Predicting Deep Brain Stimulation Outcomes Using Intra-Operative Stimulation Test Data

Probabilistic mapping of deep brain stimulation effects in essential tremor.

Background:Deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been successful in mitigating upper limb tremor, but the effect on gait and balance performance is unclear. Here, we aim to examine the effectiveness of VIM DBS on stride length variability, sway path length, and task-relevant tremor of various body segments in essential tremor (ET).Methods:Seventeen ET individuals treated with DBS (ET DBS) and 17 age-and sex-matched healthy controls (HC) performed a postural balance and overground walking task. In separate and consecutive visits, ET DBS performed gait and balance tasks with DBS ON or OFF. The main outcome measures were sway path length, stride length variability, and tremor quantified from upper limb, lower limb, upper and lower trunk (axial) during the gait and balance tasks.Results:With DBS OFF, ET DBS exhibited significantly greater stride length variability, sway path length, and tremor during gait and balance task relative to HC. Relative to DBS OFF, DBS ON reduced stride length variability and sway path length in ET DBS. The DBS-induced reduction in stride length variability was associated with the reduction in both upper trunk tremor and upper limb tremor. The DBS-induced reduction in sway path length was associated with the reduction in upper trunk tremor.Discussion:The findings of this study revealed that VIM DBS was effective in improving gait and balance in ET DBS and that improvements in gait and postural balance were associated with a reduction of axial tremor during the tasks.Highlights:ET patients exhibit tremor in various body locations during gait and balance.DBS reduced stride length variability and sway path length.DBS-induced improvements in gait and balance were associated with reduction in axial tremor.

Probabilistic Stimulation Maps (PSMs) are increasingly employed to identify brain regions associated with optimal therapeutic outcomes in Deep Brain Stimulation (DBS). However, their reliability and generalizability are challenged by the limited size of most patient cohorts and the inherent variability introduced by different statistical methods and input data configurations. This study aimed to investigate the geometrical variability of Probabilistic Sweet Spots (PSS) as a function of both the number of patients (nPat) and the number of stimulations per patient (nStim), and to model a stability boundary defining the minimum data requirements for obtaining geometrically stable PSS. Three statistical approaches-Bayesian t-test, Wilcoxon test with False Discovery Rate (FDR) correction, and Wilcoxon test with nonparametric permutation correction-were applied to two patient cohorts: a primary cohort of 36 patients undergoing DBS for Parkinson's Disease (PD), and a secondary cohort of 61 patients treated for Essential Tremor (ET), used to assess generalizability. Stimulation test data was collected intra-operatively for the first cohort and post-operatively for the second one. Geometric stability was evaluated based on variability in PSS volume extent and centroid location. The analysis revealed a non-linear trade-off between nPat and nStim to yield stable PSS. A stability boundary was defined, representing the minimum combinations of nPat-nStim required for anatomically robust PSS. Among the tested methods, the Bayesian t-test achieved stability with smaller sample sizes (∼15 patients) and demonstrated a consistent performance across both cohorts. In contrast, the Wilcoxon-based methods showed variable behavior between cohorts, which differed in symptom type and testing phase (intra-operative testing vs. post-operative screening). The proposed PSS stability boundary provides a practical reference for designing DBS studies and stimulation screening protocols aimed at probabilistic mapping. The Bayesian t-test emerged as a reliable method across both cohorts, supporting its potential in studies with limited sample sizes and scenarios where the method needs to be readily generalized to varying symptoms. These findings underscore the importance of considering both cohort size and stimulation count in probabilistic DBS mapping and call for further investigation into method-specific sensitivities to clinical and procedural factors.

Effects of Contralateral Deep Brain Stimulation and Levodopa on Subthalamic Nucleus Oscillatory Activity and Phase-Amplitude Coupling

INTRODUCTION: Deep brain stimulation (DBS) is commonly performed awake to collect intraoperative microelectrode recordings (MER) and macrostimulation to optimize efficacy and minimize side effects (Bour et al, 2010). With supplementary information from an atlas-based database (CranialVault), efficacy heat maps guide initial targeting, intraoperative final electrode position (FEP) selection and post-operative programming (D’Haese et al, 2012). A better understanding of how this data is integrated to inform all stages of DBS can assist in reducing OR time, optimizing electrode position, expediting programming, and enhancing patient outcomes. METHODS: 451 individual patients who underwent DBS for Parkinson’s Disease, Essential Tremor or Dystonia, treated with 822 individual leads, at Vanderbilt University Medical Center between 2011-2021 were included. Intraoperative testing data including MER firing rate, macrostimulation efficacy and coordinates of FEP were retrieved from the CranialVault database. Average coordinates of planned target, midpoint and bottom of FEP, active contact and centroid of heat maps per target in patient space were calculated and visualized. Medical charts were reviewed for 1-year post-operative outcomes. RESULTS: The distribution of FEPs per target include 55.2% of leads placed in center track. Average coordinates in patient space of planned target, centroid of heatmap, midpoint and bottom of FEP and active contact were recorded. MER data demonstrates how multiunit activity changes at different depths relative to target, per target. Patients who achieve 4th quartile efficacy intraoperatively are more likely to achieve maximal benefit at 1-year post-op (p = 0.003, chi-squared). CONCLUSIONS: Atlas-based data and intraoperative testing is valuable, often leads to changes in FEP and can predict post-operative outcomes.

ObjectiveGait disturbances are frequent side effects occurring during chronic thalamic deep brain stimulation (DBS) in patients with essential tremor (ET). Adapting stimulation settings to shorter pulse widths has been shown...

Objective To assess the long-term outcome of globus pallidus intema (Gpi) deep brain stimulation (DBS) in adult patients with Tourette syndrome (TS). Methods Five adult drug-resistant TS patients, performed bilateral Gpi DBS in our hospital from May 2007 to May 2008,were chosen in our study; their symptoms before DBS and 3 and 6 months and 1 year after DBS,and over a year of DBS were evaluated by Yale global tic severity scale. Results The duration of follow-up ranged from 21 to 33 months.Scores of motor tic,phonic tic and social impairment in the last follow-up were significantly decreased as compared with those before DBS (P＜0.05); Scores of motor tic,phonic tic and social impairment 3 and 6 months and 1 year after DBS,and over a year of DBS were significantly decreased as compared with those before DBS (P＜0.05).The symptoms were gradually improved; in the first 6 months,the symptoms were obviously improved; 6 months after DBS,the symptoms were solid and can be mildly improved.3 and 6 months,1 year after DBS and till to the last follow-up (mean 26.4 months),the severity of symptom meanly improved 28.50％,52.35％,57.62％ and 62.88％,respectively;and till the last follow-up,the motor tic,phonic tic and social impairment was improved 51.38％,46.16％ and 71.00％,respectively; no serious adverse effects were noted. Conclusion Gpi DBS,improving the symptoms as motor tic,phonic tic and social impairment,is a useful and safe treatment method for adult patients with medically refractory TS; the long-term efficiency is solid. Key words: Tourette syndrome; Globus pallidus intema; Deep brain stimulation

Deep Brain Stimulation (DBS) for movement disorders can greatly benefit from the insights provided by probabilistic mapping. This consists in the application of statistical approaches to stimulation data of multiple patients. Such analysis is influenced by the input data and chosen statistical method, hindering the generalizability of the obtained results. This study aims at determining the minimum sample size yielding stable results, and the statistical approach providing higher results consistency. Intra-operative stimulation test data of 36 patients who underwent DBS surgery for Parkinson's Disease (PD), were used to compute Probabilistic Sweet Spots (PSS). The PSS were calculated with sample sizes ranging from 4 to 36 (steps of 2) using Bayesian t-test, Wilcoxon test with False Discovery Rate correction and Wilcoxon test with nonparametric permutations correction. Calculations were repeated 10 times. Obtained PSS were compared in terms of size and position variability across sample sizes and between statistical methods. Only the PSS computed with the Bayesian t-test reached stability in all the three chosen metrics. Stability in size and centroid location was reached from a sample size of 14 patients, while the covered volume (Dice coefficient) stabilized from a sample size of 18 patients. The Bayesian t-test also provided higher results consistency with respect to the other approaches. The composition of the dataset in cohorts with <20 patients has a greater influence on the extent and location of computed PSS. Moreover, the Bayesian t-test demonstrated the highest suitability to extrapolate results from analyses involving small sample sizes.Clinical Relevance- Determining the minimum number of patients and most suitable method to calculate stable PSS is crucial for ensuring the reliability and clinical applicability of Probabilistic Mapping approaches. This ensures the generalizability of findings, allowing for a more accurate understanding of the underlying pathology. These insights can be used to refine diagnostic approaches and optimize clinical interventions, ultimately improving patient care.

Tremor of the upper extremity is a significant cause of disability in some patients with multiple sclerosis (MS). The MS tremor is complex because it contains an ataxic intentional tremor component due to the involvement of the cerebellum and cerebellar outflow pathways by MS plaques, which makes the MS tremor, in general, less responsive to medications or deep brain stimulation (DBS) than those associated with essential tremor or Parkinson's disease. The cerebellar component has been thought to be the main reason for making DBS less effective, although it is not clear whether it is due to the lack of suppression of the ataxic tremor by DBS or else. The goal of this study was to clarify the effect of DBS on cerebellar tremor compared to non-cerebellar tremor in a patient with MS. By wearing an accelerometer on the index finger of each hand, we were able to quantitatively characterize kinetic tremor by frequency and amplitude, with cerebellar ataxia component on one hand and that without cerebellar component on the other hand, at the beginning and end of the hand movement approaching a target at DBS Off and On status. We found that cerebellar tremor surprisingly had as good a response to DBS as the tremor without a cerebellar component, but the function control on cerebellar tremor was not as good due to its distal oscillation, which made the amplitude of tremor increasingly greater as it approached the target. This explains why cerebellar tremor or MS tremor with cerebellar component has a poor functional transformation even with a good percentage of tremor control. This case study provides a better understanding of the effect of DBS on cerebellar tremor and MS tremor by using a wearable device, which could help future studies improve patient selection and outcome prediction for DBS treatment of this disabling tremor.

Aberrant neuronal network activity likely resulting from disturbed interactions of excitatory and inhibitory systems may be a major cause of cognitive deficits in neuropsychiatric diseases, like within the spectrum of schizophrenic phenotypes. In particular, the synchrony and pattern of oscillatory brain activity appears to be disturbed within limbic networks, e.g. between prefrontal cortex and hippocampus. In a rat model of maternal immune activation (MIA), we compared the acute effects of deep brain stimulation within either medial prefrontal cortex or ventral hippocampus with the effects of repetitive transcranial magnetic stimulation (rTMS), using the intermittent theta-burst protocol (iTBS), on oscillatory activity within limbic structures. Simultaneous local field potential recordings were made from medial prefrontal cortex, ventral hippocampus, nucleus accumbens and rostral part of ventral tegmental area before and after deep brain stimulation in anaesthetized rats previously (~3h) treated with sham or verum rTMS. We found a waxing and waning pattern of theta and gamma activity in all structures which was less synchronous in particular between medial prefrontal cortex and ventral hippocampus in MIA offspring. Deep brain stimulation in medial prefrontal cortex and pre-treatment with iTBS-rTMS partly improved this pattern. Gamma-theta cross-frequency coupling was stronger in MIA offspring and could partly be reduced by deep brain stimulation in medial prefrontal cortex. We can confirm aberrant limbic network activity in a rat MIA model, and at least acute normalizing effects of the neuromodulatory methods. It has to be proven whether these procedures can have chronic effects suitable for therapeutic purposes.

Deep Brain Stimulation for Depression: Is It a Gray or White “Matter”?

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes. Subsequently, we discuss how seminal studies have propagated the ventral intermediate nucleus (Vim)-centric view of DBS effects and shaped the ongoing debate over thalamic DBS versus stimulation in the posterior subthalamic area (PSA) in ET. We then describe probabilistic- and network-mapping studies instrumental in identifying the local and network substrates subserving tremor control, which suggest that the PSA is the optimal DBS target for tremor suppression in ET. Taken together, DBS offers promising outcomes for ET, with the PSA emerging as a better target for suppression of tremor symptoms. While advanced imaging techniques have substantially improved the identification of anatomical targets within this region, uncertainties persist regarding the distinct anatomical substrates involved in optimal tremor control. Inconsistent subdivisions and nomenclature of motor areas and other subdivisions in the thalamus further obfuscate the interpretation of stimulation results. While loss of benefit and habituation to DBS remain challenging in some patients, refined DBS techniques and closed-loop paradigms may eventually overcome these limitations.

Essential Tremor (ET) is the most common tremor syndrome seen in adults. The characteristic tremor in ET is postural and action tremors, with a frequency of 4–7 Hz; while in patients with Parkinson’s disease (PD), the dominant tremor is resting tremor with a typical frequency of 5 Hz. Deep brain stimulation (DBS) in the ventral intermediate nuclei (Vim) has been shown effective in treating action or intention tremors in medically resistant ET, while DBS in the subthalamic nucleus (STN) has been shown effective in treating rigidity, rest tremor and Dopa-induced dyskinesias in PD. However, chronic bilateral DBS, whether in Vim or STN, may have negative impact on speech production. We report two cases where both patients received DBS greater than one year and developed speech impairment. When the stimulation in Vim was turned off for 30 min in ET, the patient's speech returned to the baseline while turning the STN stimulation off for 30 min in PD, minimal changes were observed and 12 h with stimulation-off were required for speech to return to the non-stimulated state.

In Parkinson's disease (PD), slow gait speed is significantly related to clinical ratings of disease severity, impaired performance of daily activities, as well as increased overall disability. Conducting a meta-analysis on gait speed is an objective and quantitative technique to summarize the effectiveness of DBS and to determine the effect sizes for future studies. We conducted a systematic review and meta-analysis that analyzed the effects of deep brain stimulation (DBS) surgery on gait speed in patients with PD to gain fundamental insight into the nature of therapeutic effectiveness. A random effects model meta-analysis on 27 studies revealed a significant overall standardized mean difference medium effect size equal to 0.60 (SE=0.06; p<0.0001; Z=10.58). Based on our synthesis of the 27 studies, we determined the following: (1) a significant and medium effect size indicating DBS improves gait speed; (2) DBS improved gait speed regardless of whether the patients were tested in the on or off medication state; (3) both bilateral and unilateral DBS led to gait speed improvement; (4) the effects of DBS on gait speed in the data collection sessions after surgery (DBS on vs. off) were comparable with data collection before surgery (before surgery vs. DBS after surgery); and (5) when evaluating the effects of DBS and medication on gait speed suprathreshold doses were comparable to normal dosages of medication and DBS. The current analysis provides objective evidence that both unilateral and bilateral DBS provide a therapeutic benefit on gait speed in persons with PD.

Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats