Reduced subthalamic and subthalamic-cortical coherences associated with the therapeutic carryover effect of coordinated reset deep brain stimulation.

Coordinated reset deep brain stimulation (CR DBS), a promising treatment for Parkinson's disease (PD), is hypothesized to desynchronize neuronal populations. However, little in vivo data probes this hypothesis. In a parkinsonian nonhuman primate, we found that subthalamic CR DBS suppressed subthalamic and cortical-subthalamic coherences in the beta band, correlating with motor improvements. Our results support the desynchronizing mechanism of CR DBS and propose potential biomarkers for closed-loop CR DBS.

A Patient-Centered Perspective on Changes in Personal Characteristics After Deep Brain Stimulation.

Importance: Deep brain stimulation (DBS) results in improvements in motor function and quality of life in patients with Parkinson disease (PD), which might impact a patient's perception of valued personal characteristics. Prior studies investigating whether DBS causes unwanted changes to oneself or one's personality have methodological limitations that should be addressed. Objective: To determine whether DBS is associated with changes in characteristics that patients with PD identify as personally meaningful. Design, Setting, and Participants: This cohort study assessed changes in visual analog scale (VAS) ratings reflecting the extent to which patients with PD manifested individually identified personal characteristics before and 6 and 12 months after DBS at a large academic medical center from February 21, 2018, to December 9, 2021. The VAS findings were tailored to reflect the top 3 individually identified personal characteristics the patient most feared losing. The VASs were scored from 0 to 10, with 0 representing the least and 10 the most extreme manifestation of the trait. Change scores were examined at the individual level. Content analysis was used to code the qualitative data. Qualitative and quantitative analyses were performed from January 12, 2019 (initial qualitative coding), to December 15, 2023. Exposure: Deep brain stimulation. Main Outcomes and Measures: The primary outcome variable was the mean VAS score for the top 3 personal characteristics. The secondary outcome was the incidence of meaningful changes on the patients' top 3 characteristics at the individual level. Results: Fifty-two of 54 dyads of patients with PD and their care partners (96.3%) were recruited from a consecutive series approved for DBS (36 patients [69.2%] were male and 45 care partners [86.5%] were female; mean [SD] age of patients, 61.98 [8.55] years). Two patients and 1 care partner were lost to follow-up. Increases in the mean VAS score (indicative of greater manifestation of [ie, positive changes in] specific characteristics) were apparent following DBS for ratings of both the patients (Wald χ2 = 16.104; P < .001) and care partners (Wald χ2 = 6.746; P < .001) over time. The slopes of the changes for both the patient and care partners were correlated, indicating agreement in observed changes over time. The individual level analyses indicated that scores for most patients and care partners remained the same or increased. Conclusions and Relevance: In this cohort study, participants reported greater (more positive) manifestations of individually identified, valued characteristics after DBS. These findings may be relevant to informing decision-making for patients with advanced PD who are considering DBS.

Neural pathways associated with reduced rigidity during pallidal deep brain stimulation for Parkinson's disease.

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) can markedly reduce muscle rigidity in people with Parkinson's disease (PD); however, the mechanisms mediating this effect are poorly understood. Computational modeling of DBS provides a method to estimate the relative contributions of neural pathway activations to changes in outcomes. In this study, we generated subject-specific biophysical models of GPi DBS (derived from individual 7-T MRI), including pallidal efferent, putamenal efferent, and internal capsule pathways, to investigate how activation of neural pathways contributed to changes in forearm rigidity in PD. Ten individuals (17 arms) were tested off medication under four conditions: off stimulation, on clinically optimized stimulation, and on stimulation specifically targeting the dorsal GPi or ventral GPi. Quantitative measures of forearm rigidity, with and without a contralateral activation maneuver, were obtained with a robotic manipulandum. Clinically optimized GPi DBS settings significantly reduced forearm rigidity (P < 0.001), which aligned with GPi efferent fiber activation. The model demonstrated that GPi efferent axons could be activated at any location along the GPi dorsal-ventral axis. These results provide evidence that rigidity reduction produced by GPi DBS is mediated by preferential activation of GPi efferents to the thalamus, likely leading to a reduction in excitability of the muscle stretch reflex via overdriving pallidofugal output.NEW & NOTEWORTHY Subject-specific computational models of pallidal deep brain stimulation, in conjunction with quantitative measures of forearm rigidity, were used to examine the neural pathways mediating stimulation-induced changes in rigidity in people with Parkinson's disease. The model uniquely included internal, efferent and adjacent pathways of the basal ganglia. The results demonstrate that reductions in rigidity evoked by deep brain stimulation were principally mediated by the activation of globus pallidus internus efferent pathways.

Deep brain stimulation pulse sequences to optimally modulate frequency-specific neural activity.

Objective. Precise neuromodulation systems are needed to identify the role of neural oscillatory dynamics in brain function and to advance the development of brain stimulation therapies tailored to each patient's signature of brain dysfunction. Low-frequency, local field potentials (LFPs) are of increasing interest for the development of these systems because they can reflect the synaptic inputs to a recorded neuronal population and can be chronically recorded in humans. In this computational study, we aim to identify stimulation pulse patterns needed to optimally maximize the suppression or amplification of frequency-specific neural activity.Approach. We derived DBS pulse patterns to minimize or maximize the 2-norm of frequency-specific neural oscillations using a generalized mathematical model of spontaneous and stimulation-evoked LFP activity, and a subject-specific model of neural dynamics in the pallidum of a Parkinson's disease patient. We leveraged convex and mixed-integer optimization tools to identify these pulse patterns, and employed constraints on the pulse frequency and amplitude that are required to keep electrical stimulation within its safety envelope.Main results. Our analysis revealed that a combination of phase, amplitude, and frequency pulse modulation is needed to attain optimal suppression or amplification of the targeted oscillations. Phase modulation is sufficient to modulate oscillations with a constant amplitude envelope. To attain optimal modulation for oscillations with a time-varying envelope, a trade-off between frequency and amplitude pulse modulation is needed. The optimized pulse sequences were invariant to changes in the dynamics of stimulation-evoked neural activity, including changes in damping and natural frequency or complexity (i.e. generalized vs. patient-specific model).Significance. Our results provide insight into the structure of pulse patterns for future closed-loop brain stimulation strategies aimed at controlling neural activity precisely and in real-time.

Slow-wave sleep dysfunction in mild parkinsonism is associated with excessive beta and reduced delta oscillations in motor cortex.

Increasing evidence suggests slow-wave sleep (SWS) dysfunction in Parkinson's disease (PD) is associated with faster disease progression, cognitive impairment, and excessive daytime sleepiness. Beta oscillations (8-35 Hz) in the basal ganglia thalamocortical (BGTC) network are thought to play a role in the development of cardinal motor signs of PD. The role cortical beta oscillations play in SWS dysfunction in the early stage of parkinsonism is not understood, however. To address this question, we used a within-subject design in a nonhuman primate (NHP) model of PD to record local field potentials from the primary motor cortex (MC) during sleep across normal and mild parkinsonian states. The MC is a critical node in the BGTC network, exhibits pathological oscillations with depletion in dopamine tone, and displays high amplitude slow oscillations during SWS. The MC is therefore an appropriate recording site to understand the neurophysiology of SWS dysfunction in parkinsonism. We observed a reduction in SWS quantity (p = 0.027) in the parkinsonian state compared to normal. The cortical delta (0.5-3 Hz) power was reduced (p = 0.038) whereas beta (8-35 Hz) power was elevated (p = 0.001) during SWS in the parkinsonian state compared to normal. Furthermore, SWS quantity positively correlated with delta power (r = 0.43, p = 0.037) and negatively correlated with beta power (r = -0.65, p < 0.001). Our findings support excessive beta oscillations as a mechanism for SWS dysfunction in mild parkinsonism and could inform the development of neuromodulation therapies for enhancing SWS in people with PD.

DiMANI: diffusion MRI for anatomical nuclei imaging-Application for the direct visualization of thalamic subnuclei.

The thalamus is a centrally located and heterogeneous brain structure that plays a critical role in various sensory, motor, and cognitive processes. However, visualizing the individual subnuclei of the thalamus using conventional MRI techniques is challenging. This difficulty has posed obstacles in targeting specific subnuclei for clinical interventions such as deep brain stimulation (DBS). In this paper, we present DiMANI, a novel method for directly visualizing the thalamic subnuclei using diffusion MRI (dMRI). The DiMANI contrast is computed by averaging, voxelwise, diffusion-weighted volumes enabling the direct distinction of thalamic subnuclei in individuals. We evaluated the reproducibility of DiMANI through multiple approaches. First, we utilized a unique dataset comprising 8 scans of a single participant collected over a 3-year period. Secondly, we quantitatively assessed manual segmentations of thalamic subnuclei for both intra-rater and inter-rater reliability. Thirdly, we qualitatively correlated DiMANI imaging data from several patients with Essential Tremor with the localization of implanted DBS electrodes and clinical observations. Lastly, we demonstrated that DiMANI can provide similar features at 3T and 7T MRI, using varying numbers of diffusion directions. Our results establish that DiMANI is a reproducible and clinically relevant method to directly visualize thalamic subnuclei. This has significant implications for the development of new DBS targets and the optimization of DBS therapy.

Paradoxical Modulation of STN ß-Band Activity with Medication Compared to Deep Brain Stimulation.

BACKGROUND: Excessive subthalamic nucleus (STN) ß-band (13-35 Hz) synchronized oscillations has garnered interest as a biomarker for characterizing disease state and developing adaptive stimulation systems for Parkinson's disease (PD). OBJECTIVES: To report on a patient with abnormal treatment-responsive modulation in the ß-band. METHODS: We examined STN local field potentials from an externalized deep brain stimulation (DBS) lead while assessing PD motor signs in four conditions (OFF, MEDS, DBS, and MEDS+DBS). RESULTS: The patient presented here exhibited a paradoxical increase in ß power following administration of levodopa and pramipexole (MEDS), but an attenuation in ß power during DBS and MEDS+DBS despite clinical improvement of 50% or greater under all three therapeutic conditions. CONCLUSIONS: This case highlights the need for further study on the role of ß oscillations in the pathophysiology of PD and the importance of personalized approaches to the development of ß or other biomarker-based DBS closed loop algorithms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Active contact proximity to the cerebellothalamic tract predicts initial therapeutic current requirement with DBS for ET: an application of 7T MRI.

Objective: To characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET). Background: DBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely. Methods: A retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores. Results: The therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58). Conclusion: Active DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

Excessive cortical beta oscillations are associated with slow-wave sleep dysfunction in mild parkinsonism.

Increasing evidence associates slow-wave sleep (SWS) dysfunction with neurodegeneration. Using a within-subject design in the nonhuman primate model of Parkinson's disease (PD), we found that reduced SWS quantity in mild parkinsonism was accompanied by elevated beta and reduced delta power during SWS in the motor cortex. Our findings support excessive beta oscillations as a mechanism for SWS dysfunction and will inform development of neuromodulation therapies for enhancing SWS in PD.

Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Introduction: Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. Methods: We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Results: Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Discussion: Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Effect of subthalamic coordinated reset deep brain stimulation on Parkinsonian gait.

Introduction: Coordinated Reset Deep Brain Stimulation (CR DBS) is a novel DBS approach for treating Parkinson's disease (PD) that uses lower levels of burst stimulation through multiple contacts of the DBS lead. Though CR DBS has been demonstrated to have sustained therapeutic effects on rigidity, tremor, bradykinesia, and akinesia following cessation of stimulation, i.e., carryover effect, its effect on Parkinsonian gait has not been well studied. Impaired gait is a disabling symptom of PD, often associated with a higher risk of falling and a reduced quality of life. The goal of this study was to explore the carryover effect of subthalamic CR DBS on Parkinsonian gait. Methods: Three non-human primates (NHPs) were rendered Parkinsonian and implanted with a DBS lead in the subthalamic nucleus (STN). For each animal, STN CR DBS was delivered for several hours per day across five consecutive days. A clinical rating scale modified for NHP use (mUPDRS) was administered every morning to monitor the carryover effect of CR DBS on rigidity, tremor, akinesia, and bradykinesia. Gait was assessed quantitatively before and after STN CR DBS. The stride length and swing speed were calculated and compared to the baseline, pre-stimulation condition. Results: In all three animals, carryover improvements in rigidity, bradykinesia, and akinesia were observed after CR DBS. Increased swing speed was observed in all the animals; however, improvement in stride length was only observed in NHP B2. In addition, STN CR DBS using two different burst frequencies was evaluated in NHP B2, and differential effects on the mUPDRS score and gait were observed. Discussion: Although preliminary, our results indicate that STN CR DBS can improve Parkinsonian gait together with other motor signs when stimulation parameters are properly selected. This study further supports the continued development of CR DBS as a novel therapy for PD and highlights the importance of parameter selection in its clinical application.

Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor.

BACKGROUND: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. METHODS: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. RESULTS: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). CONCLUSIONS: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.

Classification of electrically-evoked potentials in the parkinsonian subthalamic nucleus region.

Electrically evoked compound action potentials (ECAPs) generated in the subthalamic nucleus (STN) contain features that may be useful for titrating deep brain stimulation (DBS) therapy for Parkinson's disease. Delivering a strong therapeutic effect with DBS therapies, however, relies on selectively targeting neural pathways to avoid inducing side effects. In this study, we investigated the spatiotemporal features of ECAPs in and around the STN across parameter sweeps of stimulation current amplitude, pulse width, and electrode configuration, and used a linear classifier of ECAP responses to predict electrode location. Four non-human primates were implanted unilaterally with either a directional (n = 3) or non-directional (n = 1) DBS lead targeting the sensorimotor STN. ECAP responses were characterized by primary features (within 1.6 ms after a stimulus pulse) and secondary features (between 1.6 and 7.4 ms after a stimulus pulse). Using these features, a linear classifier was able to accurately differentiate electrodes within the STN versus dorsal to the STN in all four subjects. ECAP responses varied systematically with recording and stimulating electrode locations, which provides a subject-specific neuroanatomical basis for selecting electrode configurations in the treatment of Parkinson's disease with DBS therapy.

Parkinsonian daytime sleep-wake classification using deep brain stimulation lead recordings.

Excessive daytime sleepiness is a recognized non-motor symptom that adversely impacts the quality of life of people with Parkinson's disease (PD), yet effective treatment options remain limited. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for PD motor signs. Reliable daytime sleep-wake classification using local field potentials (LFPs) recorded from DBS leads implanted in STN can inform the development of closed-loop DBS approaches for prompt detection and disruption of sleep-related neural oscillations. We performed STN DBS lead recordings in three nonhuman primates rendered parkinsonian by administrating neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Reference sleep-wake states were determined on a second-by-second basis by video monitoring of eyes (eyes-open, wake and eyes-closed, sleep). The spectral power in delta (1-4 Hz), theta (4-8 Hz), low-beta (8-20 Hz), high-beta (20-35 Hz), gamma (35-90 Hz), and high-frequency (200-400 Hz) bands were extracted from each wake and sleep epochs for training (70% data) and testing (30% data) a support vector machines classifier for each subject independently. The spectral features yielded reasonable daytime sleep-wake classification (sensitivity: 90.68 ± 1.28; specificity: 88.16 ± 1.08; accuracy: 89.42 ± 0.68; positive predictive value; 88.70 ± 0.89, n = 3). Our findings support the plausibility of monitoring daytime sleep-wake states using DBS lead recordings. These results could have future clinical implications in informing the development of closed-loop DBS approaches for automatic detection and disruption of sleep-related neural oscillations in people with PD to promote wakefulness.

Spatiotemporal scaling changes in gait in a progressive model of Parkinson's disease.

Objective: Gait dysfunction is one of the most difficult motor signs to treat in patients with Parkinson's disease (PD). Understanding its pathophysiology and developing more effective therapies for parkinsonian gait dysfunction will require preclinical studies that can quantitatively and objectively assess the spatial and temporal features of gait. Design: We developed a novel system for measuring volitional, naturalistic gait patterns in non-human primates, and then applied the approach to characterize the progression of parkinsonian gait dysfunction across a sequence of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatments that allowed for intrasubject comparisons across mild, moderate, and severe stages. Results: Parkinsonian gait dysfunction was characterized across treatment levels by a slower stride speed, increased time in both the stance and swing phase of the stride cycle, and decreased cadence that progressively worsened with overall parkinsonian severity. In contrast, decreased stride length occurred most notably in the moderate to severe parkinsonian state. Conclusion: The results suggest that mild parkinsonism in the primate model of PD starts with temporal gait deficits, whereas spatial gait deficits manifest after reaching a more severe parkinsonian state overall. This study provides important context for preclinical studies in non-human primates studying the neurophysiology of and treatments for parkinsonian gait.

Lead location as a determinant of motor benefit in subthalamic nucleus deep brain stimulation for Parkinson's disease.

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) is regarded as an effective treatment for patients with advanced Parkinson's disease (PD). Clinical benefit, however, varies significantly across patients. Lead location has been hypothesized to play a critical role in determining motor outcome and may account for much of the observed variability reported among patients. Objective: To retrospectively evaluate the relationship of lead location to motor outcomes in patients who had been implanted previously at another center by employing a novel visualization technology that more precisely determines the location of the DBS lead and its contacts with respect to each patient's individually defined STN. Methods: Anatomical models were generated using novel imaging in 40 PD patients who had undergone bilateral STN DBS (80 electrodes) at another center. Patient-specific models of each STN were evaluated to determine DBS electrode contact locations with respect to anterior to posterior and medial to lateral regions of the individualized STNs and compared to the change in the contralateral hemi-body Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) motor score. Results: The greatest improvement in hemi-body motor function was found when active contacts were located within the posterolateral portion of the STN (71.5%). Motor benefit was 52 and 36% for central and anterior segments, respectively. Active contacts within the posterolateral portion also demonstrated the greatest reduction in levodopa dosage (77%). Conclusion: The degree of motor benefit was dependent on the location of the stimulating contact within the STN. Although other factors may play a role, we provide further evidence in support of the hypothesis that lead location is a critical factor in determining clinical outcomes in STN DBS.

Basal ganglia engagement during REM sleep movements in Parkinson's disease.

To elucidate the role of the basal ganglia during REM sleep movements in Parkinson's disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13-35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150-350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.

Controlling pallidal oscillations in real-time in Parkinson's disease using evoked interference deep brain stimulation (eiDBS): Proof of concept in the human.

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 13-35 Hz ("beta band") oscillatory dynamics in the manifestation of Parkinson's disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulses with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequency-specific (16-22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.