Gait-related frequency modulation of beta oscillatory activity in the subthalamic nucleus of parkinsonian patients

BackgroundAbnormal beta band activity in the subthalamic nucleus (STN) is known to be exaggerated in patients with Parkinson’s disease, and the amplitude of such activity has been associated with akinetic rigid symptoms. New devices for deep brain stimulation (DBS) that operate by adapting the stimulation parameters generally rely on the detection of beta activity amplitude modulations in these patients. Movement-related frequency modulation of beta oscillatory activity has been poorly investigated, despite being an attractive variable for extracting information about basal ganglia activity.ObjectiveWe studied the STN oscillatory activity associated with locomotion and proposed a new approach to extract movement related information from beta band activity.MethodsWe recorded bilateral local field potential of the STN in eight parkinsonian patients implanted with DBS electrodes during upright quiet standing and unperturbed walking. Neurophysiological recordings were combined with kinematic measurements and individual molecular brain imaging studies. We then determined the information carried by the STN oscillatory activity about locomotion and we identified task-specific biomarkers.ResultsWe found a gait-related peak frequency modulation of the beta band of STN recordings of parkinsonian patients. This novel biomarker and the associated power modulations were highly informative to detect the walking state (with respect to standing) in each single patient.ConclusionFrequency modulation in the human STN represents a fundamental aspect of information processing of locomotion. Our information-driven approach could significantly enrich the spectrum of Parkinson’s neural markers, with input signals encoding ongoing tasks execution for an appropriate online tuning of DBS delivery.     

A review on microelectrode recording selection of features for machine learning in deep brain stimulation surgery for Parkinson’s disease

ObjectiveThis study seeks to systematically review the selection of features and algorithms for machine learning and automation in deep brain stimulation surgery (DBS) for Parkinson’s disease. This will assist in consolidating current knowledge and accuracy levels to allow greater understanding and research to be performed in automating this process, which could lead to improved clinical outcomes.MethodsA systematic literature review search was conducted for all studies that utilized machine learning and DBS in Parkinson’s disease.ResultsTen studies were identified from 2006 utilizing machine learning in DBS surgery for Parkinson’s disease. Different combinations of both spike independent and spike dependent features have been utilized with different machine learning algorithms to attempt to delineate the subthalamic nucleus (STN) and its surrounding structures.ConclusionThe state-of-the-art algorithms achieve good accuracy and error rates with relatively short computing time, however, the currently achievable accuracy is not sufficiently robust enough for clinical practice. Moreover, further research is required for identifying subterritories of the STN.SignificanceThis is a comprehensive summary of current machine learning algorithms that discriminate the STN and its adjacent structures for DBS surgery in Parkinson’s disease.     

Stimulation Region Within the Globus Pallidus Does Not Affect Verbal Fluency Performance

BackgroundSubthalamic (STN) and globus pallidus (GP) deep brain stimulation (DBS) have been previously shown to be efficacious in the treatment of selected Parkinson patients with medication resistant motor fluctuations and/or tremor. Deep brain stimulation of the STN has been implicated with more cognitive and mood side effects as compared to GP DBS; however, more studies are needed to better understand possible target differences. Previously, Mikos et al. [1] reported worsening of verbal fluency depending on the stimulation location within the STN region.Objective/hypothesisThe current study applied the methods used by Mikos et al. (2011) to a different sample of Parkinson patients who underwent GP DBS. Based on differences in the size and functional somatotopy between structures (GP 412 mm³ vs. STN 167 mm³), we hypothesized that there would be a less robust relationship between volume of tissue activated, fluency performance, and stimulation contact within the GP compared to what was reported in the STN.MethodsPatient-specific DBS models were created and the volume of tissue activated within the GP was calculated. These data were correlated with patients' verbal fluency performance at dorsal, optimal, and ventral stimulation contacts.ResultsIn contrast to STN findings, there was no significant relationship between stimulation location and fluency performance in patients who received GP DBS.Conclusion(s)These results suggest that fluency may be less sensitive to stimulation location in the globus pallidus and thus there may be more flexibility in terms of DBS programming with GP DBS patients.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Utilizing 7-Tesla Subthalamic Nucleus Connectivity in Deep Brain Stimulation for Parkinson Disease

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson disease (PD). Combining 7.0-Tesla (7T) T2- and diffusion-weighted imaging (DWI) sequences allows for selective segmenting of the motor part of the STN and, thus, for possible optimization of DBS.Materials and Methods7T T2 and DWI sequences were obtained, and probabilistic segmentation of motor, associative, and limbic STN segments was performed. Left- and right-sided motor outcome (Movement Disorders Society Unified Parkinson’s Disease Rating Scale) scores were used for evaluating the correspondence between the active electrode contacts in selectively segmented STN and the clinical DBS effect. The Bejjani line was reviewed for crossing of segments.ResultsA total of 50 STNs were segmented in 25 patients and proved highly feasible. Although the highest density of motor connections was situated in the dorsolateral STN for all patients, the exact partitioning of segments differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body Unified Parkinson’s Disease Rating Scale motor improvement was 80%; outside this segment, it was 52% (p < 0.01). The Bejjani line was situated in the motor segment for 32 STNs.ConclusionThe implementation of 7T T2 and DWI segmentation of the STN in DBS for PD is feasible and offers insight into the location of the motor segment. Segmentation-guided electrode placement is likely to further improve motor response in DBS for PD. However, commercially available DBS software for postprocessing imaging would greatly facilitate widespread implementation.     

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized.ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr).MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode.ResultsInhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003).InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.     

Deep Brain Stimulation and Levodopa Affect Gait Variability in Parkinson Disease Differently

BackgroundBoth dopaminergic medication and subthalamic nucleus (STN) deep brain stimulation (DBS) can improve the amplitude and speed of gait in Parkinson disease (PD), but relatively little is known about their comparative effects on gait variability. Gait irregularity has been linked to the degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN).ObjectivesThe STN and PPN have reciprocal connections, and we hypothesized that STN DBS might improve gait variability by modulating PPN function. Dopaminergic medication should not do this, and we therefore sought to compare the effects of medication and STN DBS on gait variability.Materials and MethodsWe studied 11 patients with STN DBS systems on and off with no alteration to their medication, and 15 patients with PD without DBS systems on and off medication. Participants walked for two minutes in each state, wearing six inertial measurement units. Variability has previously often been expressed in terms of SD or coefficient of variation over a testing session, but these measures conflate long-term variability (eg, gradual slowing, which is not necessarily pathological) with short-term variability (true irregularity). We used Poincaré analysis to separate the short- and long-term variability.ResultsDBS decreased short-term variability in lower limb gait parameters, whereas medication did not have this effect. In contrast, STN DBS had no effect on arm swing and trunk motion variability, whereas medication increased them, without obvious dyskinesia.ConclusionsOur results suggest that STN DBS acts through a nondopaminergic mechanism to reduce gait variability. We believe that the most likely explanation is the retrograde activation of cholinergic PPN projection neurons.     

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease

BackgroundParkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5–12 Hz) are important in cognition.MethodsWe tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients’ peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation.ResultsAcute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions.ConclusionHere, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.     

Combining Multimodal Biomarkers to Guide Deep Brain Stimulation Programming in Parkinson Disease

BackgroundDeep brain stimulation (DBS) programming of multicontact DBS leads relies on a very time-consuming manual screening procedure, and strategies to speed up this process are needed. Beta activity in subthalamic nucleus (STN) local field potentials (LFP) has been suggested as a promising marker to index optimal stimulation contacts in patients with Parkinson disease.ObjectiveIn this study, we investigate the advantage of algorithmic selection and combination of multiple resting and movement state features from STN LFPs and imaging markers to predict three relevant clinical DBS parameters (clinical efficacy, therapeutic window, side-effect threshold).Materials and MethodsSTN LFPs were recorded at rest and during voluntary movements from multicontact DBS leads in 27 hemispheres. Resting- and movement-state features from multiple frequency bands (alpha, low beta, high beta, gamma, fast gamma, high frequency oscillations [HFO]) were used to predict the clinical outcome parameters. Subanalyses included an anatomical stimulation sweet spot as an additional feature.ResultsBoth resting- and movement-state features contributed to the prediction, with resting (fast) gamma activity, resting/movement-modulated beta activity, and movement-modulated HFO being most predictive. With the proposed algorithm, the best stimulation contact for the three clinical outcome parameters can be identified with a probability of almost 90% after considering half of the DBS lead contacts, and it outperforms the use of beta activity as single marker. The combination of electrophysiological and imaging markers can further improve the prediction.ConclusionLFP-guided DBS programming based on algorithmic selection and combination of multiple electrophysiological and imaging markers can be an efficient approach to improve the clinical routine and outcome of DBS patients.     

Acute Changes in Mood Induced by Subthalamic Deep Brain Stimulation in Parkinson Disease Are Modulated by Psychiatric Diagnosis

BackgroundDeep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood.ObjectiveThe study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS.MethodsThirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal.ResultsSTN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS.ConclusionsPD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group.     

Subthalamo-pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia

Parkinson’s disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized oscillations in the basal ganglia contribute to the expression of parkinsonian motor symptoms. However, the mechanism that generates abnormal oscillations in a dopamine‐depleted state remains poorly understood. We addressed this question by examining basal ganglia neuronal activity in two 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐treated parkinsonian monkeys. We found that systemic administration of l ‐3,4‐dihydroxyphenylalanine (l ‐DOPA; dopamine precursor) decreased abnormal neuronal oscillations (8–15 Hz) in the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during the ON state when parkinsonian signs were alleviated and during l ‐DOPA‐induced dyskinesia. GPi oscillations and parkinsonian signs were suppressed by silencing of the STN with infusion of muscimol (GABA_A receptor agonist). Intrapallidal microinjection of a mixture of 3‐(2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid (CPP; N‐methyl‐d ‐aspartate receptor antagonist) and 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzo[f]quinoxaline‐7‐sulfonamide (NBQX; AMPA/kainate receptor antagonist) also decreased the oscillations in the GPi and the external segment of the globus pallidus (GPe). Neuronal oscillations in the STN were suppressed after intrasubthalamic microinjection of CPP/NBQX to block glutamatergic afferents of the STN. The STN oscillations were further reduced by muscimol inactivation of the GPe to block GABAergic inputs from the GPe. These results suggest that, in the dopamine‐depleted state, glutamatergic inputs to the STN and reciprocal GPe–STN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinson’s disease.     

Somatosensory evoked potentials (SEPs) recorded from deep brain stimulation (DBS) electrodes in the thalamus and subthalamic nucleus (STN).

OBJECTIVE: To examine the location of deep brain stimulation (DBS) electrode somatosensory evoked potentials (SEPs) and determine the generators of the median nerve SEPs recorded in thalamus and subthalamic nucleus (STN). METHODS: SEPs were recorded from contacts of DBS electrodes and microelectrodes in thalamus and STN to establish the latencies of N13, N18 and N20 in 24 patients (8 tremor, 4 chronic pain, 12 Parkinson disease) undergoing chronic DBS. RESULTS: A large SEP with a mean latency of 17.9+/-1.7 ms was recorded from thalamic contacts. Phase reversal occurred at the horizontal level of the anterior commissure-posterior commissure line. Smaller potentials with similar latency but no reversal could be recorded from STN electrodes. CONCLUSIONS: We propose that the thalamic SEP is generated by excitatory post-synaptic potentials in sensory relay neurons in nucleus ventrocaudalis. A small potential in STN at a similar latency, may be due to volume conduction from thalamus. Intraoperative and postoperative SEP recordings from DBS electrodes could be used to determine the optimal position of the contacts relative to the sensory pathways and the choice of contacts for chronic stimulation.     

Stability and Effect of Parkinsonian State on Deep Brain Stimulation Cortical Evoked Potentials

ObjectivesTo characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming.Materials and MethodsSerial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naïve followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement.ResultsIn the naïve state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45–0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands.ConclusionsOur findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming.     

Subthalamic and pallidal oscillatory activity in patients with Neurodegeneration with Brain Iron Accumulation type I (NBIA-I)

ObjectivesNeurodegeneration with Brain Iron Accumulation type I (NBIA-I) is a rare hereditary neurodegenerative disorder with pallidal degeneration leading to disabling generalized dystonia and parkinsonism. Pallidal or subthalamic deep brain stimulation can partially alleviate motor symptoms. Disease-specific patterns of abnormally enhanced oscillatory neuronal activity recorded from the basal ganglia have been described in patients with movement disorders undergoing deep brain stimulation (DBS). Here we studied oscillatory activity recorded from the internal globus pallidus (GPi) and the subthalamic nucleus (STN) to characterize neuronal activity patterns in NBIA-I.MethodsWe recorded local field potentials (LFP) from DBS electrodes in 6 juvenile patients with NBIA-I who underwent functional neurosurgery. Four patients were implanted in the STN and two patients in the GPi. Recordings were performed during wakeful rest. An FFT-based approach was used to analyze the power spectrum in the target area.ResultsIn all patients we found distinct peaks in the low frequency (7–12 Hz) and in 5 out 6 also in the beta frequency range (15–30 Hz) with the largest beta peak in the patient that presented with the most prominent bradykinesia. No distinct peaks occurred in the gamma frequency range (35–100 Hz). The oscillatory pattern did not differ between STN and GPi.ConclusionsHere we show for the first time the oscillatory activity pattern in the STN and the GPi in juvenile patients with dystonia plus syndrome due to NBIA-I. The low frequency peak we found is in line with previous studies in patients with isolated idiopathic dystonia. In our cohort, the pallidal beta band activity may be related to more severe motor slowing in dystonia plus syndrome such as NBIA-I.SignificanceOur results further support the link between hyperkinetic motor symptoms such as dystonia and enhanced basal ganglia low frequency activity irrespective of the underlying etiology of dystonia.     

Subthalamic Nucleus Deep Brain Stimulation Induces Motor Network BOLD Activation: Use of a High Precision MRI Guided Stereotactic System for Nonhuman Primates

BackgroundFunctional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS).ObjectiveIdentify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP).MethodAn in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling.ResultsSTN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001).ConclusionOur results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.     

High functional connectivity of tremor related subthalamic neurons in Parkinson’s disease

ObjectiveTremor is a core symptom of Parkinson’s disease (PD). The subthalamic nucleus (STN) seems to be crucial for tremor pathophysiology considering that deep brain stimulation (DBS) of the STN leads to an effective reduction of Parkinsonian tremor. Here, we investigate the functional connectivity between STN neurons in patients with Parkinsonian tremor.MethodsSTN activity was analyzed in 7 patients with Parkinsonian rest tremor who underwent stereotactic surgery for DBS. Spike activity was registered in different depths of the STN using an array of five microelectrodes. Interneuronal coherence within the STN was analyzed.ResultsSignificant interneuronal coherence at the tremor frequency was detected in 78 out of 145 neurons. In contrast, interneuronal coherence in the beta band occurred only in 26 out of 145 neurons. Functional connectivity at the tremor frequency can be characterized by a slowly decaying exponential curve which describes coherence between STN neurons as a function of interneuronal distances between 0 and 4 mm.ConclusionsSpatially distributed synchronization at the tremor frequency seems to be a key feature of STN pathophysiology in patients with Parkinsonian tremor.SignificanceThe findings suggest a subthalamic tremor network which is widely extended and strongly coupled.     

Differential distribution of coherence between beta-band subthalamic oscillations and forearm muscles in Parkinson’s disease during isometric contraction

ObjectiveUnder rest condition, beta-band (13–30 Hz) activity in patients with Parkinson’s disease (PD) is prominent in the subthalamic nucleus (STN). However, the beta-band coupling between STN and muscle activity, its distribution and relation to motor symptoms remains unclear.MethodsUsing up to five electrodes, we recorded local field potentials (LFPs) above (zona incerta, ZI) and within the STN at different recording heights in 20 PD patients during isometric contraction. Simultaneously, we registered activity of the contralateral flexor and extensor muscle. We analysed LFP–EMG coherence to estimate coupling in the frequency domain.ResultsCoherence analysis showed beta–associated coupling in the ZI and STN with more significant LFP–EMG coherences in the STN. Coherence varied depending on the localisation of the LFP and muscles. We found significant difference between coherence of the extensor and the flexor muscle to the same LFP (p = 0.045).ConclusionsWe demonstrated that coherence between beta-band oscillations and forearm muscles are differentially distributed in the subthalamic region and between the forearm muscles in Parkinson’s disease during isometric contraction. However, the significant LFP–EMG coupling did not associate with motor deficits in PD patients.SignificanceThe differential distribution of beta-band activity in the STN highlights the importance of a topographically distinct therapeutic modulation.     

Correspondence of optimal stimulation and beta power varies regionally in STN DBS for Parkinson disease

IntroductionSubthalamic nucleus deep brain stimulation (STN DBS) for Parkinson disease (PD) normalizes neuronal hypersynchrony in the beta frequency range (13–30 Hz). The spatial correspondence of maximal beta power to the site of optimal stimulation along the DBS lead trajectory has been debated.MethodsWe determined the trajectory locations of the active contact, maximal beta power, and the dorsal border of the STN (DB-STN) in DBS patients. Beta power profiles were measured during intraoperative microelectrode recording (MER). Active contact locations were assigned during blinded, postoperative DBS programming. The DB-STN was identified both electrophysiologically during MER and anatomically on MRI. After grouping DBS trajectories into quadrants relative to the anatomic STN midpoint, we examined regional variations in the relative trajectory locations of the three entities.ResultsSTN DBS significantly improved motor performance for all 13 DBS patients, with active contacts at the DB-STN. Along trajectories passing posterior-medial to the STN midpoint, maximal beta power co-localized with active contacts at the DB-STN (difference Δ = 0.4 ± 1.6 mm, p = 0.57). By contrast, in posterior-lateral trajectories, maximal beta arose within the STN, ventral to active contacts (Δ = 1.9 ± 1.3 mm, p = 0.002). For trajectories anterior to the STN midpoint, maximal beta power co-localized with the DB-STN, while active contacts were ventral to peak beta power (p = 0.05).ConclusionOur findings indicate that co-localization of optimal stimulation and beta power varies by anatomical region in STN DBS for Parkinson disease.     

Subthalamic deep brain stimulation for the treatment of Parkinson disease

Background and purposeThe role of subthalamic nucleus deep brain stimulation (STN DBS) in the treatment of Parkinson disease (PD) is well established. The authors present a group of patients diagnosed with PD who were treated with STN DBS.Material and methodsBetween 2008 and 2009, 32 female and 34 male patients with PD were treated with STN DBS. Mean age at implantation was 57 ± 12 years. PD lasted from 6 to 21 years (mean 10 years). Patients were qualified for the surgery according to the CAPSIT-PD criteria. The STN was identified with direct and indirect methods. Macrostimulation and microrecording for STN identification were used in all cases. A unilateral STN DBS system was implanted in two cases and bilateral implantation was performed among rest of the group. Outcome was assessed six months after implantation.ResultsThe mean reduction of UPDRS III score among 51 patients who underwent follow-up was 45% (5-89%). Reduction of levodopa consumption varied from 15 to 100%. Infection forced the authors to remove the DBS system in one case four months after implantation. Skin erosion above the internal pulse generator was noted in four cases.ConclusionsCardinal symptoms of Parkinson's disease can be safely and effectively treated with STN DBS in selected group of patients.     

Biophysical characterization of local field potential recordings from directional deep brain stimulation electrodes

ObjectiveTwo major advances in clinical deep brain stimulation (DBS) technology have been the introduction of local field potential (LFP) recording capabilities, and the deployment of directional DBS electrodes. However, these two technologies are not operationally integrated within current clinical DBS devices. Therefore, we evaluated the theoretical advantages of using directional DBS electrodes for LFP recordings, with a focus on measuring beta-band activity in the subthalamic nucleus (STN).MethodsWe used a computational model of human STN neural activity to simulate LFP recordings. The model consisted of 235,280 anatomically and electrically detailed STN neurons surrounding the DBS electrode, which was previously optimized to mimic beta-band synchrony in the dorsolateral STN. We then used that model system to compare LFP recordings from cylindrical and directional DBS contacts, and evaluate how the selection of different contacts for bipolar recording affected the LFP measurements.ResultsThe model predicted two advantages of directional DBS electrodes over cylindrical DBS electrodes for STN LFP recording. First, recording from directional contacts could provide additional insight on the location of a synchronous volume of neurons within the STN. Second, directional contacts could detect a smaller volume of synchronous neurons than cylindrical contacts, which our simulations predicted to be a ~0.5 mm minimum radius.ConclusionsSTN LFP recordings from 8-contact directional DBS electrodes (28 possible bipolar pairs) can provide more information than 4-contact cylindrical DBS electrodes (6 possible bipolar pairs), but they also introduce additional complexity in analyzing the signals.SignificanceIntegration of directional electrodes with DBS systems that are capable of LFP recordings could improve localization of targeted volumes of synchronous neurons in PD patients.