Electrophysiological Correlates of Dentate Nucleus Deep Brain Stimulation for Poststroke Motor Recovery.

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

Functional Magnetic Resonance Imaging Correlates of Ventral Striatal Deep Brain Stimulation for Poststroke Pain.

OBJECTIVE: Deep brain stimulation (DBS) for pain has largely been implemented in an uncontrolled manner to target the somatosensory component of pain, with research leading to mixed results. We have previously shown that patients with poststroke pain syndrome who were treated with DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) demonstrated a significant improvement in measures related to the affective sphere of pain. In this study, we sought to determine how DBS targeting the VS/ALIC modifies brain activation in response to pain. MATERIALS AND METHODS: Five patients with poststroke pain syndrome who were blinded to DBS status (ON/OFF) and six age- and sex-matched healthy controls underwent functional magnetic resonance imaging (fMRI) measuring blood oxygen level-dependent activation in a block design. In this design, each participant received heat stimuli to the affected or unaffected wrist area. Statistical comparisons were performed using fMRI z-maps. RESULTS: In response to pain, patients in the DBS OFF state showed significant activation (p < 0.001) in the same regions as healthy controls (thalamus, insula, and operculum) and in additional regions (orbitofrontal and superior convexity cortical areas). DBS significantly reduced activation of these additional regions and introduced foci of significant inhibitory activation (p < 0.001) in the hippocampi when painful stimulation was applied to the affected side. CONCLUSIONS: These findings suggest that DBS of the VS/ALIC modulates affective neural networks.

Prediction of mild parkinsonism revealed by neural oscillatory changes and machine learning.

Neural oscillatory changes within and across different frequency bands are thought to underlie motor dysfunction in Parkinson's disease (PD) and may serve as biomarkers for closed-loop deep brain stimulation (DBS) approaches. Here, we used neural oscillatory signals derived from chronically implanted cortical and subcortical electrode arrays as features to train machine learning algorithms to discriminate between naive and mild PD states in a nonhuman primate model. Local field potential (LFP) data were collected over several months from a 12-channel subdural electrocorticography (ECoG) grid and a 6-channel custom array implanted in the subthalamic nucleus (STN). Relative to the naive state, the PD state showed elevated primary motor cortex (M1) and STN power in the beta, high gamma, and high-frequency oscillation (HFO) bands and decreased power in the delta band. Theta power was found to be decreased in STN but not M1. In the PD state there was elevated beta-HFO phase-amplitude coupling (PAC) in the STN. We applied machine learning with support vector machines with radial basis function (SVM-RBF) kernel and k-nearest neighbors (KNN) classifiers trained by features related to power and PAC changes to discriminate between the naive and mild states. Our results show that the most predictive feature of parkinsonism in the STN was high beta (∼86% accuracy), whereas it was HFO in M1 (∼98% accuracy). A feature fusion approach outperformed every individual feature, particularly in the M1, where ∼98% accuracy was achieved with both classifiers. Overall, our data demonstrate the ability to use various frequency band power to classify the clinical state and are also beneficial in developing closed-loop DBS therapeutic approaches.NEW & NOTEWORTHY Neurophysiological biomarkers that correlate with motor symptoms or disease severity are vital to improve our understanding of the pathophysiology in Parkinson's disease (PD) and for the development of more effective treatments, including deep brain stimulation (DBS). This work provides direct insight into the application of these biomarkers in training classifiers to discriminate between brain states, which is a first step toward developing closed-loop DBS systems.

Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study.

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes.

Pain anticipatory phenomena in patients with central poststroke pain: a magnetoencephalography study.

Central poststroke pain (CPSP) is characterized by hemianesthesia associated with unrelenting chronic pain. The final pain experience stems from interactions between sensory, affective, and cognitive components of chronic pain. Hence, managing CPSP will require integrated approaches aimed not only at the sensory but also the affective-cognitive spheres. A better understanding of the brain's processing of pain anticipation is critical for the development of novel therapeutic approaches that target affective-cognitive networks and alleviate pain-related disability. We used magnetoencephalography (MEG) to characterize the neural substrates of pain anticipation in patients suffering from intractable CPSP. Simple visual cues evoked anticipation while patients awaited impending painful (PS), nonpainful (NPS), or no stimulus (NOS) to their nonaffected and affected extremities. MEG responses were studied at gradiometer level using event-related fields analysis and time-frequency oscillatory analysis upon source localization. On the nonaffected side, significantly greater responses were recorded during PS. PS (vs. NPS and NOS) exhibited significant parietal and frontal cortical activations in the beta and gamma bands, respectively, whereas NPS (vs. NOS) displayed greater activation in the orbitofrontal cortex. On the affected extremity, PS (vs. NPS) did not show significantly greater responses. These data suggest that anticipatory phenomena can modulate neural activity when painful stimuli are applied to the nonaffected extremity but not the affected extremity in CPSP patients. This dichotomy may stem from the chronic effects of pain on neural networks leading to habituation or saturation. Future clinically effective therapies will likely be associated with partial normalization of the neurophysiological correlates of pain anticipation.

A magnetoencephalography study of visual processing of pain anticipation.

Anticipating pain is important for avoiding injury; however, in chronic pain patients, anticipatory behavior can become maladaptive, leading to sensitization and limiting function. Knowledge of networks involved in pain anticipation and conditioning over time could help devise novel, better-targeted therapies. With the use of magnetoencephalography, we evaluated in 10 healthy subjects the neural processing of pain anticipation. Anticipatory cortical activity elicited by consecutive visual cues that signified imminent painful stimulus was compared with cues signifying nonpainful and no stimulus. We found that the neural processing of visually evoked pain anticipation involves the primary visual cortex along with cingulate and frontal regions. Visual cortex could quickly and independently encode and discriminate between visual cues associated with pain anticipation and no pain during preconscious phases following object presentation. When evaluating the effect of task repetition on participating cortical areas, we found that activity of prefrontal and cingulate regions was mostly prominent early on when subjects were still naive to a cue's contextual meaning. Visual cortical activity was significant throughout later phases. Although visual cortex may precisely and time efficiently decode cues anticipating pain or no pain, prefrontal areas establish the context associated with each cue. These findings have important implications toward processes involved in pain anticipation and maladaptive pain conditioning.

Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial.

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 .

Muscle volume, strength, endurance, and exercise loads during 6-month missions in space.

INTRODUCTION: Decrements in muscular strength during long-duration missions in space could be mission-critical during construction and exploration activities. The purpose of this study was to quantify changes in muscle volume, strength, and endurance of crewmembers on the International Space Station (ISS) in the context of new measurements of loading during exercise countermeasures. METHODS: Strength and muscle volumes were measured from four male ISS crewmembers (49.5 +/- 4.7 yr, 179.3 +/- 7.1 cm, 85.2 +/- 10.4 kg) before and after long-duration spaceflight (181 +/- 15 d). Preflight and in-flight measurements of forces between foot and shoe allowed comparisons of loading from 1-g exercise and exercise countermeasures on ISS. RESULTS: Muscle volume change was greater in the calf (-10 to 16%) than the thigh (-4% to -7%), but there was no change in the upper arm (+0.4 to -0.8%). Isometric and isokinetic strength changes at the knee (range -10.4 to -24.1%), ankle (range -4 to -22.3%), and elbow (range -7.5 to -16.7%) were observed. Although there was an overall postflight decline in total work (-14%) during the endurance test, an increase in postflight resistance to fatigue was observed. The peak in-shoe forces during running and cycling on ISS were approximately 46% and 50% lower compared to 1-g values. DISCUSSION: Muscle volume and strength were decreased in the lower extremities of crewmembers during long-duration spaceflight on ISS despite the use of exercise countermeasures. in-flight countermeasures were insufficient to replicate the daily mechanical loading experienced by the crewmembers before flight. Future exercise protocols need careful assessment both in terms of intensity and duration to maximize the "dose" of exercise and to increase loads compared to the measured levels.

Cortical thickness in visuo-motor areas is related to motor outcomes after STN DBS for Parkinson's disease.

INTRODUCTION: Deep brain stimulation (DBS) is a widely accepted therapy for Parkinson's disease. While outcome predictors such as levodopa-response are well established, there remains a need for objective and unbiased predictors in clinical practice. We performed an exploratory study to examine whether cortical thickness, derived from preoperative MRI, correlates with postoperative outcome. METHODS: Using freesurfer, we retrospectively measured cortical thickness on the preoperative MRI of 38 patients who underwent bilateral STN-DBS for PD during a 4-year period. The Unified Parkinson Disease Rating motor (UPDRS III) and experiences of daily living subscales (UPDRS II) were collected at baseline and six months after surgery. As an initial analysis, a series of partial correlations was conducted to evaluate the association between postoperative outcome scores and average cortical thickness from predefined regions of interest, adjusting for candidate confounders, without correcting for multiple comparisons. A confirmatory vertex-wise analysis was performed using a cluster-wise correction for multiple comparisons. RESULTS: Based on the ROI analysis, the strongest correlation with motor outcome was found to be with the left lateral-occipital cortex. Patients with greater cortical thickness in this area presented with greater improvements in motor scores. This relationship was also supported by the vertex-wise analysis. Greater cortical thickness in frontal and temporal regions may be correlated with greater post-operative improvements in UPDRS II, but this was not confirmed in the vertex-wise analysis. CONCLUSIONS: Our data indicate that greater cortical thickness in visuo-motor areas is correlated with motor outcomes after DBS for PD. Further prospective investigations are needed to confirm our findings and better-investigate potential image biomarkers.

An ambulatory biomechanical data collection system for use in space: design and validation.

INTRODUCTION: Loss in bone mineral density and muscle strength in astronauts following long-duration spaceflight have been well documented, but the altered force and movement environments in microgravity which may contribute to these changes have not been well characterized. This paper describes the instrumentation, software, and data collection procedures developed for the "Foot" experiment that was conducted on the International Space Station (ISS) to provide insight into the biomechanics of daily activity in a microgravity environment. METHODS: The instrumentation used for data collection included the Ambulatory Data Acquisition System (ADAS), ADAS electromyography (EMG) modules, the Joint Excursion System, and the Total Force-Foot Ground interface system, which were all integrated into a specially designed Lower Extremity Monitoring Suit. There were 14 total channels of data that were collected at sampling rates between 8 Hz and 1024 Hz, including 7 channels of EMG, 4 channels of joint angle data, 2 channels of in-shoe ground reaction force, and a marker channel for event recording. Data were typically collected for between 6.5 and 11.8 h of activity during 4 d on Earth and 4-7 d in flight. RESULTS: Exemplar data sets collected preflight on astronauts in 1 g to validate the instrumentation are presented. DISCUSSION: We conclude that the system provides valid and useful biomechanical information on long-term activity. The analysis of data collected on-orbit using the system described here will be presented in a series of future papers characterizing the biomechanics of astronaut activity during complete working days on the Earth and on the ISS.

Early event related fields during visually evoked pain anticipation.

OBJECTIVE: Pain experience is not only a function of somatosensory inputs. Rather, it is strongly influenced by cognitive and affective pathways. Pain anticipatory phenomena, an important limitation to rehabilitative efforts in the chronic state, are processed by associative and limbic networks, along with primary sensory cortices. Characterization of neurophysiological correlates of pain anticipation, particularly during very early stages of neural processing is critical for development of therapeutic interventions. METHODS: Here, we utilized magnetoencephalography to study early event-related fields (ERFs) in healthy subjects exposed to a 3 s visual countdown task that preceded a painful stimulus, a non-painful stimulus or no stimulus. RESULTS: We found that the first countdown cue, but not the last cue, evoked critical ERFs signaling anticipation, attention and alertness to the noxious stimuli. Further, we found that P2 and N2 components were significantly different in response to first-cues that signaled incoming painful stimuli when compared to non-painful or no stimuli. CONCLUSIONS: The findings indicate that early ERFs are relevant neural substrates of pain anticipatory phenomena and could be potentially serve as biomarkers. SIGNIFICANCE: These measures could assist in the development of neurostimulation approaches aimed at curbing the negative effects of pain anticipation during rehabilitation.

Differential frequency modulation of neural activity in the lateral cerebellar nucleus in failed and successful grasps.

The olivo-cerebellar system has an essential role in the detection and adaptive correction of movement errors. While there is evidence of an error signal in the cerebellar cortex and inferior olivary nucleus, the deep cerebellar nuclei have been less thoroughly investigated. Here, we recorded local field potential activity in the rodent lateral cerebellar nucleus during a skilled reaching task and compared event-related changes in neural activity between unsuccessful and successful attempts. Increased low gamma (40-50 Hz) band power was present throughout the reach and grasp behavior, with no difference between successful and unsuccessful trials. Beta band (12-30 Hz) power, however, was significantly increased in unsuccessful reaches, compared to successful, throughout the trial, including during the epoch preceding knowledge of the trial's outcome. This beta band activity was greater in unsuccessful trials of high-performing days, compared to unsuccessful trials of low-performing days, indicating that this activity may reflect an error prediction signal, developed over the course of motor learning. These findings suggest an error-related discriminatory oscillatory hallmark of movement in the deep cerebellar nuclei.

The use of contact heat evoked potential stimulator (CHEPS) in magnetoencephalography for pain research.

BACKGROUND: Contact heat evoked potentials (CHEP) is a thermal stimulus modality used in pain research. We examine a commercial CHEP stimulator (CHEPS) that is designed to work in an fMRI environment, but poorly understood in the MEG environment. The CHEPS attains target temperatures rapidly using sophisticated control signals that unfortunately induce artifacts in the MEG. In this paper, we summarize our experiences using the CHEPS in MEG to study pain using an experimental paradigm, and propose a novel method for managing its artifact. NEW METHOD: We introduce a novel damped sinusoid modeling (DSM) technique to remove the CHEPS artifact based on estimates of the underlying sinusoids and damping factors. We show comparisons to signal space projection (SSP) and temporal signal space separation (tSSS) methods. RESULTS: The CHEPS artifact is highly dynamic, yet deterministic, switching rapidly from one frequency to another, with different spatial components. The galvanic connection between the subject and the CHEPS probe alters its performance, making pre-characterization difficult. COMPARISON WITH EXISTING METHODS: SSP methods failed to remove the artifact completely. TSSS performed better than SSP; however, tSSS requires the use of a multipolar head model that decreases the dimensionality and possibly the information content of the data. In contrast, DSM offers a strictly temporal modeling approach in which the artifact is estimated as a sum of damped sinusoids which is subtracted from the data. CONCLUSION: Though the CHEPS increases the noise floor and introduces artifacts to the data, we believe the device can be successfully used in MEG if appropriate artifact removal techniques are followed.

Real time monitoring of ischemic changes in electrocardiograms using discrete Hermite functions.

A novel scheme for real time detection of ischemic features from long term electrocardiograms (ECG), based on the dilated discrete Hermite expansion is proposed. The discrete Hermite functions used for the expansion are eigenvectors of a symmetric tridiagonal matrix that commutes with the centered Fourier matrix. The ECG signals were expanded in terms of Hermite functions using a simple dot product. The resulting coefficients were found to have details about the shape of the ECG signal. The first 50 coefficients had all sufficient information to reconstruct the ECG signal with acceptable percentage RMS difference (PRD). A committee neural network classifier with these 50 input parameters was trained to identify ischemic features, namely ST segment and T wave changes. A sensitivity of 98% and a specificity of 97.3% were achieved. A comparison of these figures with other contemporary classification schemes revealed a superior performance.