Christopher Tolleson

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.

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 Parkinsons 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.

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 Parkinsons disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease.

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 Parkinsons 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.

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

Deep Brain Stimulation (DBS) is an established adjunctive surgical intervention for treating Parkinsons 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.

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.

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.

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 Parkinsons 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).