Daniel Martinez-Ramirez

Chasing Tics in the Human Brain: Development of Open, Scheduled and Closed Loop Responsive Approaches to Deep Brain Stimulation for Tourette Syndrome

Tourette syndrome is a childhood-onset disorder characterized by a combination of motor and vocal tics, often associated with psychiatric comorbidities including attention deficit and hyperactivity disorder and obsessive-compulsive disorder. Despite an onset early in life, half of patients may present symptoms in adulthood, with variable degrees of severity. In select cases, the syndrome may lead to significant physical and social impairment, and a worrisome risk for self injury. Evolving research has provided evidence supporting the idea that the pathophysiology of Tourette syndrome is directly related to a disrupted circuit involving the cortex and subcortical structures, including the basal ganglia, nucleus accumbens, and the amygdala. There has also been a notion that a dysfunctional group of neurons in the putamen contributes to an abnormal facilitation of competing motor responses in basal ganglia structures ultimately underpinning the generation of tics. Surgical therapies for Tourette syndrome have been reserved for a small group of patients not responding to behavioral and pharmacological therapies, and these therapies have been directed at modulating the underlying pathophysiology. Lesion therapy as well as deep brain stimulation has been observed to suppress tics in at least some of these cases. In this article, we will review the clinical aspects of Tourette syndrome, as well as the evolution of surgical approaches and we will discuss the evidence and clinical responses to deep brain stimulation in various brain targets. We will also discuss ongoing research and future directions as well as approaches for open, scheduled and closed loop feedback-driven electrical stimulation for the treatment of Tourette syndrome.

Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tanks contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and device technologies.

Clinical Determinants of Health-related Quality of Life in Mexican Patients with Parkinson’s Disease

BACKGROUND AND AIMS Parkinsons disease (PD) is the second most common chronic neurodegenerative disorder. PD is clinically characterized by a constellation of motor and nonmotor symptoms that may have a direct effect on daily activities as well as in the quality of life of the patient. Identifying the symptoms more closely associated with a poor quality of life is central on improving the medical care of the patient. We undertook this study to identify and describe the clinical and demographic factors that predict health-related quality of life among Mexican patients with PD. METHODS One hundred seventy-seven patients with Parkinsons disease were included. Patients were evaluated using the following clinimetric instruments: motor subscale of the Unified Parkinsons disease rating scale, Hoehn and Yahr stage, Non-motor Symptoms Questionnaire, Parkinsons disease Questionnaire (PDQ-39) and the Mini Mental Status Examination. RESULTS Multivariate analysis showed that the main factors associated with a poor quality of life were motor impairment (β = 0.27, p <0.001) and the number of nonmotor symptoms (β = 2.17, p <0.001). The main nonmotor domains impacting on the quality of life were depression/anxiety (β = 6.36, p <0.001), cardiovascular (β = 5.39, p = 0.001), memory (β = 4.64, p <0.001) and miscellaneous (β = 3.15, p = 0.001). CONCLUSIONS Both motor and mainly nonmotor symptoms are negatively associated with health-related quality of life in patients with PD and should be appropriately attended in order to improve patient care.

Randomized, Blinded Pilot Testing of Nonconventional Stimulation Patterns and Shapes in Parkinson's Disease and Essential Tremor: Evidence for Further Evaluating Narrow and Biphasic Pulses

Evidence suggests that nonconventional programming may improve deep brain stimulation (DBS) therapy for movement disorders. The primary objective was to assess feasibility of testing the tolerability of several nonconventional settings in Parkinsons disease (PD) and essential tremor (ET) subjects in a single office visit. Secondary objectives were to explore for potential efficacy signals and to assess the energy demand on the implantable pulse‐generators (IPGs).

Update on deep brain stimulation in Parkinson's disease

Deep brain stimulation (DBS) is considered a safe and well tolerated surgical procedure to alleviate Parkinson’s disease (PD) and other movement disorders symptoms along with some psychiatric conditions. Over the last few decades DBS has been shown to provide remarkable therapeutic effect on carefully selected patients. Although its precise mechanism of action is still unknown, DBS improves motor functions and therefore quality of life. To date, two main targets have emerged in PD patients: the globus pallidus pars interna and the subthalamic nucleus. Two other targets, the ventralis intermedius and zona incerta have also been selectively used, especially in tremor-dominant PD patients. The main indications for PD DBS have traditionally been motor fluctuations, debilitating medication induced dyskinesias, unpredictable “off time” state, and medication refractory tremor. Medication refractory tremor and intolerable dyskinesia are potential palliative indications. Besides aforementioned targets, the brainstem pedunculopontine nucleus (PPN) is under investigation for the treatment of ON-state freezing of gait and postural instability. In this article, we will review the most recent literature on DBS therapy for PD, including cutting-edge advances and data supporting the role of DBS in advanced neural-network modulation.

Thalamocortical network activity enables chronic tic detection in humans with Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Deep brain stimulation (DBS) is an emerging therapy for severe cases of TS. We studied two patients with TS implanted with bilateral Medtronic Activa PC + S DBS devices, capable of chronic recordings, with depth leads in the thalamic centromedian–parafascicular complex (CM-PF) and subdural strips over the precentral gyrus. Low-frequency (1–10 Hz) CM-PF activity was observed during tics, as well as modulations in beta rhythms over the motor cortex. Tics were divided into three categories: long complex, complex, and simple. Long complex tics, tics involving multiple body regions and lasting longer than 5 s, were concurrent with a highly detectable thalamocortical signature (average recall [sensitivity] 88.6%, average precision 96.3%). Complex tics were detected with an average recall of 63.9% and precision of 36.6% and simple tics an average recall of 39.3% and precision of 37.9%. The detections were determined using data from both patients.

Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome : The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry

Importance Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. Exposures Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]). Main Outcomes and Measures Scores on the Yale Global Tic Severity Scale and adverse events. Results The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Conclusions and Relevance Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

Comparing the accuracy of different smell identification tests in Parkinson’s disease: Relevance of cultural aspects

OBJECTIVE The aim of this study is to determine the usefulness of the University of Pennsylvania smell identification test (UPSIT), sniffin sticks (SS-16) and brief smell identification test (B-SIT) to assess smell identification in the Mexican population and its accuracy in discriminating subjects with Parkinsons disease (PD). METHODS We included 199 nondemented PD subjects and 199 control subjects matched by gender. Smell identification was tested using the UPSIT and SS-16. Our group obtained B-SIT data from a previous report. RESULTS The mean number of UPSIT items correctly identified by controls was 27.3±6; the PD group had a mean score of 19.4±6. UPSIT had a sensitivity of 82% with a specificity of 66% for a cut-off score of ≤25 for detection of PD. The mean number of SS-16 items correctly identified by controls was 10.3±2.2, while the PD group had 7.4±2.8 correct answers. For SS-16, sensitivity was 77.8% and specificity of 71.2% when using a cut-off value of ≤9. Lemon, turpentine and rose had an identification rate below the 25th percentile for all three tests. Odors with an identification rate above the 75th percentile include banana for all three tests, and gasoline, onion and chocolate for UPSIT and B-SIT. CONCLUSION The sensitivity and specificity of the smell tests that were evaluated were lower in comparison to other published reports. Cultural biases and smell familiarity may influence the test results. The development of a true cross-culturally adapted smell identification test is warranted may improve test accuracy.

Report of a patient undergoing chronic responsive deep brain stimulation for Tourette syndrome: proof of concept

Deep brain stimulation (DBS) has emerged as a promising intervention for the treatment of select movement and neuropsychiatric disorders. Current DBS therapies deliver electrical stimulation continuously and are not designed to adapt to a patients symptoms. Continuous DBS can lead to rapid battery depletion, which necessitates frequent surgery for battery replacement. Next-generation neurostimulation devices can monitor neural signals from implanted DBS leads, where stimulation can be delivered responsively, moving the field of neuromodulation away from continuous paradigms. To this end, the authors designed and chronically implemented a responsive stimulation paradigm in a patient with medically refractory Tourette syndrome. The patient underwent implantation of a responsive neurostimulator, which is capable of responsive DBS, with bilateral leads in the centromedian-parafascicular (Cm-Pf) region of the thalamus. A spectral feature in the 5- to 15-Hz band was identified as the control signal. Clinical data collected prior to and after 12 months of responsive therapy revealed improvements from baseline scores in both Modified Rush Tic Rating Scale and Yale Global Tic Severity Scale scores (64% and 48% improvement, respectively). The effectiveness of responsive stimulation (p = 0.16) was statistically identical to that of scheduled duty cycle stimulation (p = 0.33; 2-sided Wilcoxon unpaired rank-sum t-test). Overall, responsive stimulation resulted in a 63.3% improvement in the neurostimulators projected mean battery life. Herein, to their knowledge, the authors present the first proof of concept for responsive stimulation in a patient with Tourette syndrome.

Atrophy and Other Potential Factors Affecting Long Term Deep Brain Stimulation Response: A Case Series

Objective To describe three DBS cases which presented with new side effects or loss of benefit from stimulation after long-term follow-up and to discuss the potential contributing factors. Methods A University of Florida (UF) database (INFORM) search was performed, identifying three patients, two Parkinsons disease (PD) and one Essential Tremor (ET), with an unexpected change in long-term programming thresholds as compared to initial evaluation. Clinical follow-up, programming, imaging studies, and lead measurements were reviewed. The UF Institutional Review Board (IRB) approved this study. Results A substantial increase in the 3rd ventricular width (120%), Evans index (6%), ventricular index (5%), and cella media index (17%) was uncovered. A change in thresholds across lead contacts with a decrease in current densities as well as a relative lateral change of lead location was also observed. Hardware-related complications, lead migration, and impedance variability were not identified. Conclusions Potential factors contributing to long-term side effects should be examined during a DBS troubleshooting assessment. Clinicians should be aware that in DBS therapy there is delivery of electricity to a changing brain, and atrophy may possibly affect DBS programming settings as part of long-term follow-up.