At home adaptive dual target deep brain stimulation in Parkinson's disease with proportional control.

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit. Continuous DBS is limited by a lack of responsiveness to dynamic, fluctuating symptoms intrinsic to the disease. Adaptive DBS (aDBS) adjusts stimulation in response to biomarkers to improve efficacy, side effects, and efficiency. We combined bilateral DBS of both STN and globus pallidus (dual target DBS) in a prospective within-participant, clinical trial in six patients with Parkinson's disease (n = 6, 55-65 years, n = 2 females). Dual target cDBS was tested for Parkinson's disease symptom control annually over 2 years, measured by motor rating scales, on time without dyskinesia, and medication reduction. Random amplitude experiments probed system dynamics to estimate parameters for aDBS. We then implemented proportional-plus-integral aDBS using a novel distributed (off-implant) architecture. In the home setting, we collected tremor and dyskinesia scores as well as individualized ß and DBS amplitudes. Dual target cDBS reduced motor symptoms as measured by Unified Parkinson's Disease Rating Scale (UPDRS) to a greater degree than either region alone (P < 0.05, linear mixed model) in the cohort. The amplitude of ß-oscillations in the STN correlated to the speed of hand grasp movements for five of six participants (P < 0.05, Pearson correlation). Random amplitude experiments provided insight into temporal windowing to avoid stimulation artefacts and demonstrated a correlation between STN ß amplitude and DBS amplitude. Proportional plus integral control of aDBS reduced average power, while preserving UPDRS III scores in the clinic (P = 0.28, Wilcoxon signed rank), and tremor and dyskinesia scores during blinded testing at home (n = 3, P > 0.05, Wilcoxon ranked sum). In the home setting, DBS power reductions were slight but significant. Dual target cDBS may offer an improvement in treatment of motor symptoms of Parkinson's disease over DBS of either the STN or globus pallidus alone. When combined with proportional plus integral aDBS, stimulation power may be reduced, while preserving the increased benefit of dual target DBS.

Neuromodulation-dependent effect of gated high-frequency, LFMS-like electric field stimulation in mouse cortical slices.

Low-field magnetic stimulation (LFMS) is a gated high-frequency non-invasive brain stimulation method (500 Hz gated at 2 Hz) with a proposed antidepressant effect. However, it has remained unknown how such stimulation paradigms modulate neuronal network activity and how the induced changes depend on network state. Here we examined the immediate and outlasting effects of the gated high-frequency electric field associated with LFMS on the cortical activity as a function of neuromodulatory tone that defines network state. We used a sham-controlled study design to investigate effects of stimulation (20 min of 0.5 s trains of 500 Hz charge-balanced pulse stimulation patterned at 0.5 Hz) on neural activity in mouse medial prefrontal cortex in vitro. Bath application of cholinergic and noradrenergic agents enabled us to examine the stimulation effects as a function of neuromodulatory tone. The stimulation attenuated the increase in firing rate of layer V cortical neurons during the post-stimulation period in the presence of cholinergic activation. The same stimulation had no significant immediate or outlasting effect in the absence of exogenous neuromodulators or in the presence of noradrenergic activation. These results provide electrophysiological insights into the neuromodulatory-dependent effects of gated high-frequency stimulation. More broadly, our results are the first to provide a mechanistic demonstration of how behavioral states and arousal levels may modify the effects of non-invasive brain stimulation.

Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent.

Cortical oscillations play a fundamental role in organizing large-scale functional brain networks. Noninvasive brain stimulation with temporally patterned waveforms such as repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) have been proposed to modulate these oscillations. Thus, these stimulation modalities represent promising new approaches for the treatment of psychiatric illnesses in which these oscillations are impaired. However, the mechanism by which periodic brain stimulation alters endogenous oscillation dynamics is debated and appears to depend on brain state. Here, we demonstrate with a static model and a neural oscillator model that recurrent excitation in the thalamo-cortical circuit, together with recruitment of cortico-cortical connections, can explain the enhancement of oscillations by brain stimulation as a function of brain state. We then performed concurrent invasive recording and stimulation of the human cortical surface to elucidate the response of cortical oscillations to periodic stimulation and support the findings from the computational models. We found that (1) stimulation enhanced the targeted oscillation power, (2) this enhancement outlasted stimulation, and (3) the effect of stimulation depended on behavioral state. Together, our results show successful target engagement of oscillations by periodic brain stimulation and highlight the role of nonlinear interaction between endogenous network oscillations and stimulation. These mechanistic insights will contribute to the design of adaptive, more targeted stimulation paradigms.

Interaction of Intrinsic and Synaptic Currents Mediate Network Resonance Driven by Layer V Pyramidal Cells.

Cortical oscillations modulate cellular excitability and facilitate neuronal communication and information processing. Layer 5 pyramidal cells (L5 PYs) drive low-frequency oscillations (<4 Hz) in neocortical networks in vivo. In vitro, individual L5 PYs exhibit subthreshold resonance in the theta band (4-8 Hz). This bandpass filtering of periodic input is mediated by h-current (Ih) and m-current (IM) that selectively suppress low-frequency input. It has remained unclear how these intrinsic properties of cells contribute to the emergent, network oscillation dynamics. To begin to close this gap, we studied the link between cellular and network mechanisms of network resonance driven by L5 PYs. We performed multielectrode array recordings of network activity in slices of medial prefrontal cortex from the Thy1-ChR2-eYFP line and activated the network by temporally patterned optogenetic suprathreshold stimulation. Networks driven by stimulation of L5 PYs exhibited resonance in the theta band. We found that Ih and IM play a role in resonant suprathreshold network response to depolarizing stimuli. The action of Ih in mediating resonance was dependent on synaptic transmission while that of IM was not. These results demonstrate how synergistic interaction of synaptic and intrinsic ion channels contribute to the response of networks driven by L5 PYs.

Transplantation of GABAergic Interneurons into the Neonatal Primary Visual Cortex Reduces Absence Seizures in Stargazer Mice.

Epilepsies are debilitating neurological disorders characterized by repeated episodes of pathological seizure activity. Absence epilepsy (AE) is a poorly understood type of seizure with an estimated 30% of affected patients failing to respond to antiepileptic drugs. Thus, novel therapies are needed for the treatment of AE. A promising cell-based therapeutic strategy is centered on transplantation of embryonic neural stem cells from the medial ganglionic eminence (MGE), which give rise to gamma-aminobutyric acidergic (GABAergic) interneurons during embyronic development. Here, we used the Stargazer (Stg) mouse model of AE to map affected loci using c-Fos immunohistochemistry, which revealed intense seizure-induce activity in visual and somatosensory cortices. We report that transplantation of MGE cells into the primary visual cortex (V1) of Stg mice significantly reduces AE episodes and lowers mortality. Electrophysiological analysis in acute cortical slices of visual cortex demonstrated that Stg V1 neurons exhibit more pronounced increases in activity in response to a potassium-mediated excitability challenge than wildtypes (WT). The defective network activity in V1 was significantly altered following WT MGE transplantation, associating it with behavioral rescue of seizures in Stgs. Taken together, these findings present MGE grafting in the V1 as a possible clinical approach in the treatment of AE.

Temporally non-regular patterns of deep brain stimulation (DBS) enhance assessment of evoked potentials while maintaining motor symptom management in Parkinson's disease (PD).

BACKGROUND: Traditional deep brain stimulation (DBS) at fixed regular frequencies (>100 Hz) is effective in treating motor symptoms of Parkinson's disease (PD). Temporally non-regular patterns of DBS are a new parameter space that may help increase efficacy and efficiency. OBJECTIVE: To compare the effects of temporally non-regular patterns of DBS to traditional regularly-spaced pulses. METHODS: We simultaneously recorded local field potentials (LFP) and monitored motor symptoms (tremor and bradykinesia) in persons with PD during DBS in subthalamic nucleus (STN). We quantified both oscillatory activity and DBS local evoked potentials (DLEPs) from the LFP. RESULTS: Temporally non-regular patterns were as effective as traditional pulse patterns in modulating motor symptoms, oscillatory activity, and DLEPs. Moreover, one of our novel patterns enabled recording of longer duration DLEPs during clinically effective stimulation. CONCLUSIONS: Stimulation gaps of 50 ms can be used to increase efficiency and to enable regular assessment of long-duration DLEPs while maintaining effective symptom management. This may be a promising paradigm for closed-loop DBS with biomarker assessment during the gaps.

Evoked potentials generated by deep brain stimulation for Parkinson's disease.

BACKGROUND AND OBJECTIVES: The goal of this review is to describe the general features, mechanisms, technical recording factors, and clinical applications of brain evoked potentials (EPs) generated by deep brain stimulation (DBS) for Parkinson's disease (PD). RESULTS: Evoked potentials in response to DBS pulses occur on the timescale of milliseconds and are found both locally at the site of stimulation and remotely in the cortex. DBS evoked potentials arise from a complex integration of antidromic and orthodromic conduction pathway responses, and provide information valuable for understanding the mechanisms and circuits involved in symptom treatment. Furthermore, these signals may provide biomarkers for improving DBS outcomes and function. For example, evoked potentials may have utility as control signals for DBS programming or adaptive DBS. Despite their promise there are still critical gaps in our understanding of the mechanisms by which evoked potentials arise and how these signals may be measured and applied in the clinical setting. Technical challenges of recording a highly transient signal at sufficient resolution without the interference of stimulation artifact present a barrier to understanding better DBS-induced EPs. CONCLUSIONS: We describe the current scientific landscape of evoked potentials to facilitate and stimulate further investigation.

A comparison of an implanted accelerometer with a wearable accelerometer for closed-loop DBS.

Sensing technology, as well as cloud communication, is enabling the development of closed-loop deep brain stimulation (DBS) for Parkinson's disease. The accelerometer is a practical sensor that can provide information about the disease/health state of the patient as well as physical activity levels, all of which in the long-term can provide feedback information to an adaptive closed-loop control algorithm for more effective and personalized DBS therapy. In this paper, we present for the first time, acceleration streamed from Medtronic's RC+S device in patients with Parkinson's disease while at home, and compare it to accel-eration acquired concurrently from the patient's Apple Watch. We examined correlation between the accelerometer signals at varying time scales. We also compared the spectral band power obtained from the two accelerometers. While there was an average correlation of 0.37 for subject 1 and 0.50 for subject 2 between the two acceleration signals on a time scale of 10 minutes, the correlation was lower for shorter time scales on the order of seconds. There was greater spectral power in the Parkinsonian tremor band of 4-7 Hz for the externally worn accelerometer than the internal accelerometer, but the internal accelerometer showed greater relative power distributed in the higher frequencies (7-30 Hz). Thus, based on this preliminary analysis, we expect that the internal accelerometer may be used to assess patient activity and state for closed loop DBS but tremor detection may require more sophisticated signal processing. Furthermore, the internal accelerometer may contain information in higher frequency bands that reveal information about the patient state. Clinical relevance - Closed-loop DBS is expected to improve patient outcomes for the tens of thousands of Parkinson's disease patients using DBS [1], [2]. Eliminating an additional external device in order to implement closed-loop adaptive deep brain stimulation would benefit DBS patients however an understanding of what information is lost by doing so is needed to justify the ultimate design of closed-loop DBS.

Initial Clinical Outcome With Bilateral, Dual-Target Deep Brain Stimulation Trial in Parkinson Disease Using Summit RC + S.

BACKGROUND: Deep brain stimulation (DBS) is an effective therapy in advanced Parkinson disease (PD). Although both subthalamic nucleus (STN) and globus pallidus (GP) DBS show equivalent efficacy in PD, combined stimulation may demonstrate synergism. OBJECTIVE: To evaluate the clinical benefit of stimulating a combination of STN and GP DBS leads and to demonstrate biomarker discovery for adaptive DBS therapy in an observational study. METHODS: We performed a pilot trial (n = 3) of implanting bilateral STN and GP DBS leads, connected to a bidirectional implantable pulse generator (Medtronic Summit RC + S; NCT03815656, IDE No. G180280). Initial 1-year outcome in 3 patients included Unified PD Rating Scale on and off medications, medication dosage, Hauser diary, and recorded beta frequency spectral power. RESULTS: Combined DBS improved PD symptom control, allowing >80% levodopa medication reduction. There was a greater decrease in off-medication motor Unified PD Rating Scale with multiple electrodes activated (mean difference from off stimulation off medications -18.2, range -25.5 to -12.5) than either STN (-12.8, range -20.5 to 0) or GP alone (-9, range -11.5 to -4.5). Combined DBS resulted in a greater reduction of beta oscillations in STN in 5/6 hemispheres than either site alone. Adverse events occurred in 2 patients, including a small cortical hemorrhage and seizure at 24 hours postoperatively, which resolved spontaneously, and extension wire scarring requiring revision at 2 months postoperatively. CONCLUSION: Patients with PD preferred combined DBS stimulation in this preliminary cohort. Future studies will address efficacy of adaptive DBS as we further define biomarkers and control policy.

Continuous deep brain stimulation of the subthalamic nucleus may not modulate beta bursts in patients with Parkinson's disease.

BACKGROUND: Neural oscillations represent synchronous neuronal activation and are ubiquitous throughout the brain. Oscillatory activity often includes brief high-amplitude bursts in addition to background oscillations, and burst activity may predict performance on working memory, motor, and comprehension tasks. OBJECTIVE: We evaluated beta burst activity as a possible biomarker for motor symptoms in Parkinson's disease (PD). The relationship between beta amplitude dynamics and motor symptoms is critical for adaptive DBS for treatment of PD. METHODS: We applied threshold-based and support vector machine (SVM) analyses of burst parameters to a defined on/off oscillator and to intraoperative recordings of local field potentials from the subthalamic nucleus of 16 awake patients with PD. RESULTS: Filtering and time-frequency analysis techniques critically influenced the accuracy of identifying burst activity. Threshold-based analysis lead to biased results in the presence of changes in long-term beta amplitude and accurate quantification of bursts with thresholds required unknowable a priori knowledge of the time in bursts. We therefore implemented an SVM analysis, and we did not observe changes in burst fraction, rate, or duration with the application of cDBS in the participant data, even though SVM analysis was able to correctly identify bursts of the defined on/off oscillator. CONCLUSION: Our results suggest that cDBS of the STN may not change beta burst activity. Additionally, threshold-based analysis can bias the fraction of time spent in bursts. Improved analysis strategies for continuous and adaptive DBS may achieve improved symptom control and reduce side-effects.

Evoked potentials reveal neural circuits engaged by human deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is an effective therapy for reducing the motor symptoms of Parkinson's disease, but the mechanisms of action of DBS and neural correlates of symptoms remain unknown. OBJECTIVE: To use the neural response to DBS to reveal connectivity of neural circuits and interactions between groups of neurons as potential mechanisms for DBS. METHODS: We recorded activity evoked by DBS of the subthalamic nucleus (STN) in humans with Parkinson's disease. In follow up experiments we also simultaneously recorded activity in the contralateral STN or the ipsilateral globus pallidus from both internal (GPi) and external (GPe) segments. RESULTS: DBS local evoked potentials (DLEPs) were stereotyped across subjects, and a biophysical model of reciprocal connections between the STN and the GPe recreated DLEPs. Simultaneous STN and GP recordings during STN DBS demonstrate that DBS evoked potentials were present throughout the basal ganglia and confirmed that DLEPs arose from the reciprocal connections between the STN and GPe. The shape and amplitude of the DLEPs were dependent on the frequency and duration of DBS and were correlated with resting beta band oscillations. In the frequency domain, DLEPs appeared as a 350 Hz high frequency oscillation (HFO) independent of the frequency of DBS. CONCLUSIONS: DBS evoked potentials suggest that the intrinsic dynamics of the STN and GP are highly interlinked and may provide a promising new biomarker for adaptive DBS.

Endogenous cortical oscillations constrain neuromodulation by weak electric fields.

BACKGROUND: Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation modality that may modulate cognition by enhancing endogenous neocortical oscillations by application of sine-wave electric fields. Yet, the role of endogenous network activity in enabling and shaping the effects of tACS has remained unclear. OBJECTIVE: We combined optogenetic stimulation and multichannel slice electrophysiology to elucidate how the effect of a weak sine-wave electric field depends on the ongoing cortical oscillatory activity. We hypothesized that endogenous cortical oscillations constrain neuromodulation by tACS. METHODS: We studied the effect of weak sine-wave electric fields on oscillatory activity in mouse neocortical slices. Optogenetic control of the network activity enabled the generation of in vivo-like cortical oscillations for studying the temporal relationship between network activity and sine-wave electric field stimulation. RESULTS: Weak electric fields enhanced endogenous oscillations but failed to induce a frequency shift of the ongoing oscillation for stimulation frequencies that were not matched to the endogenous oscillation. This constraint on the effect of electric field stimulation imposed by endogenous network dynamics was limited to the case of weak electric fields targeting in vivo-like network dynamics. Together, these results suggest that the key mechanism of tACS may be enhancing, but not overriding, intrinsic network dynamics. CONCLUSION: Our results contribute to understanding the inconsistent tACS results from human studies and propose that stimulation precisely adjusted in frequency to the endogenous oscillations is key to rational design of non-invasive brain stimulation paradigms.

Rational design of transcranial current stimulation (TCS) through mechanistic insights into cortical network dynamics.

Transcranial current stimulation (TCS) is a promising method of non-invasive brain stimulation to modulate cortical network dynamics. Preliminary studies have demonstrated the ability of TCS to enhance cognition and reduce symptoms in both neurological and psychiatric illnesses. Despite the encouraging results of these studies, the mechanisms by which TCS and endogenous network dynamics interact remain poorly understood. Here, we propose that the development of the next generation of TCS paradigms with increased efficacy requires such mechanistic understanding of how weak electric fields (EFs) imposed by TCS interact with the nonlinear dynamics of large-scale cortical networks. We highlight key recent advances in the study of the interaction dynamics between TCS and cortical network activity. In particular, we illustrate an interdisciplinary approach that bridges neurobiology and electrical engineering. We discuss the use of (1) hybrid biological-electronic experimental approaches to disentangle feedback interactions; (2) large-scale computer simulations for the study of weak global perturbations imposed by TCS; and (3) optogenetic manipulations informed by dynamic systems theory to probe network dynamics. Together, we here provide the foundation for the use of rational design for the development of the next generation of TCS neurotherapeutics.

Differential effects of cholinergic and noradrenergic neuromodulation on spontaneous cortical network dynamics.

Cholinergic and noradrenergic neuromodulation play a key role in determining overall behavioral state by shaping the underlying cortical network dynamics. The effects of these systems on synaptic and intrinsic cellular targets are quite diverse and a comprehensive understanding of how these neuromodulators regulate (spontaneous) cortical network activity has remained elusive. Here, we used multielectrode electrophysiology in vitro to investigate the effect of these neuromodulators on spontaneous network dynamics in acute slices of mouse visual cortex. We found that application of Carbachol (CCh) and Norepinephrine (NE) both enhanced the spontaneous network dynamics by increasing (1) the activity levels, (2) the temporal complexity of the network activity, and (3) the spatial complexity by decorrelating the network activity over a wide range of neuromodulator concentrations (1 µM, 10 µM, 50 µM, and 100 µM). Interestingly, we found that cholinergic neuromodulation was limited to the presence of CCh in the bath whereas the effects of NE, in particular for higher concentrations, induced plasticity that caused outlasting effects most prominently in the deep cortical layers. Together, these results provide a comprehensive network-level understanding of the similarities and differences of cholinergic and noradrenergic modulation of spontaneous network dynamics.