Publications | MnDRIVE DBS Core

Below are a selection of publications from DBS Core-supported projects.

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

Background: Excessive subthalamic nucleus (STN) β-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 β-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 β power following administration of levodopa and pramipexole (MEDS), but an attenuation in β 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 β oscillations in the pathophysiology of PD and the importance of personalized approaches to the development of β or other biomarker-based DBS closed loop algorithms.

Written by: Meghan E Hill, Luke A Johnson, Jing Wang, David Escobar Sanabria, Rémi Patriat, Scott E Cooper, Michael C Park, Noam Harel, Jerrold L Vitek, Joshua E Aman

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

Objectives: To report on a patient with abnormal treatment-responsive modulation in the β-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).

Written by: Hill ME, Johnson LA, Wang J, Escobar Sanabria D, Patriat R, Cooper SE, Park MC, Harel N, Vitek JL, Aman JE.

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.

Written by: Zapata Amaya V, Aman JE, Johnson LA, Wang J, Patriat R, Hill ME, MacKinnon CD, Cooper SE, Darrow D, McGovern R, Harel N, Molnar GF, Park MC, Vitek JL, Escobar Sanabria

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.

Written by: Brinda A, Slopsema JP, Butler RD, Ikramuddin S, Beall T, Guo W, Chu C, Patriat R, Braun H, Goftari M, Palnitkar T, Aman J, Schrock L, Cooper SE, Matsumoto J, Vitek JL, Harel N, Johnson MD

Dopamine replacement therapy normalizes reactive step length to postural perturbations in Parkinson's disease.

Background: Postural instability is one of the most disabling motor symptoms of Parkinson's disease (PD) given its association with falls and loss of independence. Previous studies have assessed biomechanical measures of reactive stepping in response to perturbations, showing that individuals with PD exhibit inadequate postural responses to regain balance.

Research question: Does dopamine replacement therapy normalize step length in response to balance perturbations?

Methods: In this study, we estimated reactive step length, to a postural perturbation, retrospectively from a dataset of frontal plane video using 2D motion tracking and direct linear transform methods. We compared two perturbation methods: support surface translation and shoulder pull (the clinical standard) in 14 individuals with PD and 13 without PD (on and off medication), with and without partial body weight support (BWS). The primary outcome was the length of the first step taken to regain balance after the perturbation analyzed with mixed effects ANOVA, with post hoc analysis of anteroposterior (AP) and mediolateral (ML) components.

Results: PD OFF medication exhibited shorter reactive step length compared to PD ON and compared to control groups for the surface translation perturbations, but no significant difference was observed for the shoulder pull perturbations.

Significance: Dopamine replacement therapy affects step length in response to perturbation more robustly for surface translations than for a pull by the shoulders.

Written by: Herbers C, Schroeder J, Lu C, Geng H, Zhang R, Mehregan J, Malakowsky K, Erdman A, Johnson MD, Cooper SE.

Postural instability in Parkinson's disease assessed with clinical "pull test" and standardized postural perturbations: effect of medication and body weight support.

Objective: This experiment tested if balance performance differed between a standardized treadmill surface perturbation task and a clinical pull test and was affected by medication or the presence of body weight support in people with Parkinson's disease (PD).

Methods: Twenty-seven individuals were tested (14 PD in both ON- and OFF-medication states). Clinical pull test and rapid forward (backward fall) translations of the support surface were applied to induce postural reactions requiring at least 1 step to restore balance. The effects of pull type (clinical vs. treadmill), partial bodyweight support (0 vs 20% body weight) and group (control, PD ON-meds and PD OFF-meds) on reactive stepping as well as practice/learning effect were examined. The number of steps taken and the first step duration were entered in linear repeated-measures mixed-effect models separately.

Results: The effects of pull type, group, and bodyweight support were all significant in both metrics, as was ON- vs. OFF-medication. A significant interaction term (group x pull type) was found in the first step duration, showing that the group difference was greater in treadmill compared to the clinical pull test. A significant practice effect was also observed within and across testing sessions.

Conclusions: A standardized treadmill perturbation performed slightly better than the classical pull test in distinguishing between groups, and partial weight support did not substantially degrade the test's performance to detect the balance deficits in people with PD.

Written by: Lu C, Louie KH, Stutz AM, MacKinnon CD, Cooper SE.

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

Abstract: 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.

Written by: Verma AK, Acosta Lenis SF, Aman JE, Sanabria DE, Wang J, Pearson A, Hill M, Patriat R, Schrock LE, Cooper SE, Park MC, Harel N, Howell MJ, MacKinnon CD, Vitek JL, Johnson LA.

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

Abstract: 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.

Written by: Escobar Sanabria D, Aman JE, Zapata Amaya V, Johnson LA, Farooqi H, Wang J, Hill M, Patriat R, Sovell-Brown K, Molnar GF, Darrow D, McGovern R, Cooper SE, Harel N, MacKinnon CD, Park MC, Vitek JL

Modulation of Beta Oscillations in the Pallidum During Externally Cued Gait

Abstract: Freezing of gait (FOG) is a particularly debilitating symptom of Parkinson's disease (PD) and is often refractory to treatment. A striking feature of FOG is that external sensory cues can be used to overcome freezing and improve gait. Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) and globus pallidus (GP) show that beta-band power modulates with gait phase. In the STN, beta-band oscillations are modulated by external cues, but it is unknown if this relationship holds in the globus pallidus (GP). Here we report LFP data recorded from the left GP, using a Medtronic PC + S device, in a 68-year-old man with PD and FOG during treadmill walking. A "stepping stone" task was used during which stepping was cued using visual targets of constant color or targets that unpredictably changed color, requiring a step length adjustment. Gait performance was quantified using measures of treadmill ground reaction forces and center of pressure and body kinematics from video monitoring. Beta-band power (12-30 Hz) and number of freezing episodes were measured. Cues which unpredictably changed color improved FOG more than conventional cues and were associated with greater modulation of beta-band power in phase with gait. This preliminary finding suggests that cueing-induced improvement of FOG may relate to beta-band modulation.

Written by: Chiahao Lu, Sommer L Amundsen-Huffmaster, Kenneth H Louie, Matthew N Petrucci, Tara Palnitkar, Remi Patriat, Noam Harel, Michael C Park, Jerrold L Vitek, Colum D MacKinnon, Scott E Cooper

Overground versus treadmill walking in Parkinson's disease: Relationship between speed and spatiotemporal gait metrics.

Background: Treadmills provide a safe and convenient way to study the gait of people with Parkinson's disease (PD), but outcome measures derived from treadmill gait may differ from overground walking.

Objective: To investigate how the relationships between gait metrics and walking speed vary between overground and treadmill walking in people with PD and healthy controls.

Methods: We compared 29 healthy controls to 27 people with PD in the OFF-medication state. Subjects first walked overground on an instrumented gait walkway, then on an instrumented treadmill at 85%, 100% and 115% of their overground walking speed. Average stride length and cadence were computed for each subject in both overground and treadmill walking.

Results: Stride length and cadence both differed between overground and treadmill walking. Regressions of stride length and cadence on gait speed showed a log-log relationship for both overground and treadmill gait in both PD and control groups. The difference between the PD and control groups during overground gait was maintained for treadmill gait, not only when treadmill speed matched overground speed, but also with ± 15% variation in treadmill speed from that value.

Significance: These results show that the impact of PD on stride length and cadence and their relationship to gait speed is preserved in treadmill as compared to overground walking. We conclude that a treadmill protocol is suitable for laboratory use in studies of PD gait therapeutics.

Written by: Lu C, Louie KH, Twedell EL, Vitek JL, MacKinnon CD, Cooper SE

REM Sleep Without Atonia and Gait Impairment in People with Mild-to-Moderate Parkinson's Disease

Background: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson's disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD.

Objective: We hypothesized that gait disturbances in people with mild-to-moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA.

Methods: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n = 22) and normal REM sleep muscle tone (PD-RSWA-, n = 19). Gait characteristics were compared between groups and correlated to RSWA.

Results: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group.

Conclusion: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD.

Written by: Sommer L Amundsen-Huffmaster, Matthew N Petrucci, Maria E Linn-Evans, Jae Woo Chung, Michael J Howell, Aleksandar Videnovic, Paul J Tuite, Scott E Cooper, Colum D MacKinnon

Semi-automated approaches to optimize deep brain stimulation parameters in Parkinson's disease

Background: Deep brain stimulation (DBS) is a treatment option for Parkinson's disease patients when medication does not sufficiently manage their symptoms. DBS can be a highly effect therapy, but only after a time-consuming trial-and-error stimulation parameter adjustment process that is susceptible to clinician bias. This trial-and-error process will be further prolonged with the introduction of segmented electrodes that are now commercially available. New approaches to optimizing a patient's stimulation parameters, that can also handle the increasing complexity of new electrode and stimulator designs, is needed.

Methods: To improve DBS parameter programming, we explored two semi-automated optimization approaches: a Bayesian optimization (BayesOpt) algorithm to efficiently determine a patient's optimal stimulation parameter for minimizing rigidity, and a probit Gaussian process (pGP) to assess patient's preference. Quantified rigidity measurements were obtained using a robotic manipulandum in two participants over two visits. Rigidity was measured, in 5Hz increments, between 10-185Hz (total 30-36 frequencies) on the first visit and at eight BayesOpt algorithm-selected frequencies on the second visit. The participant was also asked their preference between the current and previous stimulation frequency. First, we compared the optimal frequency between visits with the participant's preferred frequency. Next, we evaluated the efficiency of the BayesOpt algorithm, comparing it to random and equal interval selection of frequency.

Results: The BayesOpt algorithm estimated the optimal frequency to be the highest tolerable frequency, matching the optimal frequency found during the first visit. However, the participants' pGP models indicate a preference at frequencies between 70-110 Hz. Here the stimulation frequency is lowest that achieves nearly maximal suppression of rigidity. BayesOpt was efficient, estimating the rigidity response curve to stimulation that was almost indistinguishable when compared to the longer brute force method.

Conclusions: These results provide preliminary evidence of the feasibility to use BayesOpt for determining the optimal frequency, while pGP patient's preferences include more difficult to measure outcomes. Both novel approaches can shorten DBS programming and can be expanded to include multiple symptoms and parameters.

Written by: Louie KH, Petrucci MN, Grado LL, Lu C, Tuite PJ, Lamperski AG, MacKinnon CD, Cooper SE, Netoff TI

Longitudinal analysis of local field potentials recorded from directional deep brain stimulation lead implants in the subthalamic nucleus

Objective: The electrode-tissue interface surrounding a deep brain stimulation (DBS) lead is known to be highly dynamic following implantation, which may have implications on the interpretation of intraoperatively recorded local field potentials (LFPs). We characterized beta-band LFP dynamics following implantation of a directional DBS lead in the sensorimotor subthalamic nucleus (STN), which is a primary target for treating Parkinson's disease.

Approach: Directional STN-DBS leads were implanted in four healthy, non-human primates. LFPs were recorded over two weeks and again 1-4 months after implantation. Impedance was measured for two weeks post-implant without stimulation to compare the reactive tissue response to changes in LFP oscillations. Beta-band (12-30 Hz) peak power was calculated from the LFP power spectra using both common average referencing (CAR) and intra-row bipolar referencing (IRBR).

Results: Resting-state LFPs in two of four subjects revealed a steady increase of beta power over the initial two weeks post-implant whereas the other two subjects showed variable changes over time. Beta power variance across days was significantly larger in the first two weeks compared to 1-4 months post-implant in all three long-term subjects. Further, spatial maps of beta power several hours after implantation did not correlate with those measured two weeks or 1-4 months post-implant. CAR and IRBR beta power correlated across short- and long-term time points. However, depending on the time period, subjects showed a significant bias towards larger beta power using one referencing scheme over the other. Lastly, electrode-tissue impedance increased over the two weeks post-implant but showed no significant correlation to beta power.

Significance: These results suggest that beta power in the STN may undergo significant changes following DBS lead implantation. DBS lead diameter and electrode recording configurations can affect the post-implant interpretation of oscillatory features. Such insights will be important for extrapolating results from intraoperative and externalized LFP recordings.

Written by: Brinda AK, Doyle AM, Blumenfeld M, Krieg J, Alisch JSR, Spencer C, Lecy E, Wilmerding LK, DeNicola A, Johnson LA, Vitek JL, Johnson MD

High-Frequency Oscillations in the Pallidum: A Pathophysiological Biomarker in Parkinson's Disease?

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.

Written by: Luke A Johnson, Joshua E Aman, Ying Yu, David Escobar Sanabria, Jing Wang, Meghan Hill, Rajiv Dharnipragada, Remi Patriat, Mark Fiecas, Laura Li, Lauren E Schrock, Scott E Cooper, Matthew D Johnson, Michael C Park, Noam Harel, Jerrold L Vitek

Comparison of forward and backward postural perturbations in mild-to-moderate Parkinson's disease

Background: Assessing postural stability in Parkinson's disease (PD) often relies on measuring the stepping response to an imposed postural perturbation. The standard clinical technique relies on a brisk backwards pull at the shoulders by the examiner and judgement by a trained rater. In research settings, various quantitative measures and perturbation directions have been tested, but it is unclear which metrics and perturbation direction differ most between people with PD and controls.

Objectives: (1) Use standardized forward vs. backward perturbations of a support surface to evaluate reactive stepping performance between PD and control participants. (2) Evaluate the utility of using principal components analysis to capture the dynamics of the reactive response and differences between groups.

Methods: Sixty-two individuals participated (40 mild-to-moderate PD, off medication). Standardized rapid translations of the support surface were applied, requiring at least one step, backward or forward, to restore balance. The number of steps taken and the projection of the first principal component (PC1) of the center of pressure (COP) time series were entered in linear repeated-measures mixed effect models.

Results: Forward falls required significantly fewer steps to recover than backward falls. PC1 captured more than half of the variance in the COP trajectory. Analysis of the PC1 projection revealed a significant interaction effect of group (PD vs. controls) by direction, such that there was a group difference in forward stepping, but not backward.

Significance: Forward reactive stepping in PD differed from controls more than backward-stepping. PC1 projections of the COP trajectory capture the dynamics of the postural response and differ between PD and controls.

Written by: Lu C, Amundsen-Huffmaster SL, Louie KH, Lowe R, Abulu R, McGovern RA, Vitek JL, MacKinnon CD, Cooper SE.

REM sleep without atonia is associated with increased rigidity in patients with mild to moderate Parkinson's disease

Objective: Increased muscle activity during rapid eye movement (REM) sleep (i.e. REM sleep without atonia) is common in people with Parkinson's disease (PD). This study tested the hypotheses that people with PD and REM sleep without atonia (RSWA) would present with more severe and symmetric rigidity compared to individuals with PD without RSWA and age-matched controls.

Methods: Sixty-one individuals participated in this study (41 PD, 20 controls). An overnight sleep study was used to classify participants with PD as having either elevated (PD-RSWA+) or normal muscle activity (PD-RSWA-) during REM sleep. Quantitative measures of rigidity were obtained using a robotic manipulandum that passively pronated and supinated the forearm.

Results: Quantitative measures of forearm rigidity were significantly higher in the PD-RSWA+ group compared to the control group. Rigidity was significantly more asymmetric between limbs in the PD-RSWA- group compared with controls, while there was no significant difference in symmetry between the control and PD-RSWA+ groups.

Conclusion: In people with mild to moderate PD, RSWA is associated with an increased and more symmetric presentation of upper limb rigidity.

Significance: Dysfunction of brainstem systems that control muscle tone during REM sleep may contribute to increased rigidity during wakefulness in people with PD.

Written by: Linn-Evans ME, Petrucci MN, Amundsen Huffmaster SL, Chung JW, Tuite PJ, Howell MJ, Videnovic A, MacKinnon CD

Directional deep brain stimulation leads reveal spatially distinct oscillatory activity in the globus pallidus internus of Parkinson's disease patients.

Abstract: 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.

Written by: Aman JE, Johnson LA, Sanabria DE, Wang J, Patriat R, Hill M, Marshall E, MacKinnon CD, Cooper SE, Schrock LE, Park MC, Harel N, Vitek JL

Avoiding Virtual Obstacles During Treadmill Gait in Parkinson's Disease.

Abstract: Falls often occur due to spontaneous loss of balance, but tripping over an obstacle during gait is also a frequent cause of falls (Sheldon, 1960; Stolze et al., 2004). Obstacle avoidance requires that appropriate modifications of the ongoing cyclical movement be initiated and completed in time. We evaluated the available response time to avoid a virtual obstacle in 26 Parkinson's disease (PD) patients (in the off-medication state) and 26 controls (18 elderly and 8 young), using a virtual obstacle avoidance task during visually cued treadmill walking. To maintain a stable baseline of stride length and visual attention, participants stepped on virtual "stepping stones" projected onto a treadmill belt. Treadmill speed and stepping stone spacing were matched to overground walking (speed and stride length) for each individual. Unpredictably, a stepping stone changed color, indicating that it was an obstacle. Participants were instructed to try to step short to avoid the obstacle. By using an obstacle that appeared at a precise instant, this task probed the time interval required for processing new information and implementing gait cycle modifications. Probability of successful avoidance of an obstacle was strongly associated with the time of obstacle appearance, with earlier-appearing obstacles being more easily avoided. Age was positively correlated (p < 0.001) with the time required to successfully avoid obstacles. Nonetheless, the PD group required significantly more time than controls (p = 0.001) to achieve equivalent obstacle-avoidance success rates after accounting for the effect of age. Slowing of gait adaptability could contribute to high fall risk in elderly and PD. Possible mechanisms may include disturbances in motor planning, movement execution, or disordered response inhibition.

Written by: Lu C, Twedell E, Elbasher R, McCabe M, MacKinnon CD, Cooper SE

Multi-objective particle swarm optimization for postoperative deep brain stimulation targeting of subthalamic nucleus pathways.

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.

Written by: Peña E, Zhang S, Patriat R, Aman JE, Vitek JL, Harel N, Johnson MD.

Implicitly-learned spatial attention is unimpaired in patients with Parkinson's disease.

Abstract: Extensive research has examined how current goals influence spatial attention. Yet the allocation of spatial attention is also guided by previous experience, which may induce consistent spatial preferences when a visual search target is frequently found in one region of space. Here, we examined the role of the dopaminergic system in acquiring and maintaining location probability learning. We tested Parkinson's patients and age-matched controls in a difficult visual search task in two sessions. In Session 1, unbeknownst to the participants, the target appeared most often in one quadrant in an early, training phase of the experiment. The target was randomly located in a later, testing phase. Both Parkinson's patients and controls acquired an attentional preference toward the high-probability quadrant during training that persisted in the testing phase. Learning yielded a large reduction in response time (345 ms) in Parkinson's patients, and this effect was highly significant. In Session 2, administered several days later, the target's high-probability quadrant changed. Both groups acquired a new preference for Session 2's high-probability quadrant, demonstrating reversal learning. These findings contrast with previously observed deficits in PD in acquiring probabilistic learning and contextual cueing. This result suggests that not all habit-like behaviors depend on the basal ganglia and the dopaminergic system. Instead, preservation of location probability learning may compensate for other types of attentional deficits in PD.

Written by: Sisk CA, Twedell EL, Koutstaal W, Cooper SE, Jiang YV

Individualized tractography-based parcellation of the globus pallidus pars interna using 7T MRI in movement disorder patients prior to DBS surgery.

Abstract: 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.

Written by: Patriat R, Cooper SE, Duchin Y, Niederer J, Lenglet C, Aman J, Park MC, Vitek JL, Harel N