Local field potentials of subthalamic nucleus contain electrophysiological footprints of motor subtypes of Parkinson's disease.

Although motor subtypes of Parkinson's disease (PD), such as tremor dominant (TD) and postural instability and gait difficulty (PIGD), have been defined based on symptoms since the mid-1990s, no underlying neural correlates of these clinical subtypes have yet been identified. Very limited data exist regarding the electrophysiological abnormalities within the subthalamic nucleus (STN) that likely accompany the symptom severity or the phenotype of PD. Here, we show that activity in subbands of local field potentials (LFPs) recorded with multiple microelectrodes from subterritories of STN provide distinguishing neurophysiological information about the motor subtypes of PD. We studied 24 patients with PD and found distinct patterns between TD (n = 13) and PIGD (n = 11) groups in high-frequency oscillations (HFOs) and their nonlinear interactions with beta band in the superior and inferior regions of the STN. Particularly, in the superior region of STN, the power of the slow HFO (sHFO) (200-260 Hz) and the coupling of its amplitude with beta-band phase were significantly stronger in the TD group. The inferior region of STN exhibited fast HFOs (fHFOs) (260-450 Hz), which have a significantly higher center frequency in the PIGD group. The cross-frequency coupling between fHFOs and beta band in the inferior region of STN was significantly stronger in the PIGD group. Our results indicate that the spatiospectral dynamics of STN-LFPs can be used as an objective method to distinguish these two motor subtypes of PD. These observations might lead to the development of sensing and stimulation strategies targeting the subterritories of STN for the personalization of deep-brain stimulation (DBS).

Distinct subthalamic coupling in the ON state describes motor performance in Parkinson's disease.

OBJECTIVE: Cross-frequency coupling has been reported in the STN of patients with PD, but its significance and functional role are still not well understood. This study investigates pharmacological modulations of subthalamic oscillations and their nonlinear cross-frequency interactions across three consecutive cycles over unique 24-hour-long recordings. BACKGROUND: Identifying neurobiomarkers for PD can drive the development of novel personalized treatments by providing objective assessment of impairment. In particular, distinct frequency bands in LFP recordings and their interaction with one another have been shown to modulate with dopaminergic medication and thus, proposed as such biomarkers. METHODS: We recorded local field potentials 3 weeks postoperatively from externalized leads in 9 patients and correlated the neural patterns with improvements in motor signs over three medication intake cycles. We used two modalities to assess symptoms in the unmedicated OFF and the l-dopa-induced motor ON state: a subsection of the UPDRS and a keyboard tapping score measuring bradykinesia. RESULTS: In the OFF state, the amplitude of high-frequency oscillations in the 200- to 300-Hz range was coupled with the phase of low-beta (13-22 Hz) in all patients. After transition to the ON state, three distinct coupling patterns were observed among subjects. Among these, patients showing ON coupling between high-beta (22-30 Hz) and high-frequency oscillations in the 300- to 400-Hz range had significantly greater improvement in bradykinesia, according to the keyboard scores. CONCLUSION: Observing diminished coupling in the ON state, previous studies have hypothesized that the sole existence of coupling in STN has an "impeding" effect on normal processes, and thus it was considered to be pathological. In contrast, our observation of ON state coupling at distinct frequencies associated with the improvements in motor features suggest that the underlying mechanism of coupling might have impeding or enhancing effects depending on the coupled frequencies. © 2019 International Parkinson and Movement Disorder Society.

Stereotyped high-frequency oscillations discriminate seizure onset zones and critical functional cortex in focal epilepsy.

High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non-epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001.

REM sleep behaviour disorder: prodromal and mechanistic insights for Parkinson's disease.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterised by complex motor enactment of dreams and is a potential prodromal marker of Parkinson's disease (PD). Of note, patients with PD observed during RBD episodes exhibit improved motor function, relative to baseline states during wake periods. Here, we review recent epidemiological and mechanistic findings supporting the prodromal value of RBD for PD, incorporating clinical and electrophysiological studies. Explanations for the improved motor function during RBD episodes are evaluated in light of recent publications. In addition, we present preliminary findings describing changes in the activity of the basal ganglia across the sleep-wake cycle that contribute to our understanding of RBD.

Mapping of the central sulcus using non-invasive ultra-high-density brain recordings.

Brain mapping is vital in understanding the brain's functional organization. Electroencephalography (EEG) is one of the most widely used brain mapping approaches, primarily because it is non-invasive, inexpensive, straightforward, and effective. Increasing the electrode density in EEG systems provides more neural information and can thereby enable more detailed and nuanced mapping procedures. Here, we show that the central sulcus can be clearly delineated using a novel ultra-high-density EEG system (uHD EEG) and somatosensory evoked potentials (SSEPs). This uHD EEG records from 256 channels with an inter-electrode distance of 8.6 mm and an electrode diameter of 5.9 mm. Reconstructed head models were generated from T1-weighted MRI scans, and electrode positions were co-registered to these models to create topographical plots of brain activity. EEG data were first analyzed with peak detection methods and then classified using unsupervised spectral clustering. Our topography plots of the spatial distribution from the SSEPs clearly delineate a division between channels above the somatosensory and motor cortex, thereby localizing the central sulcus. Individual EEG channels could be correctly classified as anterior or posterior to the central sulcus with 95.2% accuracy, which is comparable to accuracies from invasive intracranial recordings. Our findings demonstrate that uHD EEG can resolve the electrophysiological signatures of functional representation in the brain at a level previously only seen from surgically implanted electrodes. This novel approach could benefit numerous applications, including research, neurosurgical mapping, clinical monitoring, detection of conscious function, brain-computer interfacing (BCI), rehabilitation, and mental health.

Benchmarking signal quality and spatiotemporal distribution of interictal spikes in prolonged human iEEG recordings using CorTec wireless brain interchange.

Neuromodulation through implantable pulse generators (IPGs) represents an important treatment approach for neurological disorders. While the field has observed the success of state-of-the-art interventions, such as deep brain stimulation (DBS) or responsive neurostimulation (RNS), implantable systems face various technical challenges, including the restriction of recording from a limited number of brain sites, power management, and limited external access to the assessed neural data in a continuous fashion. To the best of our knowledge, for the first time in this study, we investigated the feasibility of recording human intracranial EEG (iEEG) using a benchtop version of the Brain Interchange (BIC) unit of CorTec, which is a portable, wireless, and externally powered implant with sensing and stimulation capabilities. We developed a MATLAB/SIMULINK-based rapid prototyping environment and a graphical user interface (GUI) to acquire and visualize the iEEG captured from all 32 channels of the BIC unit. We recorded prolonged iEEG (~ 24 h) from three human subjects with externalized depth leads using the BIC and commercially available clinical amplifiers simultaneously in the epilepsy monitoring unit (EMU). The iEEG signal quality of both streams was compared, and the results demonstrated a comparable power spectral density (PSD) in all the systems in the low-frequency band (< 80 Hz). However, notable differences were primarily observed above 100 Hz, where the clinical amplifiers were associated with lower noise floor (BIC-17 dB vs. clinical amplifiers < - 25 dB). We employed an established spike detector to assess and compare the spike rates in each iEEG stream. We observed over 90% conformity between the spikes rates and their spatial distribution captured with BIC and clinical systems. Additionally, we quantified the packet loss characteristic in the iEEG signal during the wireless data transfer and conducted a series of simulations to compare the performance of different interpolation methods for recovering the missing packets in signals at different frequency bands. We noted that simple linear interpolation has the potential to recover the signal and reduce the noise floor with modest packet loss levels reaching up to 10%. Overall, our results indicate that while tethered clinical amplifiers exhibited noticeably better noise floor above 80 Hz, epileptic spikes can still be detected successfully in the iEEG recorded with the externally powered wireless BIC unit opening the road for future closed-loop neuromodulation applications with continuous access to brain activity.

Intraoperative language mapping guided by real-time visualization of gamma band modulation electrocorticograms: Case report and proof of concept.

Background: Electrocorticography (ECoG) language mapping is often performed extraoperatively, frequently involves offline processing, and relationships with direct cortical stimulation (DCS) remain variable. We sought to determine the feasibility and preliminary utility of an intraoperative language mapping approach guided by real-time visualization of electrocorticograms. Methods: A patient with astrocytoma underwent awake craniotomy with intraoperative language mapping, utilizing a dual iPad stimulus presentation system coupled to a real-time neural signal processing platform capable of both ECoG recording and delivery of DCS. Gamma band modulations in response to 4 language tasks at each electrode were visualized in real-time. Next, DCS was conducted for each neighboring electrode pair during language tasks. Results: All language tasks resulted in strongest heat map activation at an electrode pair in the anterior to mid superior temporal gyrus. Consistent speech arrest during DCS was observed for Object and Action naming tasks at these same electrodes, indicating good correspondence with ECoG heat map recordings. This region corresponded well with posterior language representation via preoperative functional MRI. Conclusions: Intraoperative real-time visualization of language task-based ECoG gamma band modulation is feasible and may help identify targets for DCS. If validated, this may improve the efficiency and accuracy of intraoperative language mapping.

Construction of semi-supervised spatial projections to identify the source of beta- and high frequency oscillations in Parkinson's disease.

Traditional deep brain stimulation (DBS) treatment for Parkinson's disease (PD) targets the placement of DBS leads into subthalamic nucleus (STN). Extraction of neurobiomarkers from STN local field potential activity can be used for the optimization of DBS. Beta (12-30 Hz) and high frequency oscillations (200-450 Hz, HFO) of STN and their phase-amplitude coupling have been previously correlated with symptom severity in PD. The typical approach is to take bipolar derivations of electrode contacts in order to enhance recordings of local brain activity and suppress noise levels. This approach can often cancel the signals in correlated neighboring contacts and create ambiguity in which monopolar contact to select for the identification of the main source of the oscillatory signal. To improve local specificity and help identify the source of beta and HFO in terms of electrode contact, we propose a semi supervised blind-source separation method. This approach presents a novel perspective to investigate electrophysiology by projecting the recorded channels into a subspace of virtual channels. We show the contribution of each channel to the identified source and correlate the spatial information with imaging and postoperative programming parameters. We anticipate such a source identification strategy can be used in the future to investigate the distribution of beta and HFO on individual contacts of the DBS lead and can improve the interpretation of these signals.

Dynamic Visualization of Gyral and Sulcal Stereoelectroencephalographic Contacts in Humans.

Stereoelectroencephalography (SEEG) is a neurosurgical method to survey electrophysiological activity within the brain to treat disorders such as Epilepsy. In this stereotactic approach, leads are implanted through straight trajectories to survey both cortical and sub-cortical activity.Visualizing the recorded locations covering sulcal and gyral activity while staying true to the cortical architecture is challenging due to the folded, three-dimensional nature of the human cortex.To overcome this challenge, we developed a novel visualization concept, allowing investigators to dynamically morph between the subjects' cortical reconstruction and an inflated cortex representation. This inflated view, in which gyri and sulci are viewed on a smooth surface, allows better visualization of electrodes buried within the sulcus while staying true to the underlying cortical architecture.Clinical relevance- These visualization techniques might also help guide clinical decision-making when defining seizure onset zones or resections for patients undergoing SEEG monitoring for intractable epilepsy.

Long-latency gamma modulation after median nerve stimulation delineates the central sulcus and contrasts the states of consciousness.

OBJECTIVE: To evaluate the functional use of sub-band modulations in somatosensory evoked potentials (SSEPs) to discriminate between the primary somatosensory (S1) and motor (M1) areas and contrast the states of consciousness. METHODS: During routine intraoperative cortical mapping, SSEPs were recorded with electrocorticography (ECoG) grids from the sensorimotor cortex of eight patients in the anesthetized and awake states. We conducted a time-frequency analysis on the SSEP trace to extract the spectral modulations in each state and visualize their spatial topography. RESULTS: We observed late gamma modulation (60-250 Hz) in all subjects approximately 50 ms after stimulation onset, extending up to 250 ms in each state. The late gamma activity enhancement was predominant in S1 in the awake state, where it discriminated S1 from M1 at a higher accuracy (92 %) than in the anesthetized state (accuracy = 70 %). CONCLUSIONS: These results showed that sensorimotor mapping does not need to rely on only SSEP phase reversal. The long latency gamma modulation can serve as a biomarker for primary sensorimotor localization and monitor the level of consciousness in neurosurgical practice. SIGNIFICANCE: While the intraoperative assessment of SSEP phase reversal with ECoG is widely employed to delineate the central sulcus, the median nerve stimulation-induced spatio-spectral patterns can distinctly localize it and distinguish between conscious states.

The Entropy of Adaptively Segmented Beta Oscillations Predict Motor Improvement in Patients With Parkinson's Disease.

OBJECTIVE: Beta bursts of local fields potentials (LFPs) recorded from subthalamic nucleus (STN) have been recently proposed as a new temporal feature for patients with Parkinson's disease (PD). We introduce a new technique for the adaptive time-domain segmentation of STN-LFP recordings such that the constructed time segments are proportional to the duration of stationary beta activity. We investigated whether the spectral entropy of the adaptively captured beta oscillations can describe the improvement in motor signs following dopaminergic medication. METHODS: STN-LFP recordings from externalized chronic deep brain stimulation (DBS) leads were obtained in 9 PD patients. During this monitoring, each patient underwent 3 medication intake cycles where short acting agents (L-DOPA equivalent dose) were administered. We analyzed 2-minute resting state LFP data in each OFF and L-DOPA-induced ON medication states and constructed time domain segmentation of LFP signal in which the length segmentations are adapted to time-varying nature of the oscillatory activity. RESULTS: Adaptively constructed segments were noted to be significantly longer in OFF- and shorter in ON-state (p<0.001). Interestingly, in the OFF state, the peak frequency of long beta bursts (>375 ms) was in the low range (12-23 Hz) of the beta spectrum, whereas shorter beta bursts (<375 ms) were widespread in the 13-30 Hz band. Measured clinical improvement was highly correlated with the difference in the spectral entropy of beta bursts between OFF and ON states (r = -0.83, p<0.01). CONCLUSION AND SIGNIFICANCE: Our findings suggest that beta oscillations can be adaptively segmented without the use of a predetermined amplitude threshold, thereby allowing for objective quantification of burst itself. Compared to the shorter ones, longer oscillations with duration ≥ 375 ms were highly correlated with the clinical improvement, supporting a pathological role for them. Overall, these findings coupled with our adaptive approach could enable the quantitative use of temporal dynamics of beta activity in assessing severity of PD and improvements in motor features.

Real-Time Delineation of the Central Sulcus with the Spatial Profile of SSEPs Captured with High-Density Ecog Grid.

Cortical mapping is widely employed to define the sensorimotor area and delineate the central sulcus (CS) during awake craniotomies. The approach involves the gold standard somatosensory evoked potentials (SSEPs) recorded with electrocorticogram (ECoG) strip electrodes. However, the evoked response can be misconstrued from the manual peak interpretation due to the poor spatial resolution of the strip electrode or when the electrode does not precisely cover the desired cortical area. This can lead to unintentional damage to the eloquent cortex. We present a soft real-time computer based visualization system that uses recorded SSEPs with a subdural grid to aid in cortical mapping. The neural data during electrical stimulation of the median nerve at 0.6Hz are picked up with a bio-amplifier at 2.4kHz. The stimulation artifact recorded from the bipolar electromyogram (EMG) is used as the stimulation onset. The ECoG data are assessed online with MATLAB Simulink to process and visualize the SSEPs waveform. The visualization system is programmed to display the SSEPs peak activation as a heat map on a 2D grid and projected onto a screen, showcasing the nature of the cortical activities over the contact surface area. Since the grid occupies a large cortical surface, the heatmap is able to delineate the central sulcus. The map can be viewed at any time point along the SSEP trace without the need for peak interpretation. With the goal to provide additional information during cortical mapping and facilitate interpretation of ECoG grid data, we believe that this visualization system will aid in rapid definition of the sensorimotor area during surgical planning. Clinical Relevance- This real-time visualization system can be used to delineate the central sulcus in a short time during awake craniotomies.

Elimination of pseudo-HFOs in iEEG using sparse representation and Random Forest classifier.

High-Frequency Oscillation (HFO) is a promising biomarker of the epileptogenic zone. However, sharp artifacts might easily pass the conventional HFO detectors as real HFOs and reduce the seizure onset zone (SOZ) localization. We hypothesize that, unlike pseudo-HFOs, which originates from artifacts with sharp changes or arbitrary waveform characteristic, real HFOs could be represented by a limited number of oscillatory waveforms. Accordingly, to distinguish true ones from pseudo-HFOs, we established a new classification method based on sparse representation of candidate events that passed an initial detector with high sensitivity but low specificity. Specifically, using the Orthogonal Matching Pursuit (OMP) and a redundant Gabor dictionary, each event was represented sparsely in an iterative fashion. The approximation error was estimated over 30 iterations which were concatenated to form a 30-dimensional feature vector and fed to a random forest classifier. Based on the selected dictionary elements, our method can further classify HFOs into Ripples (R) and Fast Ripples (FR). In this scheme, two experts visually inspected 2075 events captured in iEEG recordings from 5 different subjects and labeled them as true-HFO or Pseudo-HFO. We reached 90.22% classification accuracy in labeled events and a 21.16% SOZ localization improvement compared to the conventional amplitude-threshold-based detector. Our sparse representation framework also classified the detected HFOs into R and FR subcategories. We reached 91.24% SOZ accuracy with the detected [Formula: see text] events. Clinical Relevance---This sparse representation framework establishes a new approach to distinguish real from pseudo-HFOs in prolonged iEEG recordings. It also provides reliable SOZ identification without the selection of artifact-free segments.

A sparse representation strategy to eliminate pseudo-HFO events from intracranial EEG for seizure onset zone localization.

Objective.High-frequency oscillations (HFOs) are considered a biomarker of the epileptogenic zone in intracranial EEG recordings. However, automated HFO detectors confound true oscillations with spurious events caused by the presence of artifacts.Approach.We hypothesized that, unlike pseudo-HFOs with sharp transients or arbitrary shapes, real HFOs have a signal characteristic that can be represented using a small number of oscillatory bases. Based on this hypothesis using a sparse representation framework, this study introduces a new classification approach to distinguish true HFOs from the pseudo-events that mislead seizure onset zone (SOZ) localization. Moreover, we further classified the HFOs into ripples and fast ripples by introducing an adaptive reconstruction scheme using sparse representation. By visualizing the raw waveforms and time-frequency representation of events recorded from 16 patients, three experts labeled 6400 candidate events that passed an initial amplitude-threshold-based HFO detector. We formed a redundant analytical multiscale dictionary built from smooth oscillatory Gabor atoms and represented each event with orthogonal matching pursuit by using a small number of dictionary elements. We used the approximation error and residual signal at each iteration to extract features that can distinguish the HFOs from any type of artifact regardless of their corresponding source. We validated our model on sixteen subjects with thirty minutes of continuous interictal intracranial EEG recording from each.Main results.We showed that the accuracy of SOZ detection after applying our method was significantly improved. In particular, we achieved a 96.65% classification accuracy in labeled events and a 17.57% improvement in SOZ detection on continuous data. Our sparse representation framework can also distinguish between ripples and fast ripples.Significance.We show that by using a sparse representation approach we can remove the pseudo-HFOs from the pool of events and improve the reliability of detected HFOs in large data sets and minimize manual artifact elimination.

Beta-band activity during motor planning reflects response uncertainty.

It has been known for many years that the power of beta-band oscillatory activity in motor-related brain regions decreases during the preparation and execution of voluntary movements. However, it is not clear yet whether the amplitude of this desynchronization is modulated by any parameter of the motor task. Here, we examined whether the degree of uncertainty about the upcoming movement direction modulated beta-band desynchronization during motor preparation. To this end, we recorded whole-head neuromagnetic signals while human subjects performed an instructed-delay reaching task with one, two, or three possible target directions. We found that the reduction of power of beta-band activity (16-28 Hz) during motor preparation was scaled relative to directional uncertainty. Furthermore, we show that the change of beta-band power correlates with the change of latency of response associated with response uncertainty. Finally, we show that the main source of beta-band desynchronization was located in the peri-Rolandic region. The results establish directional uncertainty as an important determinant of beta-band power during motor preparation and indicate that neural activity in the sensorimotor cortex during motor preparation covaries with directional uncertainty.

Electroceutically induced subthalamic high-frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson's disease.

Despite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by electrical stimulation of the subthalamic nucleus (STN) at therapeutic and non-therapeutic frequencies in Parkinson's disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130-180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20 Hz) stimulation, the HFOs were induced only with therapeutic frequencies, and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA. We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

Randomized, Double-Blind Assessment of LFP Versus SUA Guidance in STN-DBS Lead Implantation: A Pilot Study.

Background: The efficacy of deep brain stimulation (DBS) therapy in Parkinson's disease (PD) patients is highly dependent on the precise localization of the target structures such as subthalamic nucleus (STN). Most commonly, microelectrode single unit activity (SUA) recordings are performed to refine the target. This process is heavily experience based and can be technically challenging. Local field potentials (LFPs), representing the activity of a population of neurons, can be obtained from the same microelectrodes used for SUA recordings and allow flexible online processing with less computational complexity due to lower sampling rate requirements. Although LFPs have been shown to contain biomarkers capable of predicting patients' symptoms and differentiating various structures, their use in the localization of the STN in the clinical practice is not prevalent. Methods: Here we present, for the first time, a randomized and double-blinded pilot study with intraoperative online LFP processing in which we compare the clinical benefit from SUA- versus LFP-based implantation. Ten PD patients referred for bilateral STN-DBS were randomly implanted using either SUA or LFP guided targeting in each hemisphere. Although both SUA and LFP were recorded for each STN, the electrophysiologist was blinded to one at a time. Three months postoperatively, the patients were evaluated by a neurologist blinded to the intraoperative recordings to assess the performance of each modality. While SUA-based decisions relied on the visual and auditory inspection of the raw traces, LFP-based decisions were given through an online signal processing and machine learning pipeline. Results: We found a dramatic agreement between LFP- and SUA-based localization (16/20 STNs) providing adequate clinical improvement (51.8% decrease in 3-month contralateral motor assessment scores), with LFP-guided implantation resulting in greater average improvement in the discordant cases (74.9%, n = 3 STNs). The selected tracks were characterized by higher activity in beta (11-32 Hz) and high-frequency (200-400 Hz) bands (p < 0.01) of LFPs and stronger non-linear coupling between these bands (p < 0.05). Conclusion: Our pilot study shows equal or better clinical benefit with LFP-based targeting. Given the robustness of the electrode interface and lower computational cost, more centers can utilize LFP as a strategic feedback modality intraoperatively, in conjunction to the SUA-guided targeting.

Unsupervised clustering reveals spatially varying single neuronal firing patterns in the subthalamic nucleus of patients with Parkinson's disease.

INTRODUCTION: Subthalamic nucleus (STN) is an effective target for deep brain stimulation (DBS) to reduce the motor symptoms of Parkinson's disease (PD). It is important to identify firing patterns within the structure for a better understanding of the electro-pathophysiology of the disease. Using recently established metrics, our study aims to autonomously identify the discharge patterns of individual cells and examine their spatial distribution within the STN. METHODS: We recorded single unit activity (SUA) from 12 awake PD patients undergoing a standard clinical DBS surgery. Three extracted features from raw SUA (local variation, bursting index and prominence of peak) were used with k-means clustering to achieve the aforementioned unsupervised grouping of firing patterns. RESULTS: 279 neurons were isolated and four distinct firing patterns were identified across patients: tonic (11%), irregular (55%), periodic (9%) and non-periodic bursts (25%). The mean firing rates for irregular discharges were significantly lower (p < 0.05) than the rest. Tonic firings were significantly ventral (p < 0.05) while periodic (p < 0.05) and non-periodic (p < 0.01) bursts were dorsal. The percentage of periodically bursting neurons in dorsal region and entire STN were significantly correlated with off state UPDRS tremor scores (r = 0.51, p = 0.04) and improvement in bradykinesia and rigidity (r = 0.57, p = 0.02) respectively. CONCLUSION: Strengthening the application of unsupervised clustering for firing patterns of individual cells, this study shows a unique spatial affinity of tonic activity towards the ventral and bursting activity towards the dorsal region of STN in PD patients. This spatial preference, together with the correlation of clinical scores, can provide a clue towards understanding Parkinsonian symptom generation.

Subthalamic Single Cell and Oscillatory Neural Dynamics of a Dyskinetic Medicated Patient With Parkinson's Disease.

Single cell neuronal activity (SUA) and local field potentials (LFP) in the subthalamic nucleus (STN) of unmedicated Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery have been well-characterized during microelectrode recordings (MER). However, there is limited knowledge about the changes in the firing patterns and oscillations above and within the territories of STN after the intake of dopaminergic medication. Here, for the first time, we report the STN single cell and oscillatory neural dynamics in a medicated patient with idiopathic PD using intraoperative MER. We recorded LFP and SUA with microelectrodes at various depths during bilateral STN-DBS electrode implantation. We isolated 26 neurons in total and observed that tonic and irregular firing patterns of individual neurons predominated throughout the territories of STN. While burst-type firings have been well-characterized in the dorsal territories of STN in unmedicated patients, interestingly, this activity was not observed in our medicated subject. LFP recordings lacked the excessive beta (8-30 Hz) activity, characteristic of the unmedicated state and signal energy was mainly dominated by slow oscillations below 8 Hz. We observed sharp gamma oscillations between 70 and 90 Hz within and above the STN. Despite the presence of a broadband high frequency activity in 200-400 Hz range, no cross-frequency interaction in the form of phase-amplitude coupling was noted between low and high frequency oscillations of LFPs. While our results are in agreement with the previously reported LFP recordings from the DBS lead in medicated PD patients, the sharp gamma peak present throughout the depth recordings and the lack of bursting firings after levodopa intake have not been reported before. The lack of bursting in SUA, the lack of excessive beta activity and cross frequency coupling between HFOs and lower rhythms further validate the link between bursting firing regime of neurons and pathological oscillatory neural activity in PD-STN. Overall, these observations not only validate the existing literature on the PD electrophysiology in healthy/medicated animal models but also provide insights regarding the underlying electro-pathophysiology of levodopa-induced dyskinesias in PD patients through demonstration of multiscale relationships between single cell firings and field potentials.

Power Modulations of ECoG Alpha/Beta and Gamma Bands Correlate With Time-Derivative of Force During Hand Grasp.

It is well-known that motor cortical oscillatory components are modulated in their amplitude during voluntary and imagined movements. These patterns have been used to develop brain-machine interfaces (BMI) which focused mostly on movement kinematics. In contrast, there have been only a few studies on the relation between brain oscillatory activity and the control of force, in particular, grasping force, which is of primary importance for common daily activities. In this study, we recorded intraoperative high-density electrocorticography (ECoG) from the sensorimotor cortex of four patients while they executed a voluntary isometric hand grasp following verbal instruction. The grasp was held for 2 to 3 s before being instructed to relax. We studied the power modulations of neural oscillations during the whole time-course of the grasp (onset, hold, and offset phases). Phasic event-related desynchronization (ERD) in the low-frequency band (LFB) from 8 to 32 Hz and event-related synchronization (ERS) in the high-frequency band (HFB) from 60 to 200 Hz were observed at grasp onset and offset. However, during the grasp holding period, the magnitude of LFB-ERD and HFB-ERS decreased near or at the baseline level. Overall, LFB-ERD and HFB-ERS show phasic characteristics related to the changes of grasp force (onset/offset) in all four patients. More precisely, the fluctuations of HFB-ERS primarily, and of LFB-ERD to a lesser extent, correlated with the time-course of the first time-derivative of force (yank), rather than with force itself. To the best of our knowledge, this is the first study that establishes such a correlation. These results have fundamental implications for the decoding of grasp in brain oscillatory activity-based neuroprosthetics.