Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Introduction: Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. Methods: We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Results: Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Discussion: Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Parkinsonian daytime sleep-wake classification using deep brain stimulation lead recordings.

Excessive daytime sleepiness is a recognized non-motor symptom that adversely impacts the quality of life of people with Parkinson's disease (PD), yet effective treatment options remain limited. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for PD motor signs. Reliable daytime sleep-wake classification using local field potentials (LFPs) recorded from DBS leads implanted in STN can inform the development of closed-loop DBS approaches for prompt detection and disruption of sleep-related neural oscillations. We performed STN DBS lead recordings in three nonhuman primates rendered parkinsonian by administrating neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Reference sleep-wake states were determined on a second-by-second basis by video monitoring of eyes (eyes-open, wake and eyes-closed, sleep). The spectral power in delta (1-4 Hz), theta (4-8 Hz), low-beta (8-20 Hz), high-beta (20-35 Hz), gamma (35-90 Hz), and high-frequency (200-400 Hz) bands were extracted from each wake and sleep epochs for training (70% data) and testing (30% data) a support vector machines classifier for each subject independently. The spectral features yielded reasonable daytime sleep-wake classification (sensitivity: 90.68 ± 1.28; specificity: 88.16 ± 1.08; accuracy: 89.42 ± 0.68; positive predictive value; 88.70 ± 0.89, n = 3). Our findings support the plausibility of monitoring daytime sleep-wake states using DBS lead recordings. These results could have future clinical implications in informing the development of closed-loop DBS approaches for automatic detection and disruption of sleep-related neural oscillations in people with PD to promote wakefulness.

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

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 13-35 Hz ("beta band") oscillatory dynamics in the manifestation of Parkinson's disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulses with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequency-specific (16-22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.

Quantifying Viscous Damping and Stiffness in Parkinsonism Using Data-Driven Model Estimation and Admittance Control.

Rigidity of upper and lower limbs in Parkinson's disease (PD) is typically assessed via a clinical rating scale that is subject to human perception biases. Methodologies to quantify changes in rigidity associated with the angular position (stiffness) or velocity (viscous damping) are needed to enhance our understanding of PD pathophysiology and objectively assess therapies. In this proof of concept study, we developed a robotic system and a model-based approach to estimate viscous damping and stiffness of the elbow. Our methodology enables the subject to freely rotate the elbow using an admittance controller while torque perturbations tailored to identify the arm dynamics are delivered. The viscosity and stiffness are calculated based on the experimental data using least-squares estimation. We validated our technique using computer simulations and experiments with a nonhuman animal model of PD in the presence and absence of deep brain stimulation therapy. Our data show that stiffness and viscosity measurements can better differentiate rigidity changes than scores previously used for research, including the work and impulse scores, and the modified unified Parkinson's disease rating scale. Our estimation method is suitable for quantifying the effect of therapies on viscous damping and stiffness and studying the pathophysiological mechanisms underlying rigidity in PD.

Shuffling Improves the Acute and Carryover Effect of Subthalamic Coordinated Reset Deep Brain Stimulation.

Coordinated reset deep brain stimulation (CR DBS) in the subthalamic nucleus (STN) has been demonstrated effective for the treatment of the motor signs associated with Parkinson's disease (PD). A critical CR parameter is an order in which stimulation is delivered across contacts. The relative effect of alternating vs. not alternating this order, i.e., shuffling vs. non-shuffling, however, has not been evaluated in vivo. The objective of this study is to compare the effect of shuffled vs. non-shuffled STN CR DBS on Parkinsonian motor signs. Two Parkinsonian non-human primates were implanted with a DBS lead in the STN. The effects of STN CR DBS with and without shuffling were compared with the traditional isochronal DBS (tDBS) using a within-subject design. For each stimulation setting, DBS was delivered for 2 or 4 h/day for 5 consecutive days. The severity of PD was assessed using a modified clinical rating scale immediately before, during, and 1 h after DBS, as well as on days following the discontinuation of the 5 days of daily stimulation, i.e., carryover effect. Shuffled STN CR DBS produced greater acute and carryover improvements on Parkinsonian motor signs compared with non-shuffled CR. Moreover, this difference was more pronounced when more effective stimulation intensity and burst frequency settings were used. tDBS showed limited carryover effects. Given the significant effect of shuffling on the effectiveness of CR DBS, it will be critical for future studies to further define the relative role of different CR parameters for the clinical implementation of this novel stimulation paradigm.

Real-time suppression and amplification of frequency-specific neural activity using stimulation evoked oscillations.

BACKGROUND: Approaches to predictably control neural oscillations are needed to understand their causal role in brain function in healthy or diseased states and to advance the development of neuromodulation therapies. OBJECTIVE: We present a closed-loop neural control and optimization framework to actively suppress or amplify low-frequency neural oscillations observed in local field potentials in real-time by using electrical stimulation. The rationale behind this control approach and our working hypothesis is that neural oscillatory activity evoked by electrical pulses can suppress or amplify spontaneous oscillations via destructive or constructive interference when the pulses are continuously delivered with appropriate amplitudes and at precise phases of the modulated oscillations in a closed-loop scheme. METHODS: We tested our hypothesis in two nonhuman primates that exhibited a robust increase in low-frequency (8-30 Hz) oscillatory power in the subthalamic nucleus (STN) following administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test our neural control approach, we targeted 8-17 Hz oscillations and used electrode arrays and electrical stimulation waveforms similar to those used in humans chronically implanted with brain stimulation systems. Stimulation parameters that maximize the suppression or amplification of neural oscillations were predicted using mathematical models of the stimulation evoked oscillations. RESULTS: Our neural control and optimization approach was capable of actively and robustly suppressing or amplifying oscillations in the targeted frequency band (8-17 Hz) in real-time in the studied subjects. CONCLUSIONS: The results from this study support our hypothesis and suggest that the proposed neural control framework allows one to characterize in controlled experiments the functional role of frequency-specific neural oscillations by using electrodes and stimulation waveforms currently being employed in humans.

Predictive encoding of motor behavior in the supplementary motor area is disrupted in parkinsonism.

Many studies suggest that Parkinson's disease (PD) is associated with changes in neuronal activity patterns throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts the presupplementary motor area (pre-SMA) and SMA proper (SMAp), cortical areas known to be involved in movement planning and motor control. In this study, local field potentials (LFPs) were recorded in the pre-SMA/SMAp of a nonhuman primate during a visually cued reaching task. Recordings were made in the same subject in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism. We found that in the naive animal, well before a go-cue providing instruction of reach onset and direction was given, LFP activity was dynamically modulated in both high (20-30 Hz) and low beta (10-20 Hz) bands, and the magnitude of this modulation (e.g., decrease/increase in beta amplitude for each band, respectively) correlated linearly with reaction time (RT) on a trial-to-trial basis, suggesting it may predictively encode for RT. Consistent with this hypothesis, we observed that this activity was more prominent within the pre-SMA compared with SMAp. In the parkinsonian state, however, pre-SMA/SMAp beta band modulation was disrupted, particularly in the high beta band, such that the predictive encoding of RT was significantly diminished. In addition, the predictive encoding of RT preferentially within pre-SMA over SMAp was lost. These findings add to our understanding of the role of pre-SMA/SMAp in motor behavior and suggest a fundamental role of these cortical areas in early preparatory and premovement processes that are altered in parkinsonism. NEW & NOTEWORTHY Goal-directed movements, such as reaching for an object, necessitate temporal preparation and organization of information processing within the basal ganglia-thalamocortical motor network. Impaired movement in parkinsonism is thought to be the result of pathophysiological activity disrupting information flow within this network. This work provides neurophysiological evidence linking altered motor preplanning processes encoded in pre-SMA/SMAp beta band modulation to the pathogenesis of motor disturbances in parkinsonism.

Public Regulatory Databases as a Source of Insight for Neuromodulation Devices Stimulation Parameters.

OBJECTIVE: The Shannon model is often used to define an expected boundary between non-damaging and damaging modes of electrical neurostimulation. Numerous preclinical studies have been performed by manufacturers of neuromodulation devices using different animal models and a broad range of stimulation parameters while developing devices for clinical use. These studies are mostly absent from peer-reviewed literature, which may lead to this information being overlooked by the scientific community. We aimed to locate summaries of these studies accessible via public regulatory databases and to add them to a body of knowledge available to a broad scientific community. METHODS: We employed web search terms describing device type, intended use, neural target, therapeutic application, company name, and submission number to identify summaries for premarket approval (PMA) devices and 510(k) devices. We filtered these records to a subset of entries that have sufficient technical information relevant to safety of neurostimulation. RESULTS: We identified 13 product codes for 8 types of neuromodulation devices. These led us to devices that have 22 PMAs and 154 510(k)s and six transcripts of public panel meetings. We found one PMA for a brain, peripheral nerve, and spinal cord stimulator and five 510(k) spinal cord stimulators with enough information to plot in Shannon coordinates of charge and charge density per phase. CONCLUSIONS: Analysis of relevant entries from public regulatory databases reveals use of pig, sheep, monkey, dog, and goat animal models with deep brain, peripheral nerve, muscle and spinal cord electrode placement with a variety of stimulation durations (hours to years); frequencies (10-10,000 Hz) and magnitudes (Shannon k from below zero to 4.47). Data from located entries indicate that a feline cortical model that employs acute stimulation might have limitations for assessing tissue damage in diverse anatomical locations, particularly for peripheral nerve and spinal cord simulation.

Parkinsonism and vigilance: alteration in neural oscillatory activity and phase-amplitude coupling in the basal ganglia and motor cortex.

Oscillatory neural activity in different frequency bands and phase-amplitude coupling (PAC) are hypothesized to be biomarkers of Parkinson's disease (PD) that could explain dysfunction in the motor circuit and be used for closed-loop deep brain stimulation (DBS). How these putative biomarkers change from the normal to the parkinsonian state across nodes in the motor circuit and within the same subject, however, remains unknown. In this study, we characterized how parkinsonism and vigilance altered oscillatory activity and PAC within the primary motor cortex (M1), subthalamic nucleus (STN), and globus pallidus (GP) in two nonhuman primates. Static and dynamic analyses of local field potential (LFP) recordings indicate that 1) after induction of parkinsonism using the neurotoxin MPTP, low-frequency power (8-30 Hz) increased in the STN and GP in both subjects, but increased in M1 in only one subject; 2) high-frequency power (~330 Hz) was present in the STN in both normal subjects but absent in the parkinsonian condition; 3) elevated PAC measurements emerged in the parkinsonian condition in both animals, but in different sites in each animal (M1 in one subject and GPe in the other); and 4) the state of vigilance significantly impacted how oscillatory activity and PAC were expressed in the motor circuit. These results support the hypothesis that changes in low- and high-frequency oscillatory activity and PAC are features of parkinsonian pathophysiology and provide evidence that closed-loop DBS systems based on these biomarkers may require subject-specific configurations as well as adaptation to changes in vigilance.NEW & NOTEWORTHY Chronically implanted electrodes were used to record neural activity across multiple nodes in the basal ganglia-thalamocortical circuit simultaneously in a nonhuman primate model of Parkinson's disease, enabling within-subject comparisons of electrophysiological biomarkers between normal and parkinsonian conditions and different vigilance states. This study improves our understanding of the role of oscillatory activity and phase-amplitude coupling in the pathophysiology of Parkinson's disease and supports the development of more effective DBS therapies based on pathophysiological biomarkers.

Network-wide oscillations in the parkinsonian state: alterations in neuronal activities occur in the premotor cortex in parkinsonian nonhuman primates.

A number of studies suggest that Parkinson's disease (PD) is associated with alterations of neuronal activity patterns in the basal-ganglia-thalamocortical circuit. There are limited electrophysiological data, however, describing how the premotor cortex, which is involved in movement and decision-making, is likely impacted in PD. In this study, spontaneous local field potential (LFP) and single unit neuronal activity were recorded in the dorsal premotor area of nonhuman primates in both the naïve and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. In both animals, we observed a shift of power in LFP power spectral densities (1-350 Hz) from higher to lower frequency bands; parkinsonism resulted in increased power in frequencies <8 Hz and decreased power at frequencies >30 Hz. A comparable but not identical trend was observed in the power spectral analysis of single unit spike trains: alpha power increased in both animals and gamma power decreased in one; power in other frequency bands remaining unchanged. Although not consistent across animals, we also observed changes in discharge rates and bursting activity. Overall, the LFP and single unit analysis suggest that abnormalities in premotor neural activity are a feature of parkinsonism, although specific details of those abnormalities may differ between subjects. This study further supports the concept that PD is a network disorder that induces abnormal spontaneous neural activities across the basal-ganglia-thalamocortical circuit including the premotor cortex and provides foundational knowledge for future studies regarding the relationship between changes in neuronal activity in this region and the development of motor deficits in PD.NEW & NOTEWORTHY This study begins to fill a gap in knowledge regarding how Parkinson's disease (PD) may cause abnormal functioning of the premotor cortex. It is novel as the premotor activity is examined in both the naïve and parkinsonian states, in the same subjects, at the single unit and LFP level. It provides foundational knowledge on which to build future studies to explore the relationships between premotor activities and specific parkinsonian motor and cognitive deficits.

Spinal Cord Stimulation (SCS) and Functional Magnetic Resonance Imaging (fMRI): Modulation of Cortical Connectivity With Therapeutic SCS.

INTRODUCTION: The neurophysiological basis of pain relief due to spinal cord stimulation (SCS) and the related cortical processing of sensory information are not completely understood. The aim of this study was to use resting state functional magnetic resonance imaging (rs-fMRI) to detect changes in cortical networks and cortical processing related to the stimulator-induced pain relief. METHODS: Ten patients with complex regional pain syndrome (CRPS) or neuropathic leg pain underwent thoracic epidural spinal cord stimulator implantation. Stimulation parameters associated with "optimal" pain reduction were evaluated prior to imaging studies. Rs-fMRI was obtained on a 3 Tesla, Philips Achieva MRI. Rs-fMRI was performed with stimulator off (300TRs) and stimulator at optimum (Opt, 300 TRs) pain relief settings. Seed-based analysis of the resting state functional connectivity was conducted using seeds in regions established as participating in pain networks or in the default mode network (DMN) in addition to the network analysis. NCUT (normalized cut) parcellation was used to generate 98 cortical and subcortical regions of interest in order to expand our analysis of changes in functional connections to the entire brain. We corrected for multiple comparisons by limiting the false discovery rate to 5%. RESULTS: Significant differences in resting state connectivity between SCS off and optimal state were seen between several regions related to pain perception, including the left frontal insula, right primary and secondary somatosensory cortices, as well as in regions involved in the DMN, such as the precuneus. In examining changes in connectivity across the entire brain, we found decreased connection strength between somatosensory and limbic areas and increased connection strength between somatosensory and DMN with optimal SCS resulting in pain relief. This suggests that pain relief from SCS may be reducing negative emotional processing associated with pain, allowing somatosensory areas to become more integrated into default mode activity. CONCLUSION: SCS reduces the affective component of pain resulting in optimal pain relief. Study shows a decreased connectivity between somatosensory and limbic areas associated with optimal pain relief due to SCS.

Short and long latency afferent inhibition in Parkinson's disease.

Sensory abnormalities have been reported in Parkinson's disease and may contribute to the motor deficits. Peripheral sensory stimulation inhibits the motor cortex, and the effects depend on the interstimulus interval (ISI) between the sensory stimulus and transcranial magnetic stimulation (TMS) to the motor cortex. Short latency afferent inhibition (SAI) occurs at an ISI of approximately 20 ms, and long latency afferent inhibition (LAI) at an ISI of approximately 200 ms. We studied SAI and LAI in 10 Parkinson's disease patients with the aim of assessing whether sensorimotor processing is altered in Parkinson's disease. Patients were studied on and off medication, and the findings were compared with 10 age-matched controls. Median nerve and middle finger stimulation were delivered 20-600 ms before TMS to the contralateral motor cortex. The motor evoked potentials were recorded from the relaxed first dorsal interosseous (FDI) muscle. SAI was normal in Parkinson's disease patients off dopaminergic medications, but it was reduced on the more affected side in Parkinson's disease patients on medication. LAI was reduced in Parkinson's disease patients compared with controls independent of their medication status. LAI reduced long interval intracortical inhibition in normal subjects but not in Parkinson's disease patients. The different results for SAI and LAI indicate that it is likely that separate mechanisms mediate these two forms of afferent inhibition. SAI probably represents the direct interaction of a sensory signal with the motor cortex. This pathway is unaffected by Parkinson's disease but is altered by dopaminergic medication in Parkinson's disease patients and may contribute to the side effects of dopaminergic drugs. LAI probably involves other pathways such as the basal ganglia or cortical association areas. This defective sensorimotor integration may be a non-dopaminergic manifestation of Parkinson's disease.

An automated method to determine the transcranial magnetic stimulation-induced contralateral silent period.

BACKGROUND: The transcranial magnetic stimulation (TMS)-induced contralateral silent period (CSP) refers to a period of interruption of voluntary muscle activity measured in tonically active muscles. The length of the CSP is generally interpreted to reflect cortical inhibition. The determination of the return of voluntary motor activity is typically accomplished via visual inspection of the electromyography (EMG) waveform and may be subject to inaccuracy on the part of the rater. OBJECTIVE: To present and evaluate an automated method (AM) to determine the CSP. METHODS: The CSP of 11 healthy controls was recorded using stimulus intensities 20 and 50% above the resting motor threshold (RMT). The mean CSP duration obtained by the two raters using visual inspection and our automated approach were compared. RESULTS: The interclass correlation coefficient (ICC) between the two raters and the AM was 0.99 at 150% of RMT and was 0.97 at 120% of RMT. The level of pre-stimulus EMG amplitude and sampling rate did not affect agreement between the AM and more conventional visually guided methods. CONCLUSIONS: Our study demonstrates that this AM is a simple, objective and reliable approach for CSP determination. SIGNIFICANCE: The CSP is an important neurophysiological measure of cortical inhibition and its determination by our AM provides a more objective and automated approach compared to visually guided methods.

Effects of peripheral sensory input on cortical inhibition in humans.

Cortical inhibitory systems play an important role in motor output. The motor cortex can be inhibited by intracortical mechanisms and by peripheral sensory inputs. We examined whether cortical inhibition from peripheral sensory input is mediated through previously identified intracortical inhibitory systems and how these inhibitory systems interact. Two types of intracortical inhibition were assessed by paired-pulse transcranial magnetic stimulation (TMS). Short-interval intracortical inhibition (SICI) was determined with a subthreshold conditioning stimulus (CS) followed by a test stimulus 2 ms later and long-interval intracortical inhibition (LICI) with suprathreshold conditioning and test stimuli 100 ms apart. Cortical inhibition from peripheral sensory input was induced by median nerve stimulation (MNS) of the right hand and followed by a suprathreshold TMS over the left motor cortex 200 ms later. The first set of experiments tested the effects of different test stimulus intensities on SICI, LICI and cortical inhibition induced by median nerve stimulation (MNSI). With higher test stimulus intensities, LICI and MNSI decreased whereas SICI showed a trend towards an increase. The extent of SICI, LICI and MNSI did not correlate. The second experiment assessed the interaction between MNSI and LICI. The results of applying MNSI and LICI simultaneously were compared with MNSI and LICI alone. MNSI was virtually abolished in the presence of LICI and LICI was also significantly decreased in the presence of MNSI. Thus, the effects of MNSI and LICI when applied together were much less than their expected additive effects when applied alone. The degree of interaction between MNSI and LICI was related to the combined strength of MNSI and LICI but not to the strength of LICI alone. The third experiment investigated the interaction between SICI and MNSI. MNSI and SICI were applied together and the results were compared with MNSI and SICI alone. SICI remained unchanged in the presence of MNSI. We conclude that MNSI is mediated by circuits distinct from those mediating LICI or SICI. The MNSI circuits seem to have an inhibitory interaction with the LICI circuits, whereas the SICI and MNSI circuits do not seem to interact.