding TAPS treatment to SOC versus SOC alone. Methods: This randomized pragmatic trial recruited patients from a large health plan's Commercially Insured and Medicare Advantage population. All 310 patients received a TAPS device and were randomized 1:1 to either one month adding TAPS therapy to usual care (TX arm) or usual care with tremor assessment only (SOC arm). The pre-specified endpoints were changes in tremor power measured by motion sensors on the device (primary) and improvement in Bain & Findley Activities of Daily Living (BF-ADL) upper limb scores (secondary) between TX and SOC in all patients who completed the one-month study. Results: 276 patients completed the one-month study (N = 133 TX, N = 143 SOC). The study met the primary and secondary endpoints, with significantly reduced tremor power in TX compared with SOC (0.017 (0.003) versus 0.08 (0.014) (m/s2)2; geometric mean (SE); p < 0.0001) and greater improvement in the BF-ADL score in TX than SOC (1.6 (0.43) vs 0.2 (0.37) points; mean (SE); p < 0.05). No serious device-related adverse events were reported. Discussion: This trial demonstrates that adding TAPS treatment to SOC significantly improves tremor power and BF-ADLs in patients with ET compared to SOC alone over one month of home use. Highlights: This study found that adding TAPS treatment to SOC significantly improves tremor power and BF-ADL scores in patients with ET compared to SOC alone over one month of home use. This real-world evidence study suggests that non-invasive TAPS therapy is a safe and valuable treatment option for patients with ET.

Long-Term Follow-Up of Unilateral Deep Brain Stimulation Targeting the Caudal Zona Incerta in 13 Patients with Parkinsonian Tremor.

INTRODUCTION: Deep brain stimulation (DBS) is an established treatment for Parkinson's disease (PD) and other movement disorders. The ventral intermediate nucleus of the thalamus is considered as the target of choice for tremor disorders, including tremor-dominant PD not suitable for DBS in the subthalamic nucleus (STN). In the last decade, several studies have shown promising results on tremor from DBS in the posterior subthalamic area (PSA), including the caudal zona incerta (cZi) located posteromedial to the STN. The aim of this study was to evaluate the long-term effect of unilateral cZi/PSA-DBS in patients with tremor-dominant PD. METHODS: Thirteen patients with PD with medically refractory tremor were included. The patients were evaluated using the motor part of the Unified Parkinson Disease Rating Scale (UPDRS) off/on medication before surgery and off/on medication and stimulation 1-2 years (short-term) after surgery and at a minimum of 3 years after surgery (long-term). RESULTS: At short-term follow-up, DBS improved contralateral tremor by 88% in the off-medication state. This improvement persisted after a mean of 62 months. Contralateral bradykinesia was improved by 40% at short-term and 20% at long-term follow-up, and the total UPDRS-III by 33% at short-term and by 22% at long-term follow-up with stimulation alone. CONCLUSIONS: Unilateral cZi/PSA-DBS seems to remain an effective treatment for patients with severe Parkinsonian tremor several years after surgery. There was also a modest improvement on bradykinesia.

Temporally non-regular patterns of deep brain stimulation (DBS) enhance assessment of evoked potentials while maintaining motor symptom management in Parkinson's disease (PD).

BACKGROUND: Traditional deep brain stimulation (DBS) at fixed regular frequencies (>100 Hz) is effective in treating motor symptoms of Parkinson's disease (PD). Temporally non-regular patterns of DBS are a new parameter space that may help increase efficacy and efficiency. OBJECTIVE: To compare the effects of temporally non-regular patterns of DBS to traditional regularly-spaced pulses. METHODS: We simultaneously recorded local field potentials (LFP) and monitored motor symptoms (tremor and bradykinesia) in persons with PD during DBS in subthalamic nucleus (STN). We quantified both oscillatory activity and DBS local evoked potentials (DLEPs) from the LFP. RESULTS: Temporally non-regular patterns were as effective as traditional pulse patterns in modulating motor symptoms, oscillatory activity, and DLEPs. Moreover, one of our novel patterns enabled recording of longer duration DLEPs during clinically effective stimulation. CONCLUSIONS: Stimulation gaps of 50 ms can be used to increase efficiency and to enable regular assessment of long-duration DLEPs while maintaining effective symptom management. This may be a promising paradigm for closed-loop DBS with biomarker assessment during the gaps.