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Deep brain stimulation (DBS) surgery has been shown to dramatically improve the quality of life for patients with various motor dysfunctions, such as those afflicted with Parkinson's disease (PD), dystonia, and essential tremor (ET), by relieving motor symptoms associated with such pathologies. The success of DBS procedures is directly related to the proper placement of the electrodes, which requires the ability to accurately detect and identify relevant target structures within the subcortical basal ganglia region. In particular, accurate and reliable segmentation of the globus pallidus (GP) interna is of great interest for DBS surgery for PD and dystonia. In this study, we present a deep‐learning based neural network, which we term GP‐net, for the automatic segmentation of both the external and internal segments of the globus pallidus. High resolution 7 Tesla images from 101 subjects were used in this study; GP‐net is trained on a cohort of 58 subjects, containing patients with movement disorders as well as healthy control subjects. GP‐net performs 3D inference in a patient‐specific manner, alleviating the need for atlas‐based segmentation. GP‐net was extensively validated, both quantitatively and qualitatively over 43 test subjects including patients with movement disorders and healthy control and is shown to consistently produce improved segmentation results compared with state‐of‐the‐art atlas‐based segmentations. We also demonstrate a postoperative lead location assessment with respect to a segmented globus pallidus obtained by GP‐net., Deep brain stimulation (DBS) surgery has been shown to improve the quality of life for patients with various motor dysfunctions. The success of DBS is directly related to the proper placement of the electrodes, which requires accurate detection and identification of the relevant target structures. We present a deep‐learning based automatic, robust and accurate segmentation technique from 7 Tesla MRI acquisitions of the globus pallidus externa and interna for DBS surgery planning and postoperative electrode localization.

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.

The purpose of this work is to present a new method that can be used to estimate and mitigate RF induced currents on Deep Brain Stimulation (DBS) leads. Here, we demonstrate the effect of RF induced current mitigation on both RF heating and image quality for a variety of brain MRI sequences at 3 T. We acquired pre-scan images around a DBS lead (in-situ and ex-vivo) using conventional Gradient Echo Sequence (GRE) accelerated by parallel imaging (i.e GRAPPA) and quantified the magnitude and phase of RF induced current using the relative location of the B1+ null with respect to the lead position. We estimated the RF induced current on a DBS lead implanted in a gel phantom as well as in a cadaver head study for a variety of RF excitation patterns. We also measured the increase in tip temperature using fiber-optic probes for both phantom and cadaver studies. Using the magnitude and phase information of the current induced separately by two transmit channels of the body coil, we calculated an implant friendly (IF) excitation. Using the IF excitation, we acquired T1, T2 weighted Turbo Spin Echo (TSE), T2 weighted SPACE-Dark Fluid, and Ultra Short Echo Time (UTE) sequences around the lead. Our induced current estimation demonstrated linear relationship between the magnitude of the induced current and the square root SAR at the tip of the lead as measured in phantom studies. The “IF excitation pattern” calculated after the pre-scan mitigated RF artifacts and increased the image quality around the lead. In addition, it reduced the tip temperature significantly in both phantom and cadaver studies compared to a conventional quadrature excitation while keeping equivalent overall image quality. We present a relatively fast method that can be used to calculate implant friendly excitation, reducing image artifacts as well as the temperature around the DBS electrodes. When combined with a variety of MR sequences, the proposed method can improve the image quality and patient safety in clinical imaging scenarios.

Background Abnormal oscillatory neural activity in the beta-frequency band (13-35 Hz) is thought to play a role in Parkinson's disease (PD); however, increasing evidence points to alterations in high-frequency ranges (>100 Hz) also having pathophysiological relevance. Objectives Studies have found that power in subthalamic nucleus (STN) high-frequency oscillations is increased with dopaminergic medication and during voluntary movements, implicating these brain rhythms in normal basal ganglia function. The objective of this study was to investigate whether similar signaling occurs in the internal globus pallidus (GPi), a nucleus increasingly used as a target for deep brain stimulation (DBS) for PD. Methods Spontaneous and movement-related GPi field potentials were recorded from DBS leads in 5 externalized PD patients on and off dopaminergic medication, as well as from 3 rhesus monkeys before and after the induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. Results In the parkinsonian condition, we identified a prominent oscillatory peak centered at 200-300 Hz that increased during movement. In patients the magnitude of high-frequency oscillation modulation was negatively correlated with bradykinesia. In monkeys, high-frequency oscillations were mostly absent in the naive condition but emerged after the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. In patients, spontaneous high-frequency oscillations were significantly attenuated on-medication. Conclusions Our findings provide evidence in support of the hypothesis that exaggerated, movement-modulated high-frequency oscillations in the GPi are pathophysiological features of PD. These findings suggest that the functional role(s) of high-frequency oscillations may differ between the STN and GPi and motivate additional investigations into their relationship to motor control in normal and diseased states.

Deep brain stimulation (DBS) surgery has been shown to dramatically improve the quality of life for patients with various motor dysfunctions, such as those afflicted with Parkinson’s disease (PD), dystonia, and essential tremor (ET), by relieving motor symptoms associated with such pathologies. The success of DBS procedures is directly related to the proper placement of the electrodes, which requires the ability to accurately detect and identify relevant target structures within the subcortical basal ganglia region. In particular, accurate and reliable segmentation of the globus pallidus (GP) interna is of great interest for DBS surgery for PD and dystonia. In this work, we present a deep-learning based neural network, which we term GP-net, for the automatic segmentation of both the external and internal segments of the globus pallidus. High resolution 7 Tesla images from 101 subjects were used in this study; GP-net is trained on a cohort of 58 subjects, containing patients with movement disorders as well as healthy control subjects. GP-net performs 3D inference in a patient-specific manner, alleviating the need for atlas-based segmentation. GP-net was extensively validated, both quantitatively and qualitatively over 43 test subjects including patients with movement disorders and healthy control and is shown to consistently produce improved segmentation results compared with state-of-the-art atlas-based segmentations. We also demonstrate a post-operative lead location assessment with respect to a segmented globus pallidus obtained by GP-net.

Abnormal oscillatory neural activity in the basal ganglia is thought to play a pathophysiological role in Parkinson’s disease. Many patient studies have focused on beta frequency band (13-35 Hz) local field potential activity in the subthalamic nucleus, however increasing evidence points to alterations in neural oscillations in high frequency ranges (>100 Hz) having pathophysiological relevance. Prior studies have found that power in subthalamic high frequency oscillations (HFOs) is positively correlated with dopamine tone and increased during voluntary movements, implicating these brain rhythms in normal basal ganglia function. Contrary to this idea, in the current study we present a combination of clinical and preclinical data that support the hypothesis that HFOs in the internal globus pallidus (GPi) are a pathophysiological feature of Parkinson’s disease. Spontaneous and movement-related pallidal field potentials were recorded from deep brain stimulation (DBS) leads targeting the GPi in five externalized Parkinson’s disease patients, on and off dopaminergic medication. We identified a prominent oscillatory peak centered at 200-300 Hz in the off-medication rest recordings in all patients. High frequency power increased during movement, and the magnitude of modulation was negatively correlated with bradykinesia. Moreover, high frequency oscillations were significantly attenuated in the on-medication condition, suggesting they are a feature of the parkinsonian condition. To further confirm that GPi high frequency oscillations are characteristic of dopamine depletion, we also collected field potentials from DBS leads chronically implanted in three rhesus monkeys before and after the induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). High frequency oscillations and their modulation during movement were not prominent in the normal condition but emerged in the parkinsonian condition in the monkey model. These data provide the first evidence demonstrating that exaggerated, movement-modulated high frequency oscillations in the internal globus pallidus are a pathophysiological feature of Parkinson’s disease, and motivate additional investigations into the functional roles of high frequency neural oscillations across the basal ganglia-thalamocortical motor circuit and their relationship to motor control in normal and diseased states. These findings also provide rationale for further exploration of these signals for electrophysiological biomarker-based device programming and stimulation strategies in patients receiving deep brain stimulation therapy.

The success of deep brain stimulation (DBS) surgeries for the treatment of movement disorders relies on the accurate placement of an electrode within the motor portion of subcortical brain targets. However, the high number of electrodes requiring relocation indicates that today's methods do not ensure sufficient accuracy for all patients. Here, with the goal of aiding DBS targeting, we use 7 Tesla (T) MRI data to identify the functional territories and parcellate the globus pallidus pars interna (GPi) into motor, associative and limbic regions in individual subjects. 7 T MRI scans were performed in seventeen patients (prior to DBS surgery) and one healthy control. Tractography-based parcellation of each patient's GPi was performed. The cortex was divided into four masks representing motor, limbic, associative and “other” regions. Given that no direct connections between the GPi and the cortex have been shown to exist, the parcellation was carried out in two steps: 1) The thalamus was parcellated based on the cortical targets, 2) The GPi was parcellated using the thalamus parcels derived from step 1. Reproducibility, via repeated scans of a healthy subject, and validity of the findings, using different anatomical pathways for parcellation, were assessed. Lastly, post-operative imaging data was used to validate and determine the clinical relevance of the parcellation. The organization of the functional territories of the GPi observed in our individual patient population agrees with that previously reported in the literature: the motor territory was located posterolaterally, followed anteriorly by the associative region, and further antero-ventrally by the limbic territory. While this organizational pattern was observed across patients, there was considerable variability among patients. The organization of the functional territories of the GPi was remarkably reproducible in intra-subject scans. Furthermore, the organizational pattern was observed consistently by performing the parcellation of the GPi via the thalamus and via a different pathway, going through the striatum. Finally, the active therapeutic contact of the DBS electrode, identified with a combination of post-operative imaging and post-surgery DBS programming, overlapped with the high-probability “motor” region of the GPi as defined by imaging-based methods. The consistency, validity, and clinical relevance of our findings have the potential for improving DBS targeting, by increasing patient-specific knowledge of subregions of the GPi to be targeted or avoided, at the stage of surgical planning, and later, at the stage when stimulation is adjusted.

The goal of this study was to characterize the spectral characteristics and spatial topography of local field potential (LFP) activity in the internal segment of the globus pallidus (GPi) in patients with Parkinson's disease utilizing directional (segmented) deep brain stimulation (dDBS) leads. Data were collected from externalized dDBS leads of three patients with idiopathic Parkinson's disease after overnight withdrawal of parkinsonian medication at rest and during a cued reach-to-target task. Oscillatory activity across lead contacts/segments was examined in the context of lead locations and contact orientations determined using co-registered preoperative 7 Tesla (T) MRI and postoperative CT scans. Each of the three patients displayed a unique frequency spectrum of oscillatory activity in the pallidum, with prominent peaks ranging from 5 to 35 Hz, that modulated variably across subjects during volitional movement. Despite subject-specific spectral profiles, a consistent finding across patients was that oscillatory power was strongest and had the largest magnitude of modulation during movement in LFPs recorded from segments facing the postero-lateral “sensorimotor” region of GPi, whereas antero-medially-directed segmented contacts facing the internal capsule and/or anterior GPi, had relatively weaker LFP power and less modulation in the 5 to 35 Hz. In each subject, contact configurations chosen for clinically therapeutic stimulation (following data collection and blinded to physiology recordings), were in concordance with the contact pairs showing the largest amplitude of LFP oscillations in the 5–35 Hz range. Although limited to three subjects, these findings provide support for the hypothesis that the sensorimotor territory of the GPi corresponds to the site of maximal power of oscillatory activity in the 5 to 35 Hz and provides the greatest benefit in motor signs during stimulation in the GPi. Variability in oscillatory activity across patients is likely related to Parkinson's disease phenotype as well as small differences in recording location (i.e. lead location), highlighting the importance of lead location for optimizing stimulation efficacy. These data also provide compelling evidence for the use of LFP activity for the development of predictive stimulation models that may optimize patient benefits while reducing clinic time needed for programming.

BACKGROUND Cerebellar Purkinje cell axonal degeneration has been identified in horses with shivering but its relationship with abnormal hindlimb movement has not been elucidated. OBJECTIVES To characterise surface electromyographic (sEMG) hindlimb muscle activity in horses with shivering, correlate with clinical scores and examine horses for Purkinje axonal degeneration. STUDY DESIGN Descriptive controlled clinical study. METHODS The hindlimb of seven shivering and six control draught horses were clinically scored. Biceps femoris (BF), vastus lateralis (VL), tensor fasciae latae and extensor digitorum longus were recorded via sEMG during forward/backward walking and trotting. Integrated (iEMG) and peak EMG activity were compared between groups and correlated with clinical locomotor exam scores. Sections of the deep cerebellar nuclei (DCN) of six of the seven shivering horses were examined with calbindin immunohistochemistry. RESULTS In control horses, backward walking resembled forward walking (right hindlimb peak EMG: backward: 47.5 ± 21.9%, forward: 36.9 ± 15.7%) but displayed significantly higher amplitudes during trotting (76.1 ± 3.4%). However, in shivering horses, backward walking was significantly different from forward (backward: 88.5 ± 21.5%, forward: 49.2 ± 8.9%), and resembled activity during trotting (81.4 ± 4.8%). Specific to backward walking, mean sEMG amplitude fell outside two standard deviations of mean control sEMG for ≥25% of the stride in the BF for all seven and the VL for six of the seven shivering horses. Locomotor exam scores were correlated with peak EMG (r = 0.87) and iEMG (r = 0.87). Calbindin-positive spheroids were present in Purkinje axons in DCN of all shivering horses examined. MAIN LIMITATIONS The neuropathological examination focused specifically on the DCN and, therefore, we cannot fully exclude additional lesions that may have influenced abnormal sEMG findings in shivering horses. CONCLUSION Shivering is characterised by abnormally elevated muscle recruitment particularly in BF and VL muscles during backward walking and associated with selective Purkinje cell distal axonal degeneration.

Spasmodic dysphonia (SD) is an incurable focal dystonia of the larynx that impairs speech and communication. Vibro-tactile stimulation (VTS) alters afferent proprioceptive input to sensorimotor cortex that controls speech. This proof-of-concept study examined the effect of laryngeal VTS on speech quality and cortical activity in 13 SD participants who vocalized the vowel /a/ while receiving VTS for 29 minutes. In response to VTS, 9 participants (69%) exhibited a reduction of voice breaks and/or a meaningful increase in smoothed cepstral peak prominence, an acoustic measure of voice/speech quality. Symptom improvements persisted for 20 minutes past VTS. Application of VTS induced a significant suppression of theta band power over the left somatosensory-motor cortex and a significant rise of gamma rhythm over right somatosensory-motor cortex. Such suppression of theta oscillations is observed in patients with cervical dystonia who apply effective sensory tricks, suggesting that VTS in SD may activate a similar neurophysiological mechanism. Results of this feasibility study indicate that laryngeal VTS modulates neuronal synchronization over sensorimotor cortex, which can induce short-term improvements in voice quality. The effects of long-term VTS and its optimal dosage for treating voice symptoms in SD are still unknown and require further systematic study.

Proprioceptive function can become enhanced during motor learning. Yet, we have incomplete knowledge to what extent proprioceptive function is trainable and how a training that enhances proprioception may influence performance in untrained motor skills. To address this knowledge gap, healthy young adults (N = 14) trained in a visuomotor task that required learners to make increasingly accurate wrist movements. Using a robotic exoskeleton coupled with a virtual visual environment, participants tilted a virtual table through continuous wrist flexion/extension movements with the goal to position a rolling ball on table into a target. With learning progress, the level of difficulty increased by altering the virtual ball mechanics and the gain between joint movement and ball velocity. Before and after training, wrist position sense acuity and spatial movement accuracy in an untrained, discrete wrist-pointing task was assessed using the same robot. All participants showed evidence of proprioceptive-motor learning. Mean position sense discrimination threshold improved by 34%. Wrist movement accuracy in the untrained pointing task improved by 27% in 13/14 participants. This demonstrates that a short sensorimotor training challenging proprioception can a) effectively enhance proprioceptive acuity and b) improve the accuracy of untrained movement. These findings provide a scientific basis for applying such somatosensory-based motor training to clinical populations with known proprioceptive dysfunction to enhance sensorimotor performance.

Objective The effectiveness of deep brain stimulation (DBS) therapy strongly depends on precise surgical targeting of intracranial leads and on clinical optimization of stimulation settings. Recent advances in surgical targeting, multi-electrode designs, and multi-channel independent current-controlled stimulation are poised to enable finer control in modulating pathways within the brain. However, the large stimulation parameter space enabled by these technologies also poses significant challenges for efficiently identifying the most therapeutic DBS setting for a given patient. Here, we present a computational approach for programming directional DBS leads that is based on a non-convex optimization framework for neural pathway targeting. Approach The algorithm integrates patient-specific pre-operative 7 T MR imaging, post-operative CT scans, and multi-objective particle swarm optimization (MOPSO) methods using dominance based-criteria and incorporating multiple neural pathways simultaneously. The algorithm was evaluated on eight patient-specific models of subthalamic nucleus (STN) DBS to identify electrode configurations and stimulation amplitudes to optimally activate or avoid six clinically relevant pathways: motor territory of STN, non-motor territory of STN, internal capsule, superior cerebellar peduncle, thalamic fasciculus, and hyperdirect pathway. Main results Across the patient-specific models, single-electrode stimulation showed significant correlations across modeled pathways, particularly for motor and non-motor STN efferents. The MOPSO approach was able to identify multi-electrode configurations that achieved improved targeting of motor STN efferents and hyperdirect pathway afferents than that achieved by any single-electrode monopolar setting at equivalent power levels. Significance These results suggest that pathway targeting with patient-specific model-based optimization algorithms can efficiently identify non-trivial electrode configurations for enhancing activation of clinically relevant pathways. However, the results also indicate that inter-pathway correlations can limit selectivity for certain pathways even with directional DBS leads.

Summary Objectives Focal dystonia of the head and neck are associated with a loss of kinesthetic acuity at muscles distant from the dystonic sites. That is, while the motor deficits in focal dystonia are confined, the associated somatosensory deficits are generalized. This is the first systematic study to examine, if patients diagnosed with spasmodic dystonia (SD) show somatosensory impairments similar in scope to other forms of focal dystonia. Methods Proprioceptive acuity (ability to discriminate between two stimuli) for forearm position and motion sense was assessed in 14 spasmodic dystonia subjects and 28 age-matched controls using a passive motion apparatus. Psychophysical thresholds, uncertainty area (UA), and a proprioceptive acuity index (AI) were computed based on the subjects' verbal responses. Results The main findings are as follows: first, the SD group showed significantly elevated thresholds and UAs for forearm position sense compared with the control group. Second, 9 of 14 dystonia subjects (64%) exhibited an AI for position sense above the control group maximum. Three SD subjects had a motion sense AI above the control group maximum. Conclusions The results indicate that impaired limb proprioception is a common feature of SD. Like other forms of focal dystonia, spasmodic dystonia does affect the somatosensation of nondystonic muscle systems. That is, SD is associated with a generalized somatosensory deficit.

Objective: Numerous reports advocate that training of the proprioceptive sense is a viable behavioral therapy for improving impaired motor function. However, there is little agreement of what constitutes proprioceptive training and how effective it is. We therefore conducted a comprehensive, systematic review of the available literature in order to provide clarity to the notion of training the proprioceptive system. Methods: Four major scientific databases were searched. The following criteria were subsequently applied: (1) A quantified pre- and post-treatment measure of proprioceptive function. (2) An intervention or training program believed to influence or enhance proprioceptive function. (3) Contained at least one form of treatment or outcome measure that is indicative of somatosensory function. From a total of 1284 articles, 51 studies fulfilled all criteria and were selected for further review. Results: Overall, proprioceptive training resulted in an average improvement of 52% across all outcome measures. Applying muscle vibration above 30 Hz for longer durations (i.e., min vs. s) induced outcome improvements of up to 60%. Joint position and target reaching training consistently enhanced joint position sense (up to 109%) showing an average improvement of 48%. Cortical stroke was the most studied disease entity but no clear evidence indicated that proprioceptive training is differentially beneficial across the reported diseases. Conclusions: There is converging evidence that proprioceptive training can yield meaningful improvements in somatosensory and sensorimotor function. However, there is a clear need for further work. Those forms of training utilizing both passive and active movements with and without visual feedback tended to be most beneficial. There is also initial evidence suggesting that proprioceptive training induces cortical reorganization, reinforcing the notion that proprioceptive training is a viable method for improving sensorimotor function.

An established treatment for the motor symptoms of Parkinson's disease (PD) is deep brain stimulation (DBS) of the subthalamic nucleus (STN). Mounting evidence suggests that PD is also associated with somatosensory deficits, yet the effect of STN-DBS on somatosensory processing is largely unknown. This study investigated whether STN-DBS affects somatosensory processing, specifically the processing of tactile and proprioceptive cues, by systematically examining the accuracy of haptic perception of object size. (Haptic perception refers to one's ability to extract object features such as shape and size by active touch.) Without vision, 13 PD patients with implanted STN-DBS and 13 healthy controls haptically explored the heights of 2 successively presented 3-dimensional (3D) blocks using a precision grip. Participants verbally indicated which block was taller and then used their nonprobing hand to motorically match the perceived size of the comparison block. Patients were tested during ON and OFF stimulation, following a 12-hour medication washout period. First, when compared to controls, the PD group's haptic discrimination threshold during OFF stimulation was elevated by 192% and mean hand aperture error was increased by 105%. Second, DBS lowered the haptic discrimination threshold by 26% and aperture error decreased by 20%. Third, during DBS ON, probing with the motorically more affected hand decreased haptic precision compared to probing with the less affected hand. This study offers the first evidence that STN-DBS improves haptic precision, further indicating that somatosensory function is improved by STN-DBS. We conclude that DBS-related improvements are not explained by improvements in motor function alone, but rather by enhanced somatosensory processing.