Detection of evoked resonant neural activity in Parkinson's disease.

Objective. This study investigated a machine-learning approach to detect the presence of evoked resonant neural activity (ERNA) recorded during deep brain stimulation (DBS) of the subthalamic nucleus (STN) in people with Parkinson's disease.Approach. Seven binary classifiers were trained to distinguish ERNA from the background neural activity using eight different time-domain signal features.Main results. Nested cross-validation revealed a strong classification performance of 99.1% accuracy, with 99.6% specificity and 98.7% sensitivity to detect ERNA. Using a semi-simulated ERNA dataset, the results show that a signal-to-noise ratio of 15 dB is required to maintain a 90% classifier sensitivity. ERNA detection is feasible with an appropriate combination of signal processing, feature extraction and classifier. Future work should consider reducing the computational complexity for use in real-time applications.Significance. The presence of ERNA can be used to indicate the location of a DBS electrode array during implantation surgery. The confidence score of the detector could be useful for assisting clinicians to adjust the position of the DBS electrode array inside/outside the STN.

Evaluation of the PaCER Algorithm for Postoperative Subthalamic Nucleus Deep Brain Stimulation Electrode Localization.

Deep Brain Stimulation (DBS) is an established therapy for many movement disorders. DBS entails electrical stimulation of precise brain structures using permanently implanted electrodes. Following implantation, locating the electrodes relative to the target brain structure assists patient outcome optimization. Here we evaluated an open-source automatic algorithm (PaCER) to localize individual electrodes on Computed Tomography imaging (co-registered to Magnetic Resonance Imaging). In a dataset of 111 participants, we found a modified version of the algorithm matched manual-markups with median error less than 0.191 mm (interquartile range 0.698 mm). Given the error is less than the voxel resolution (1 mm3) of the images, we conclude that the automatic algorithm is suitable for DBS electrode localizations.Clinical Relevance- Automated DBS electrode localization identifies the closest electrode to the target brain structure; allowing the neurologist to direct electrical stimulation to maximize patient outcomes. Further, if none of the electrodes are deemed suitable, localization will guide re-implantation.

Anatomical targeting for electrode localization in subthalamic nucleus deep brain stimulation: A comparative study.

BACKGROUND AND PURPOSE: In deep brain stimulation (DBS), accurate electrode placement is essential for optimizing patient outcomes. Localizing electrodes enables insight into therapeutic outcomes and development of metrics for use in clinical trials. Methods of defining anatomical targets have been described with varying accuracy and objectivity. To assess variability in anatomical targeting, we compare four methods of defining an appropriate target for DBS of the subthalamic nucleus for Parkinson's disease. METHODS: The methods compared are direct visualization, red nucleus-based indirect targeting, mid-commissural point-based indirect targeting, and automated template-based targeting. This study assessed 226 hemispheres in 113 DBS recipients (39 females, 73 males, 62.2 ± 7.7 years). We utilized the electrode placement error (the Euclidean distance between the defined target and closest DBS electrode) as a metric for comparative analysis. Pairwise differences in electrode placement error across the four methods were compared using the Kruskal-Wallis H-test and Wilcoxon signed-rank tests. RESULTS: Interquartile ranges of the differences in electrode placement error spanned 1.18-1.56 mm. A Kruskal-Wallis H-test reported a statistically significant difference in the median of at least two groups (H(5) = 41.052, p < .001). Wilcoxon signed-rank tests reported statistically significant difference in two comparisons: direct visualization versus red nucleus-based indirect, and direct visualization versus automated template-based methods (T < 9215, p < .001). CONCLUSIONS: All methods were similarly discordant in their relative accuracy, despite having significant technical differences in their application. The differing protocols and technical aspects of each method, however, have the implication that one may be more practical depending on the clinical or research application at hand.

Paroxysmal fast activity is a biomarker of treatment response in deep brain stimulation for Lennox-Gastaut syndrome.

OBJECTIVE: Epilepsy treatment trials typically rely on seizure diaries to determine seizure frequency, but these are time-consuming and difficult to maintain accurately. Fast, reliable, and objective biomarkers of treatment response are needed, particularly in Lennox-Gastaut syndrome (LGS), where high seizure frequency and comorbid cognitive and behavioral issues are additional obstacles to accurate diary-keeping. Here, we measured generalized paroxysmal fast activity (GPFA), a key interictal electrographic feature of LGS, and correlated GPFA burden with seizure diaries during a thalamic deep brain stimulation (DBS) treatment trial (Electrical Stimulation of the Thalamus in Epilepsy of Lennox-Gastaut Phenotype [ESTEL]). METHODS: GPFA and electrographic seizure counts from intermittent, 24-h electroencephalograms (EEGs) were compared to 3-month diary-recorded seizure counts in 17 young adults with LGS (mean age ± SD = 24.9 ± 6.6) in the ESTEL study, a randomized clinical trial of DBS lasting 12 months (comprising a 3-month baseline and 9 months of postimplantation follow-up). RESULTS: Baseline median seizures measured by diaries numbered 2.6 (interquartile range [IQR] = 1.4-5) per day, compared to 284 (IQR = 120.5-360) electrographic seizures per day, confirming that diaries capture only a small fraction of seizure burden. Across all patient EEGs, the average number of GPFA discharges per hour of sleep was 138 (IQR =72-258). GPFA duration and frequency, quantified over 2-h windows of sleep EEG, were significantly associated with diary-recorded seizure counts over 3-month intervals (p < .001, η2 p  = .30-.48). For every GPFA discharge, there were 20-25 diary seizures witnessed over 3 months. There was high between-patient variability in the ratio between diary seizure burden and GPFA burden; however, within individual patients, the ratio was similar over time, such that the percentage change from pre-DBS baseline in seizure diaries strongly correlated with the percentage change in GPFA. SIGNIFICANCE: When seeking to optimize treatment in patients with LGS, monitoring changes in GPFA may allow rapid titration of treatment parameters, rather than waiting for feedback from seizure diaries.

Cognition, adaptive skills and epilepsy disability/severity in patients with Lennox-Gastaut syndrome undergoing deep brain stimulation for epilepsy in the ESTEL trial.

PURPOSE: We previously reported seizure and EEG outcomes of the ESTEL study (Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut phenotype). To assess potential cognitive and behavioral changes during chronic, duty-cycle stimulation of bilateral thalamic centromedian nucleus, we compared standardized cognitive and behavioral measurements, as well as caregiver assessments of disability/severity, before implantation and after 3-months stimulation. METHODS: Twenty patients with LGS (17-37 years;13 females) were studied; one participant was not randomized due to DBS device removal, with outcomes of 19 remaining participants reported here. Cognitive and behavioral measurements were performed at baseline (i.e., before DBS implantation), at the end of the blinded stimulation phase, and at study exit. Instruments measured cognition (NIH toolbox cognitive battery, NIHTB-CB), adaptive skills (ABAS-3), epilepsy severity (GASE) and disability (GAD), quality of life (QOLIE-31), and depression (PHQ-9). Changes in scores after 3-months of stimulation relative to baseline were explored using Wilcoxon matched-pairs signed rank tests. RESULTS: After 3-months of stimulation, caregiver-reported epilepsy severity (GASE) and disability (GAD) improved (p<0.05). No other instrument showed a significant change from baseline. Measurements that required direct participant involvement, rather than caregivers, was completed by only a subset of higher-functioning individuals (NIHTB-CB, n = 13; QOLIE-31, n = 3; and PHQ-9, n = 6). In addition to cognitive impairments, behavioral and physical limitations were common obstacles to instrument completion. Standardized scores were hindered by 'floor effects'; however, raw scores better reflected clinical impressions of participants' functioning and were more sensitive to caregiver-reported changes following treatment. CONCLUSION: DBS treatment is associated with reduced epilepsy severity and disability in young adults with LGS. Performing cognitive and behavioral outcome measurement in patients with cognitive impairment is challenging but possible and requires careful selection of instruments and modifications of score interpretation to avoid floor effects.

Can brain signals and anatomy refine contact choice for deep brain stimulation in Parkinson's disease?

INTRODUCTION: Selecting the ideal contact to apply subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease is time-consuming and reliant on clinical expertise. The aim of this cohort study was to assess whether neuronal signals (beta oscillations and evoked resonant neural activity (ERNA)), and the anatomical location of electrodes, can predict the contacts selected by long-term, expert-clinician programming of STN-DBS. METHODS: We evaluated 92 hemispheres of 47 patients with Parkinson's disease receiving chronic monopolar and bipolar STN-DBS. At each contact, beta oscillations and ERNA were recorded intraoperatively, and anatomical locations were assessed. How these factors, alone and in combination, predicted the contacts clinically selected for chronic deep brain stimulation at 6 months postoperatively was evaluated using a simple-ranking method and machine learning algorithms. RESULTS: The probability that each factor individually predicted the clinician-chosen contact was as follows: ERNA 80%, anatomy 67%, beta oscillations 50%. ERNA performed significantly better than anatomy and beta oscillations. Combining neuronal signal and anatomical data did not improve predictive performance. CONCLUSION: This work supports the development of probability-based algorithms using neuronal signals and anatomical data to assist programming of deep brain stimulation.

The Optimal Target and Connectivity for Deep Brain Stimulation in Lennox-Gastaut Syndrome.

OBJECTIVE: Deep brain stimulation (DBS) can reduce seizures in Lennox-Gastaut syndrome (LGS). However, little is known about the optimal target and whether efficacy depends on connectivity of the stimulation site. Using outcome data from the ESTEL trial, we aimed to determine the optimal target and connectivity for DBS in LGS. METHODS: A total of 20 patients underwent bilateral DBS of the thalamic centromedian nucleus (CM). Outcome was percentage seizure reduction from baseline after 3 months of DBS, defined using three measures (monthly seizure diaries, 24-hour scalp electroencephalography [EEG], and a novel diary-EEG composite). Probabilistic stimulation mapping identified thalamic locations associated with higher/lower efficacy. Two substitute diffusion MRI datasets (a normative dataset from healthy subjects and a "disease-matched" dataset from a separate group of LGS patients) were used to calculate structural connectivity between DBS sites and a map of areas known to express epileptic activity in LGS, derived from our previous EEG-fMRI research. RESULTS: Results were similar across the three outcome measures. Stimulation was most efficacious in the anterior and inferolateral "parvocellular" CM border, extending into the ventral lateral nucleus (posterior subdivision). There was a positive association between diary-EEG composite seizure reduction and connectivity to areas of a priori EEG-fMRI activation, including premotor and prefrontal cortex, putamen, and pontine brainstem. In contrast, outcomes were not associated with baseline clinical variables. INTERPRETATION: Efficacious CM-DBS for LGS is linked to stimulation of the parvocellular CM and the adjacent ventral lateral nucleus, and is associated with connectivity to, and thus likely modulation of, the "secondary epileptic network" underlying the shared electroclinical manifestations of LGS. ANN NEUROL 2022;92:61-74.

Towards guided and automated programming of subthalamic area stimulation in Parkinson's disease.

Selecting the ideal contact to apply subthalamic nucleus deep brain stimulation in Parkinson's disease can be an arduous process, with outcomes highly dependent on clinician expertise. This study aims to assess whether neuronal signals recorded intraoperatively in awake patients, and the anatomical location of contacts, can assist programming. In a cohort of 14 patients with Parkinson's disease, implanted with subthalamic nucleus deep brain stimulation, the four contacts on each lead in the 28 hemispheres were ranked according to proximity to a nominated ideal anatomical location and power of the following neuronal signals: evoked resonant neural activity, beta oscillations and high-frequency oscillations. We assessed how these rankings predicted, on each lead: (i) the motor benefit from deep brain stimulation applied through each contact and (ii) the 'ideal' contact to apply deep brain stimulation. The ranking of contacts according to each factor predicted motor benefit from subthalamic nucleus deep brain stimulation, as follows: evoked resonant neural activity; r 2 = 0.50, Akaike information criterion 1039.9, beta; r 2 = 0.50, Akaike information criterion 1041.6, high-frequency oscillations; r 2 = 0.44, Akaike information criterion 1057.2 and anatomy; r 2 = 0.49, Akaike information criterion 1048.0. Combining evoked resonant neural activity, beta and high-frequency oscillations ranking data yielded the strongest predictive model (r 2 = 0.61, Akaike information criterion 1021.5). The 'ideal' contact (yielding maximal benefit) was ranked first according to each factor in the following proportion of hemispheres; evoked resonant neural activity 18/28, beta 17/28, anatomy 16/28, high-frequency oscillations 7/28. Across hemispheres, the maximal available deep brain stimulation benefit did not differ from that yielded by contacts chosen by clinicians for chronic therapy or contacts ranked first according to evoked resonant neural activity. Evoked resonant neural activity, beta oscillations and anatomy similarly predicted how motor benefit from subthalamic nucleus deep brain stimulation varied across contacts on each lead. This could assist programming by providing a probability ranking of contacts akin to a 'monopolar survey'. However, these factors identified the 'ideal' contact in only a proportion of hemispheres. More advanced signal processing and anatomical techniques may be needed for the full automation of contact selection.

DBS of Thalamic Centromedian Nucleus for Lennox-Gastaut Syndrome (ESTEL Trial).

OBJECTIVE: Prior uncontrolled studies have reported seizure reductions following deep brain stimulation (DBS) in patients with Lennox-Gastaut syndrome (LGS), but evidence from randomized controlled studies is lacking. We aimed to formally assess the efficacy and safety of DBS to the centromedian thalamic nucleus (CM) for the treatment of LGS. METHODS: We conducted a prospective, double-blind, randomized study of continuous, cycling stimulation of CM-DBS, in patients with LGS. Following pre- and post-implantation periods, half received 3 months of stimulation (blinded phase), then all received 3 months of stimulation (unblinded phase). The primary outcome was the proportion of participants with ≥50% reduction in diary-recorded seizures in stimulated versus control participants, measured at the end of the blinded phase. A secondary outcome was the proportion of participants with a ≥50% reduction in electrographic seizures on 24-hour ambulatory electroencephalography (EEG) at the end of the blinded phase. RESULTS: Between November 2017 and December 2019, 20 young adults with LGS (17-37 years;13 women) underwent bilateral CM-DBS at a single center in Australia, with 19 randomized (treatment, n = 10 and control, n = 9). Fifty percent of the stimulation group achieved ≥50% seizure reduction, compared with 22% of controls (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 0.44-21.45, p = 0.25). For electrographic seizures, 59% of the stimulation group had ≥50% reduction at the end of the blinded phase, compared with none of the controls (OR= 23.25, 95% CI = 1.0-538.4, p = 0.05). Across all patients, median seizure reduction (baseline vs study exit) was 46.7% (interquartile range [IQR] = 28-67%) for diary-recorded seizures and 53.8% (IQR = 27-73%) for electrographic seizures. INTERPRETATION: CM-DBS in patients with LGS reduced electrographic rather than diary-recorded seizures, after 3 months of stimulation. Fifty percent of all participants had diary-recorded seizures reduced by half at the study exit, providing supporting evidence of the treatment effect. ANN NEUROL 2022;91:253-267.

Lesser-Known Aspects of Deep Brain Stimulation for Parkinson's Disease: Programming Sessions, Hardware Surgeries, Residential Care Admissions, and Deaths.

OBJECTIVE: The long-term treatment burden, duration of community living, and survival of patients with Parkinson's disease (PD) after deep brain stimulation (DBS) implantation are unclear. This study aims to determine the frequency of programming, repeat hardware surgeries (of the intracranial electrode, implantable pulse generator [IPG], and extension-cable), and the timings of residential care and death in patients with PD treated with DBS. MATERIALS AND METHODS: In this cross-sectional, population-based study, individual-level data were collected from the Australian government covering a 15-year period (2002-2016) on 1849 patients with PD followed from DBS implantation. RESULTS: The mean DBS implantation age was 62.6 years and mean follow-up 5.0 years. Mean annual programming rates were 6.9 in the first year and 2.8 in subsequent years. 51.4% of patients required repeat hardware surgery. 11.3% of patients had repeat intracranial electrode surgery (including an overall 1.1% of patients who were completely explanted). 47.6% of patients had repeat IPG/extension-cable surgery including for presumed battery depletion. 6.2% of patients had early repeat IPG/extension-cable surgery (within one year of any previous such surgery). Thirty-day postoperative mortality was 0.3% after initial DBS implantation and 0.6% after any repeat hardware surgery. 25.3% of patients were admitted into residential care and 17.4% died. The median interval to residential care and death was 10.2 years and 11.4 years, respectively. Age more than 65 years was associated with fewer repeat hardware surgeries for presumed complications (any repeat surgery of electrodes, extension-cables, and early IPG surgery) and greater rates of residential care admission and death. CONCLUSIONS: Data from a large cohort of patients with PD treated with DBS found that the median life span after surgery is ten years. Repeat hardware surgery, including of the intracranial electrodes, is common. These findings support development of technologies to reduce therapy burden such as enhanced surgical navigation, hardware miniaturization, and improved battery efficiency.

Electrically evoked and spontaneous neural activity in the subthalamic nucleus under general anesthesia.

OBJECTIVE: Deep brain stimulation (DBS) surgery is commonly performed with the patient awake to facilitate assessments of electrode positioning. However, awake neurosurgery can be a barrier to patients receiving DBS. Electrode implantation can be performed with the patient under general anesthesia (GA) using intraoperative imaging, although such techniques are not widely available. Electrophysiological features can also aid in the identification of target neural regions and provide functional evidence of electrode placement. Here we assess the presence and positional variation under GA of spontaneous beta and high-frequency oscillation (HFO) activity, and evoked resonant neural activity (ERNA), a novel evoked response localized to the subthalamic nucleus. METHODS: ERNA, beta, and HFO were intraoperatively recorded from DBS leads comprising four individual electrodes immediately after bilateral awake implantation into the subthalamic nucleus of 21 patients with Parkinson's disease (42 hemispheres) and after subsequent GA induction deep enough to perform pulse generator implantation. The main anesthetic agent was either propofol (10 patients) or sevoflurane (11 patients). RESULTS: GA reduced the amplitude of ERNA, beta, and HFO activity (p < 0.001); however, ERNA amplitudes remained large in comparison to spontaneous local field potentials. Notably, a moderately strong correlation between awake ERNA amplitude and electrode distance to an "ideal" therapeutic target within dorsal STN was preserved under GA (awake: ρ = -0.73, adjusted p value [padj] < 0.001; GA: ρ = -0.69, padj < 0.001). In contrast, correlations were diminished under GA for beta (awake: ρ = -0.45, padj < 0.001; GA: ρ = -0.13, padj = 0.12) and HFO (awake: ρ = -0.69, padj < 0.001; GA: ρ = -0.33, padj < 0.001). The largest ERNA occurred at the same electrode (awake vs GA) for 35/42 hemispheres (83.3%) and corresponded closely to the electrode selected by the clinician for chronic therapy at 12 months (awake ERNA 77.5%, GA ERNA 82.5%). The largest beta amplitude occurred at the same electrode (awake vs GA) for only 17/42 (40.5%) hemispheres and 21/42 (50%) for HFO. The electrode measuring the largest awake beta and HFO amplitudes corresponded to the electrode selected by the clinician for chronic therapy at 12 months in 60% and 70% of hemispheres, respectively. However, this correspondence diminished substantially under GA (beta 20%, HFO 35%). CONCLUSIONS: ERNA is a robust electrophysiological signal localized to the dorsal subthalamic nucleus subregion that is largely preserved under GA, indicating it could feasibly guide electrode implantation, either alone or in complementary use with existing methods.

How accurately are subthalamic nucleus electrodes implanted relative to the ideal stimulation location for Parkinson's disease?

INTRODUCTION: The efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on how closely electrodes are implanted relative to an individual's ideal stimulation location. Yet, previous studies have assessed how closely electrodes are implanted relative to the planned location, after homogenizing data to a reference. Thus here, we measured how accurately electrodes are implanted relative to an ideal, dorsal STN stimulation location, assessed on each individual's native imaging. This measure captures not only the technical error of stereotactic implantation but also constraints imposed by planning a suitable trajectory. METHODS: This cross-sectional study assessed 226 electrodes in 113 consecutive PD patients implanted with bilateral STN-DBS by experienced clinicians utilizing awake, microelectrode guided, surgery. The error (Euclidean distance) between the actual electrode trajectory versus a nominated ideal, dorsal STN stimulation location was determined in each hemisphere on native imaging and predictive factors sought. RESULTS: The median electrode location error was 1.62 mm (IQR = 1.23 mm). This error exceeded 3 mm in 28/226 electrodes (12.4%). Location error did not differ between hemispheres implanted first or second, suggesting brain shift was minimised. Location error did not differ between electrodes positioned with (48/226), or without, a preceding microelectrode trajectory shift (suggesting such shifts were beneficial). There was no relationship between location error and case order, arguing against a learning effect. DISCUSSION/CONCLUSION: The proximity of STN-DBS electrodes to a nominated ideal, dorsal STN, stimulation location is highly variable, even when implanted by experienced clinicians with brain shift minimized, and without evidence of a learning effect. Using this measure, we found that assessments on awake patients (microelectrode recordings and clinical examination) likely yielded beneficial intraoperative decisions to improve positioning. In many patients the error is likely to have reduced therapeutic efficacy. More accurate methods to implant STN-DBS electrodes relative to the ideal stimulation location are needed.

Cortex leads the thalamic centromedian nucleus in generalized epileptic discharges in Lennox-Gastaut syndrome.

OBJECTIVE: We aimed to assess the roles of the cortex and thalamus (centromedian nucleus [CM]) during epileptic activity in Lennox-Gastaut syndrome (LGS) patients undergoing deep brain stimulation (DBS) surgery as part of the ESTEL (Electrical Stimulation of the Thalamus for Epilepsy of Lennox-Gastaut Phenotype) trial. METHODS: Twelve LGS patients (mean age = 26.8 years) underwent bilateral CM-DBS implantation. Intraoperatively, simultaneous electroencephalogram (EEG) was recorded (range = 10-34 minutes) from scalp electrodes and bilateral thalamic DBS electrodes. Temporal onsets of epileptic discharges (generalized paroxysmal fast activity [GPFA] and slow spike-and-wave [SSW]) were manually marked on recordings from scalp (ie, "cortex") and thalamus (ie, CM-DBS electrodes). Phase transfer entropy (PTE) analysis quantified the degree of information transfer from cortex to thalamus within different frequency bands around GPFA events. RESULTS: GPFA was captured in eight of 12 patients (total event number across patients = 168, cumulative duration = 358 seconds). Eighty-six percent of GPFA events were seen in both scalp and thalamic recordings. In most events (83%), onset occurred first at scalp, with thalamic onset lagging by a median of 98 milliseconds (interquartile range = 78.5 milliseconds). Results for SSW were more variable and seen in 11 of 12 patients; 25.4% of discharges were noted in both scalp and thalamus. Of these, 74.5% occurred first at scalp, with a median lag of 75 milliseconds (interquartile range = 228 milliseconds). One to 0.5 seconds and 0.5-0 seconds before GPFA onset, PTE analysis showed significant energy transfer from scalp to thalamus in the delta (1-3 Hz) frequency band. For alpha (8-12 Hz) and beta (13-30 Hz) frequencies, PTE was greatest 1-0.5 seconds before GPFA onset. SIGNIFICANCE: Epileptic activity is detectable in CM of thalamus, confirming that this nucleus participates in the epileptic network of LGS. Temporal onset of GPFA mostly occurs earlier at the scalp than in the thalamus. This supports our prior EEG-functional magnetic resonance imaging results and provides further evidence for a cortically driven process underlying GPFA in LGS.

Proceedings of the Seventh Annual Deep Brain Stimulation Think Tank: Advances in Neurophysiology, Adaptive DBS, Virtual Reality, Neuroethics and Technology.

The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both "markers of progress" and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.

Targeting the centromedian thalamic nucleus for deep brain stimulation.

OBJECTIVES: Deep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) is an emerging treatment for multiple brain diseases, including the drug-resistant epilepsy Lennox-Gastaut syndrome (LGS). We aimed to improve neurosurgical targeting of the CM by: (1) developing a structural MRI approach for CM visualisation, (2) identifying the CM's neurophysiological characteristics using microelectrode recordings (MERs) and (3) mapping connectivity from CM-DBS sites using functional MRI (fMRI). METHODS: 19 patients with LGS (mean age=28 years) underwent presurgical 3T MRI using magnetisation-prepared 2 rapid acquisition gradient-echoes (MP2RAGE) and fMRI sequences; 16 patients proceeded to bilateral CM-DBS implantation and intraoperative thalamic MERs. CM visualisation was achieved by highlighting intrathalamic borders on MP2RAGE using Sobel edge detection. Mixed-effects analysis compared two MER features (spike firing rate and background noise) between ventrolateral, CM and parafasicular nuclei. Resting-state fMRI connectivity was assessed using implanted CM-DBS electrode positions as regions of interest. RESULTS: The CM appeared as a hyperintense region bordering the comparatively hypointense pulvinar, mediodorsal and parafasicular nuclei. At the group level, reduced spike firing and background noise distinguished CM from the ventrolateral nucleus; however, these trends were not found in 20%-25% of individual MER trajectories. Areas of fMRI connectivity included basal ganglia, brainstem, cerebellum, sensorimotor/premotor and limbic cortex. CONCLUSIONS: In the largest clinical trial of DBS undertaken in patients with LGS to date, we show that accurate targeting of the CM is achievable using 3T MP2RAGE MRI. Intraoperative MERs may provide additional localising features in some cases; however, their utility is limited by interpatient variability. Therapeutic effects of CM-DBS may be mediated via connectivity with brain networks that support diverse arousal, cognitive and sensorimotor processes.

Deep brain stimulation for Parkinson's disease modulates high-frequency evoked and spontaneous neural activity.

Deep brain stimulation is an established therapy for Parkinson's disease; however, its effectiveness is hindered by limited understanding of therapeutic mechanisms and the lack of a robust feedback signal for tailoring stimulation. We recently reported that subthalamic nucleus deep brain stimulation evokes a neural response resembling a decaying high-frequency (200-500 Hz) oscillation that typically has a duration of at least 10 ms and is localizable to the dorsal sub-region. As the morphology of this response suggests a propensity for the underlying neural circuitry to oscillate at a particular frequency, we have named it evoked resonant neural activity. Here, we determine whether this evoked activity is modulated by therapeutic stimulation - a critical attribute of a feedback signal. Furthermore, we investigated whether any related changes occurred in spontaneous local field potentials. Evoked and spontaneous neural activity was intraoperatively recorded from 19 subthalamic nuclei in patients with Parkinson's disease. Recordings were obtained before therapeutic stimulation and during 130 Hz stimulation at increasing amplitudes (0.67-3.38 mA), 'washout' of therapeutic effects, and non-therapeutic 20 Hz stimulation. Therapeutic efficacy was assessed using clinical bradykinesia and rigidity scores. The frequency and amplitude of evoked resonant neural activity varied with the level of 130 Hz stimulation (p < .001). This modulation coincided with improvement in bradykinesia and rigidity (p < .001), and correlated with spontaneous beta band suppression (p < .001). Evoked neural activity occupied a similar frequency band to spontaneous high-frequency oscillations (200-400 Hz), both of which decreased to around twice the 130 Hz stimulation rate. Non-therapeutic stimulation at 20 Hz evoked, but did not modulate, resonant activity. These results indicate that therapeutic deep brain stimulation alters the frequency of evoked and spontaneous oscillations recorded in the subthalamic nucleus that are likely generated by loops within the cortico-basal ganglia-thalamo-cortical network. Evoked resonant neural activity therefore has potential as a tool for providing insight into brain network function and has key attributes of a dynamic feedback signal for optimizing therapy.

An Instrumented Pull Test to Characterize Postural Responses.

Impairment of postural reflexes, termed postural instability, is a common and disabling deficit in Parkinson's disease. To assess postural reflexes, clinicians typically employ the pull test to grade corrective responses to a backward perturbation at the shoulders. However, the pull test is prone to issues with reliability and scaling (score/4). Here, we present an instrumented version of the pull test to more precisely quantify postural responses. Akin to the clinical test, pulls are manually administered except pull force is also recorded. Displacements of the trunk and feet are captured by a semi-portable motion tracking system. Raw data represent distance traveled (in millimeter units), making subsequent interpretation and analysis intuitive. The instrumented pull test also detects variabilities influencing pull test administration, such as pull force, thereby identifying and quantifying potential confounds that can be accounted for by statistical techniques. The instrumented pull test could have application in studies seeking to capture early abnormalities in postural responses, track postural instability over time, and detect responses to therapy.

Alternate Subthalamic Nucleus Deep Brain Stimulation Parameters to Manage Motor Symptoms of Parkinson's Disease: Systematic Review and Meta-analysis.

BACKGROUND: The use of alternate frequencies, amplitudes, and pulse widths to manage motor symptoms in Parkinson's disease (PD) patients with subthalamic nucleus deep brain stimulation (STN-DBS) is of clinical interest, but currently lacks systematic evidence. OBJECTIVE/HYPOTHESIS: Systematically review whether alternate STN-DBS settings influence the therapy's efficacy for managing PD motor symptoms. METHODS: Systematic searches identified studies that; involved bilateral STN-DBS PD patients; manipulated ≥ 1 STN-DBS parameter (e.g., amplitude); assessed ≥ 1 motor symptom (e.g., tremor); and contrasted the experimental and chronic stimulation settings. A Mantel-Haenszel random-effects meta-analysis compared the UPDRS-III sub-scores at low (60-Hz) and high frequencies ( ≥ 130 Hz). Inter-study heterogeneity was assessed with the Cohen's χ2 and I2 index, while the standard GRADE evidence assessment examined strength of evidence. RESULTS: Of the 21 included studies, 17 investigated the effect of alternate stimulation frequencies, five examined alternate stimulation amplitudes, and two studied changes in pulse width. Given the available data, meta-analyses were only possible for alternate stimulation frequencies. Analysis of the heterogeneity amongst the included studies indicated significant variability between studies and, on the basis of the GRADE framework, the pooled evidence from the meta-analysis studies was of very low quality due to the significant risks of bias. CONCLUSIONS: The meta-analysis reported a very low quality of evidence for the efficacy of low-frequency STN-DBS for managing PD motor symptoms. Furthermore, it highlighted that lower amplitudes lead to the re-emergence of motor symptoms and further research is needed to understand the potential benefits of alternate STN-DBS parameters for PD patients.

What is the therapeutic mechanism of pedunculopontine nucleus stimulation in Parkinson's disease?

Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) is an experimental treatment for Parkinson's disease (PD) which offers a fairly circumscribed benefit for gait freezing and perhaps balance impairment. The benefit on gait freezing is variable and typically incomplete, which may reflect that the clinical application is yet to be optimised or reflect a fundamental limitation of the therapeutic mechanism. Thus, a better understanding of the therapeutic mechanism of PPN DBS may guide the further development of this therapy. The available evidence supports that the PPN is underactive in PD due to a combination of both degeneration and excessive inhibition. Low frequency PPN DBS could enhance PPN network activity, perhaps via disinhibition. A clinical implication is that in some PD patients, the PPN may be too degenerate for PPN DBS to work. Reaction time studies report that PPN DBS mediates a very specific benefit on pre-programmed movement. This seems relevant to the pathophysiology of gait freezing, which can be argued to reflect impaired release of pre-programmed adjustments to locomotion. Thus, the benefit of PPN DBS on gait freezing could be akin to that mediated by external cues. Alpha band activity is a prominent finding in local field potential recordings from PPN electrodes in PD patients. Alpha band activity is implicated in the suppression of task irrelevant processes and thus the effective allocation of attention (processing resources). Attentional deficits are prominent in patients with PD and gait freezing and PPN alpha activity has been observed to drop out prior to gait freezing episodes and to increase with levodopa. This raises the hypothesis that PPN DBS could support or emulate PPN alpha activity and consequently enhance the allocation of attention. Although PPN DBS has not been convincingly shown to increase general alertness or attention, it remains possible that PPN DBS may enhance the allocation of processing resources within the motor system, or "motor attention". For example, this could facilitate the 'switching' of motor state between continuation of pattern generated locomotion towards the intervention of pre-programmed adjustments. However, if the downstream consequence of PPN DBS on movement is limited to a circumscribed unblocking of pre-programmed movement, then this may have a similarly circumscribed degree of benefit for gait. If this is the case, then it may be possible to identify patients who may benefit most from PPN DBS. For example, those in whom pre-programmed deficits are the major contributors to gait freezing.