Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor.

BACKGROUND: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. METHODS: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. RESULTS: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). CONCLUSIONS: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

Motivational Sensitivities Linked to Impulsive Motor Errors in Parkinson's Disease.

OBJECTIVES: We investigated how broad motivational tendencies are related to the expression and suppression of action impulses in Parkinson's disease (PD). METHODS: Sixty-nine participants with PD completed a Simon response conflict task and Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) scales based on Gray's (1987) reinforcement sensitivity theory. Analyses determined relationships between BIS, BAS, and the susceptibility to making impulsive action errors and the proficiency of inhibiting interference from action impulses. RESULTS: BIS scores correlated positively with rates of impulsive action errors, indicating that participants endorsing low BIS tendencies were much more susceptible to acting on strong motor impulses. Analyses of subgroups with high versus low BIS scores confirmed this pattern and ruled out alternative explanations in terms of group differences in speed-accuracy tradeoffs. None of the scores on the BIS or BAS scales correlated with reactive inhibitory control. CONCLUSIONS: PD participants who endorse diminished predilection toward monitoring and avoiding aversive experiences (low BIS) show much greater difficulty restraining fast, impulsive motor errors. Establishing relationships between motivational sensitivities and cognitive control processes may have important implications for treatment strategies and positive health outcomes in participants with PD, particularly those at risk for falling and driving difficulties related to impulsive reactions. (JINS, 2018, 24, 128-138).

Parkinson's Disease Subtypes Show Distinct Tradeoffs Between Response Initiation and Inhibition Latencies.

OBJECTIVES: In unpredictable situations, individuals often show tradeoffs between response initiation and inhibition speeds. We tested the hypothesis that Parkinson's disease (PD) motor subtypes differentially impact tradeoffs between these two action-oriented processes. We predicted that, compared to tremor dominant (TD) patients, predominant postural instability and gait dysfunction (PIGD) patients would show exacerbated tradeoffs between response initiation and inhibition in situations requiring the sudden potential need to interrupt an action. METHODS: Fifty-one PD patients (subdivided into PIGD [n=27] and TD [n=24]) and 21 healthy controls (HCs) completed a choice reaction task to establish baseline response initiation speed between groups. Subsequently, participants completed a stop-signal task which introduced an occasional, unpredictable stop stimulus. We measured changes in initiation speed in preparation of an unpredictable stop (i.e., proactive slowing) and inhibition latency (i.e., stop-signal reaction time). RESULTS: Compared to HCs, PD patients showed slower response initiation speeds in the choice reaction task. All groups showed proactive slowing in the stop-signal task but the magnitude was considerably larger in PIGD patients, almost twice as large as TD patients. PD patients, irrespective of motor subtype, showed longer inhibition latencies than HCs. CONCLUSIONS: PIGD and TD subtypes both showed exacerbated response inhibition deficits. However, PIGD patients showed much more pronounced proactive slowing in situations with an expected yet unpredictable need to stop action abruptly. This suggests that PIGD is accompanied by exaggerated tradeoffs between response initiation and inhibition processes to meet situational action demands. We discuss putative neural mechanisms and clinical implications of these findings. (JINS, 2017, 23, 665-674).

The role of deep brain stimulation in Parkinson's disease: an overview and update on new developments.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of neuronal dopamine production in the brain. Oral therapies primarily augment the dopaminergic pathway. As the disease progresses, more continuous delivery of therapy is commonly needed. Deep brain stimulation (DBS) has become an effective therapy option for several different neurologic and psychiatric conditions, including PD. It currently has US Food and Drug Administration approval for PD and essential tremor, as well as a humanitarian device exception for dystonia and obsessive-compulsive disorder. For PD treatment, it is currently approved specifically for those patients suffering from complications of pharmacotherapy, including motor fluctuations or dyskinesias, and a disease process of at least 4 years of duration. Studies have demonstrated superiority of DBS and medical management compared to medical management alone in selected PD patients. Optimal patient selection criteria, choice of target, and programming methods for PD and the other indications for DBS are important topics that continue to be explored and remain works in progress. In addition, new hardware options, such as different types of leads, and different software options have recently become available, increasing the potential for greater efficacy and/or reduced side effects. This review gives an overview of therapeutic management in PD, specifically highlighting DBS and some of the recent changes with surgical therapy.

Rescue Procedures after Suboptimal Deep Brain Stimulation Outcomes in Common Movement Disorders.

Deep brain stimulation (DBS) is a unique, functional neurosurgical therapy indicated for medication refractory movement disorders as well as some psychiatric diseases. Multicontact electrodes are placed in "deep" structures within the brain with targets varying depending on the surgical indication. An implanted programmable pulse generator supplies the electrodes with a chronic, high frequency electrical current that clinically mimics the effects of ablative lesioning techniques. DBS's efficacy has been well established for its movement disorder indications (Parkinson's disease, essential tremor, and dystonia). However, clinical outcomes are sometimes suboptimal, even in the absence of common, potentially reversible complications such as hardware complications, infection, poor electrode placement, and poor programming parameters. This review highlights some of the rescue procedures that have been explored in suboptimal DBS cases for Parkinson's disease, essential tremor, and dystonia. To date, the data is limited and difficult to generalize, but a large majority of published reports demonstrate positive results. The decision to proceed with such treatments should be made on a case by case basis. Larger studies are needed to clearly establish the benefit of rescue procedures and to establish for which patient populations they may be most appropriate.

The Impact of Pallidal and Subthalamic Deep Brain Stimulation on Urologic Function in Parkinson's Disease.

OBJECTIVE: Deep Brain Stimulation (DBS) is an established adjunctive surgical intervention for treating Parkinson's disease (PD) motor symptoms. Both surgical targets, the globus pallidus interna (GPi) and subthalamic nucleus (STN), appear equally beneficial when treating motor symptoms but effects on nonmotor symptoms are not clear. Lower urinary tract symptoms (LUTS) are a common PD complaint. Given prior data in STN-DBS, we aimed to further explore potential benefits in LUTS in both targets. METHODS: We performed a prospective, nonblinded clinical trial evaluating LUTS in PD patients in both targets pre and post DBS using validated urologic surveys. Participants were already slated for DBS and target selection predetermined before study entry. LUTS was evaluated using: the American Urological Association (AUA-SI), Quality of Life score (QOL), Overactive Bladder 8 Questionnaire (OAB-q), and Sexual Health Inventory for Men (SHIM). RESULTS: Of 33 participants, 20 underwent STN DBS and 13 had GPi DBS. Patients demonstrated moderate baseline LUTS. The urologic QOL score significantly improved post DBS (3.24 ± 1.77vs. 2.52 ± 1.30; p = 0.03). Analyzed by target, only the STN showed significant change in QOL (3.20 ± 1.61 vs 2.25 ± 1.33; p = 0.04). There were no other significant differences in urologic scores post DBS noted in either target. CONCLUSION: In PD patients with moderate LUTS, there were notable improvements in QOL for LUTS post DBS in the total sample and STN target. There may be differences in DBS effects on LUTS between targets but this will require further larger, blinded studies.

A Pilot Study Assessing the Effects of Pallidal Deep Brain Stimulation on Sleep Quality and Polysomnography in Parkinson's Patients.

OBJECTIVE: Deep Brain Stimulation (DBS) is an established adjunctive surgical intervention to treat poorly controlled motor symptoms in Parkinson's disease (PD). Both surgical targets (the subthalamic nucleus and globus pallidus) have proven equally efficacious in treating motor symptoms but unique differences may exist in effects on nonmotor symptoms. Sleep dysfunction, a common disabling symptom in PD, has only been examined directly in the subthalamic target, demonstrating some beneficial changes in sleep quality. We aimed to explore sleep changes after pallidal stimulation; hypothesizing similar benefits would be seen. METHODS: We performed a prospective nonblinded clinical trial evaluating sleep in five PD patients already slated for pallidal DBS pre and six months postimplantation using validated sleep surveys and polysomnograms (PSGs). Surveys included the Epworth sleepiness scale, PD sleep scale, Insomnia severity index (ISI), and RLS severity scale. RESULTS: Most patients had notable improvements in sleep quality as measured by PSG metrics such as sleep efficiency and latency to sleep but they did not reach statistical significance. Most surveys reflected an improvement as well with the ISI scale showing the most promising trend post pallidal DBS (14.4 ± 7.02 vs. 9.0 ± 2.55; p = 0.07). CONCLUSION: In this small pilot trial, pallidal DBS failed to demonstrate statistically significant improvements in sleep metrics postimplantation but did reveal improving trends in several PSG measures including sleep efficiency and latency to sleep onset as well as sleep survey scores. A larger, blinded clinical trial is needed to more definitively determine whether pallidal DBS may benefit sleep.

Generalized motor inhibitory deficit in Parkinson's disease patients who freeze.

Freezing of gait is a disabling symptom of Parkinson's disease (PD) that involves failure to initiate and continue motor activity appropriately. PD disrupts fronto-basal ganglia circuitries that also implement the inhibition of responses, leading to the hypothesis that freezing of gait may involve fundamental changes in both initiation and inhibition of motor actions. We asked whether PD patients who show freezing of gait show selective deficits in their ability to inhibit upper and lower extremity reactions. We compared older healthy controls, older PD controls without freezing of gait, and older PD participants with freezing of gait, in stop-signal tasks that measured the initiation (go trials) and inhibition (stop trials) of both hand and foot responses. When only go trials were presented, all three groups showed similar initiation speeds across lower and upper extremity responses. When stop-signal trials were introduced, both PD groups slowed their reactions nearly twice as much as healthy controls. While this adjustment helped PD controls stop their actions as quickly as healthy controls, PD patients with freezing showed significantly delayed inhibitory control of both upper and lower extremities. When anticipating the need to stop their actions urgently, PD patients show greater adjustments (i.e., slowing) to reaction speed than healthy controls. Despite these proactive adjustments, PD patients who freeze show marked impairments in inhibiting both upper and lower extremity responses, suggesting that freezing may involve a fundamental disruption to the brain's inhibitory control system.

Dysrhythmia of timed movements in Parkinson's disease and freezing of gait.

A well-established motor timing paradigm, the Synchronization-Continuation Task (SCT), quantifies how accurately participants can time finger tapping to a rhythmic auditory beat (synchronization phase) then maintain this rhythm after the external auditory cue is extinguished, where performance depends on an internal representation of the beat (continuation phase). In this study, we investigated the hypothesis that Parkinson's disease (PD) patients with clinical symptoms of freezing of gait (FOG) exhibit exaggerated motor timing deficits. We predicted that dysrhythmia is exacerbated when finger tapping is stopped temporarily and then reinitiated under the guidance of an internal representation of the beat. Healthy controls and PD patients with and without FOG performed the SCT with and without the insertion of a 7-s cessation of motor tapping between synchronization and continuation phases. With no interruption between synchronization and continuation phases, PD patients, especially those with FOG, showed pronounced motor timing hastening at the slowest inter-stimulus intervals during the continuation phase. The introduction of a gap prior to the continuation phase had a beneficial effect for healthy controls and PD patients without FOG, although patients with FOG continued to show pronounced and persistent motor timing hastening. Ratings of freezing of gait severity across the entire sample of PD tracked closely with the magnitude of hastening during the continuation phase. These results suggest that PD is accompanied by a unique dysrhythmia of measured movements, with FOG reflecting a particularly pronounced disruption to internal rhythmic timing.

The optimal pallidal target in deep brain stimulation for dystonia: a study using a functional atlas based on nonlinear image registration.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus is established as efficacious for dystonia, yet the optimal target within this structure is not well defined. Published evidence suggests that spatial normalization provides a better estimate of DBS lead location than traditional methods based on standard stereotactic coordinates. METHODS: We retrospectively reviewed our pallidal implanted dystonia population. Patient imaging scans were morphed into an MRI atlas using a nonlinear image registration algorithm. Active contact locations were projected onto the atlas and clusters analyzed for the degree of variance in two groups: (1) good and poor responders and (2) cervical (CD) and generalized dystonia (GD). RESULTS: The average active contact location between CD and GD good responders was distinct but not significantly different. The mean active contact for CD poor responders was significantly different from CD responders and GD poor responders in the dorsoventral direction. CONCLUSIONS: A normalized imaging space is arguably more accurate in visualizing postoperative leads. Despite some separation between groups, this data suggests there was not an optimal pallidal target for common dystonia patients. Degrees of variance overlapped due to a large degree of individual target variation. Patient selection may ultimately be the key to maximizing patient outcomes.

Use of efficacy probability maps for the post-operative programming of deep brain stimulation in essential tremor.

INTRODUCTION: Post-operative programming of deep brain stimulation for movement disorders can be both time consuming and difficult, which can delay the optimal symptom control for the patient. Probabilistic maps of stimulation response could improve programming efficiency and optimization. METHODS: The clinically selected contacts of patients who had undergone ventral intermediate nucleus deep brain stimulation for the treatment of essential tremor at our institution were compared against contacts selected based on a probability map of symptom reduction built by populating data from a number of patients using non-rigid image registration. A subgroup of patients whose clinical contacts did not match the map-based selections prospectively underwent a tremor rating scale evaluation to compare the symptom relief achieved by the two options. Both the patient and video reviewer were blinded to the selection. RESULTS: 54% of the map-based and clinical contacts were an exact match retrospectively and were within one contact 83% of the time. In 5 of the 8 mismatched leads that were evaluated prospectively in a double blind fashion, the map-based contact showed equivalent or better tremor improvement than the clinically active contact. CONCLUSIONS: This study suggests that probability maps of stimulation responses can assist in selecting the clinically optimal contact and increase the efficiency of programming.

New targets for treating the underlying pathophysiology and nonmotor aspects of Parkinson's disease.

Parkinson's disease is a common neurodegenerative disease diagnosed by well established clinical motor symptoms. However, the disease also encompasses many nonmotor issues that can impact a myriad of processes such as cardiovascular status, gastrointestinal function, autonomic function, mood and sleep. These issues can be more debilitating and impactful on health status in part because of a lack of effective treatments. The pathophysiology of the disease process is under active investigation with postulated mechanisms involving both the central nervous system and the periphery. More in depth examination of the many nonmotor symptoms may aid in the discovery of the overarching pathological origin and progression of Parkinson's disease. Examining the disease process from the perspective of nonmotor symptoms may also provide additional target pathways and potential drug development options not considered previously.

The factors involved in deep brain stimulation infection: a large case series.

BACKGROUND: Deep brain stimulation (DBS) is a proven treatment for various movement disorders resistant to medical management. Complications such as postsurgical infection can negate benefits and increase patient morbidity. We sought to better define risk factors for infection. METHODS: We performed a review of DBS cases at our institution from January 1996 to June 2011. Information on multiple metrics including surgical complications, procedural complications and infection were entered into a secure online database. RESULTS: A total of 447 patients received DBS surgery. Twenty-six (5.82%) developed infection sometime after DBS surgery with 9 (2.01%) developing infection within 30 days after the final staged surgery. Operating surgeon (p = 0.012), scalp erosion (p = 0.0001), surgical incision opening time (0.0001) and number of individuals in the operating room (0.0027) were significant in the cumulative infection group. CONCLUSION: The 30-day infection rate was comparably low to other published studies. Several factors were noted to be significant in the cumulative infection group, but none in the 30-day infection group. Further understanding of infection risk factors is important to optimize patient selection and standardize infection-preventative techniques.

The success of traumatic brain injury registry outreach.

BACKGROUND: Traumatic brain injury (TBI) affects a large percentage of the US population. Survivors are under-served and recognized. The current mechanisms to contact patients and provide access to needed services appear ineffective. OBJECTIVE: To review the effectiveness of current TBI outreach using registries. METHODS: This study reviewed practices of the local TBI programme containing a registry utilized for outreach. Then, using a standardized questionnaire focusing on the TBI registry structure and its follow-up techniques, self-proclaimed registries were contacted and compared across the nation. RESULTS: Twelve additional TBI programmes were contacted. Eight others had actual registries used for follow-up. The principal mechanism was postal mail. Mail response rates varied from 0.54-25%. Programmes were limited by funding, staffing and access to contact information. CONCLUSION: Postal mail has not been a successful follow-up method for TBI registries. New structuring of letters and alternative contact techniques are needed. Improved access to those individuals with TBI's contact information and funding would likely also aid programmes managing this public health epidemic.

Neurologist consistency in interpreting information provided by an interactive visualization software for deep brain stimulation postoperative programming assistance.

INTRODUCTION: Postoperative programming in deep brain stimulation (DBS) therapy for movement disorders can be challenging and time consuming. Providing the neurologist with tools to visualize the electrode location relative to the patient's anatomy along with models of tissue activation and statistical data can therefore be very helpful. In this study, we evaluate the consistency between neurologists in interpreting and using such information provided by our DBS programming assistance software. METHODS: Five neurologists experienced in DBS programming were each given a dataset of 29 leads implanted in 17 patients. For each patient, probabilistic maps of stimulation response, anatomical images, models of tissue activation volumes, and electrode positions were presented inside a software framework called CRAnialVault Explorer (CRAVE) developed in house. Consistency between neurologists in optimal contact selection using the software was measured. RESULTS: With only the efficacy map, the average consistency among the five neurologists with respect to the mode and mean of their selections was 97% and 95%, respectively, while these numbers were 93% and 89%, respectively, when both efficacy and an adverse effect map were used simultaneously. Fleiss' kappa statistic also showed very strong agreement among the neurologists (0.87 when using one map and 0.72 when using two maps). CONCLUSION: Our five neurologists demonstrated high consistency in interpreting information provided by the CRAVE interactive visualization software for DBS postoperative programming assistance. Three of our five neurologists had no prior experience with the software, which suggests that the software has a short learning curve and contact selection is not dependent on familiarity with the program tools.

Advances in the mechanisms of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disorder. Despite fairly typical clinical and pathologic features, the etiology remains unknown. Many cellular mechanisms such as oxidative stress, mitochondrial dysfunction, lysosomal dysfunction, neuroinflammatory changes, and the formation of pathologic inclusions have been proposed as potential causes. Potential links between environmental and genetic changes appear to predispose individuals to develop Parkinson's disease. Considering these observations, albeit with different levels of evidence, it is becoming more probable that Parkinson's disease is a heterogeneous disorder or a syndrome that arises from the contribution of many different factors.

The function of tyrosine hydroxylase in the normal and Parkinsonian brain.

Tyrosine hydroxylase (TH) is the rate limiting step in the biosynthesis of dopamine and other catecholamines. Differences have been noted in concentration and availability of this enzyme and its cofactors in disease states such as Parkinson's disease (PD) which are subject to alterations in catecholamines. More evidence suggests in fact that TH may play a direct role in the pathogenesis of PD, especially through oxidative stress and pro-inflammatory mechanisms. Treatment for PD has classically involved maximizing endogenous dopamine by medicinal options that either replace dopamine or augment the dopaminergic pathway. The medications are unfortunately limited, given they are not curative and involve potential short-term and long-term side effects. Gene therapy in PD is a burgeoning field which provides a way to augment dopamine production, and potentially protect the dopaminergic neurons from further degeneration. Given its importance in dopamine catabolism and the possibility that it may contribute to pathogenesis, TH is one target of gene therapy. Further research into the regulatory mechanisms and function of TH are promising in improving gene therapy approaches as well as other treatment modalities.

Pilot study assessing the feasibility of applying bilateral subthalamic nucleus deep brain stimulation in very early stage Parkinson's disease: study design and rationale.

BACKGROUND: Deep brain stimulation provides significant symptomatic benefit for people with advanced Parkinson's disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinson's disease, and results of animal studies suggest that it may spare dopaminergic neurons in the substantia nigra. OBJECTIVE: We report the methodology and design of a novel Phase I clinical trial testing the safety and tolerability of deep brain stimulation in early Parkinson's disease and discuss previous failed attempts at neuroprotection. METHODS: We recently conducted a prospective, randomized, parallel-group, single-blind pilot clinical trial of deep brain stimulation in early Parkinson's disease. Subjects were randomized to receive either optimal drug therapy or deep brain stimulation plus optimal drug therapy. Follow-up visits occurred every six months for a period of two years and included week-long therapy washouts. RESULTS: Thirty subjects with Hoehn & Yahr Stage II idiopathic Parkinson's disease were enrolled over a period of 32 months. Twenty-nine subjects completed all follow-up visits; one patient in the optimal drug therapy group withdrew from the study after baseline. Baseline characteristics for all thirty patients were not significantly different. CONCLUSIONS: This study demonstrates that it is possible to recruit and retain subjects in a clinical trial testing deep brain stimulation in early Parkinson's disease. The results of this trial will be used to support the design of a Phase III, multicenter trial investigating the efficacy of deep brain stimulation in early Parkinson's disease.