Cortical signatures of sleep are altered following effective deep brain stimulation for depression.

Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep-slow-wave activity (SWA, 0.5-4.5 Hz) and sleep spindles-in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep.

Embedding digital chronotherapy into bioelectronic medicines.

Biological rhythms pervade physiology and pathophysiology across multiple timescales. Because of the limited sensing and algorithm capabilities of neuromodulation device technology to-date, insight into the influence of these rhythms on the efficacy of bioelectronic medicine has been infeasible. As the development of new devices begins to mitigate previous technology limitations, we propose that future devices should integrate chronobiological considerations in their control structures to maximize the benefits of neuromodulation therapy. We motivate this proposition with preliminary longitudinal data recorded from patients with Parkinson's disease and epilepsy during deep brain stimulation therapy, where periodic symptom biomarkers are synchronized to sub-daily, daily, and longer timescale rhythms. We suggest a physiological control structure for future bioelectronic devices that incorporates time-based adaptation of stimulation control, locked to patient-specific biological rhythms, as an adjunct to classical control methods and illustrate the concept with initial results from three of our recent case studies using chronotherapy-enabled prototypes.

Thalamic deep brain stimulation modulates cycles of seizure risk in epilepsy.

Chronic brain recordings suggest that seizure risk is not uniform, but rather varies systematically relative to daily (circadian) and multiday (multidien) cycles. Here, one human and seven dogs with naturally occurring epilepsy had continuous intracranial EEG (median 298 days) using novel implantable sensing and stimulation devices. Two pet dogs and the human subject received concurrent thalamic deep brain stimulation (DBS) over multiple months. All subjects had circadian and multiday cycles in the rate of interictal epileptiform spikes (IES). There was seizure phase locking to circadian and multiday IES cycles in five and seven out of eight subjects, respectively. Thalamic DBS modified circadian (all 3 subjects) and multiday (analysis limited to the human participant) IES cycles. DBS modified seizure clustering and circadian phase locking in the human subject. Multiscale cycles in brain excitability and seizure risk are features of human and canine epilepsy and are modifiable by thalamic DBS.

Developing Collaborative Platforms to Advance Neurotechnology and Its Translation.

Neurotechnological devices are failing to deliver on their therapeutic promise because of the time it takes to translate them from bench to clinic. In this Perspective, we reflect on lessons learned from medical device successes and failures and consider how such lessons might shape a strategic vision for translating neurotechnologies in the future. We articulate how the intentional design and deployment of "scientific platforms," from the technology stack of hardware and software through the supporting ecosystem, could catalyze a new wave of innovation, discovery, and therapy. We also identify specific actions that could promote future neurotechnology roadmaps and industrial-academic-government collaborative activities. We believe that community-supported neurotechnology platforms will prove to be transformational in accelerating ideas from bench to bedside, maximizing scientific discovery and improving patient care.

Industrial perspectives on brain-computer interface technology.

Neuromodulation therapies offer a unique opportunity for translating brain-computer interface (BCI) technologies into a clinical setting. Several diseases such as Parkinson's disease are effectively treated by invasive device stimulation therapies, and the addition of sensing and algorithm technology is an obvious evolutionary expansion of capabilities. In addition, this infrastructure might enable a roadmap of novel BCI technologies. While the initial applications are focused on epilepsy and movement disorders, the technology is potentially transferable to a broader base of disorders, including stroke and rehabilitation. The ultimate potential of BCI technology will be determined by forthcoming chronic evaluation in multiple neurologic disorders.

Circadian and multiday seizure periodicities, and seizure clusters in canine epilepsy.

Advances in ambulatory intracranial EEG devices have enabled objective analyses of circadian and multiday seizure periodicities, and seizure clusters in humans. This study characterizes circadian and multiday seizure periodicities, and seizure clusters in dogs with naturally occurring focal epilepsy, and considers the implications of an animal model for the study of seizure risk patterns, seizure forecasting and personalized treatment protocols. In this retrospective cohort study, 16 dogs were continuously monitored with ambulatory intracranial EEG devices designed for humans. Detailed medication records were kept for all dogs. Seizure periodicity was evaluated with circular statistics methods. Circular non-uniformity was assessed for circadian, 7-day and approximately monthly periods. The Rayleigh test was used to assess statistical significance, with correction for multiple comparisons. Seizure clusters were evaluated with Fano factor (index of dispersion) measurements, and compared to a Poisson distribution. Relationships between interseizure interval (ISI) and seizure duration were evaluated. Six dogs met the inclusion criteria of having at least 30 seizures and were monitored for an average of 65 weeks. Three dogs had seizures with circadian seizure periodicity, one dog had a 7-day periodicity, and two dogs had approximately monthly periodicity. Four dogs had seizure clusters and significantly elevated Fano factor values. There were subject-specific differences in the dynamics of ISI and seizure durations, both within and between lead and clustered seizure categories. Our findings show that seizure timing in dogs with naturally occurring epilepsy is not random, and that circadian and multiday seizure periodicities, and seizure clusters are common. Circadian, 7-day, and monthly seizure periodicities occur independent of antiseizure medication dosing, and these patterns likely reflect endogenous rhythms of seizure risk.

Applying a Sensing-Enabled System for Ensuring Safe Anterior Cingulate Deep Brain Stimulation for Pain.

Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) was offered to chronic pain patients who had exhausted medical and surgical options. However, several patients developed recurrent seizures. This work was conducted to assess the effect of ACC stimulation on the brain activity and to guide safe DBS programming. A sensing-enabled neurostimulator (Activa PC + S) allowing wireless recording through the stimulating electrodes was chronically implanted in three patients. Stimulation patterns with different amplitude levels and variable ramping rates were tested to investigate whether these patterns could provide pain relief without triggering after-discharges (ADs) within local field potentials (LFPs) recorded in the ACC. In the absence of ramping, AD activity was detected following stimulation at amplitude levels below those used in chronic therapy. Adjustment of stimulus cycling patterns, by slowly ramping on/off (8-s ramp duration), was able to prevent ADs at higher amplitude levels while maintaining effective pain relief. The absence of AD activity confirmed from the implant was correlated with the absence of clinical seizures. We propose that AD activity in the ACC could be a biomarker for the likelihood of seizures in these patients, and the application of sensing-enabled techniques has the potential to advance safer brain stimulation therapies, especially in novel targets.

Brain stimulation for epilepsy--local and remote modulation of network excitability.

BACKGROUND: The use of Deep Brain Stimulation (DBS) as a potential therapy for treatment resistant epilepsy remains an area of active clinical investigation. We recently reported the first chronic evaluation of an implantable, clinical-grade system that permits concurrent stimulation and recording, in a large animal (ovine) model developed to study DBS for epilepsy. OBJECTIVE: In this study we extended this work to compare the effects of remote (anterior thalamic) and direct (hippocampal) stimulation on local field potential (LFP) activity and network excitability, and to assess closed-loop stimulation within this neural network. METHODS: Following anesthesia and 1.5T MRI acquisition, unilateral anterior thalamic and hippocampal DBS leads were implanted in three subjects using a frameless stereotactic system. Chronic, awake recordings of evoked potentials (EPs) and LFPs in response to thalamic and hippocampal stimulation were collected with the implanted device and analyzed off-line. RESULTS: Consistent with earlier reports, thalamic DBS and direct stimulation of the hippocampus produced parameter-dependent effects on hippocampal activity. LFP suppression could be reliably induced with specific stimulation parameters, and was shown to reflect a state of reduced network excitability, as measured by effects on hippocampal EP amplitudes and after-discharge thresholds. Real-time modulation of network excitability via the implanted device was demonstrated using hippocampal theta-band power level as a control signal for closed-loop stimulation. CONCLUSIONS: The results presented provide evidence of network excitability changes induced by stimulation that could underlie the clinical effects that have been reported with both thalamic and direct cortical stimulation.

Chronic evaluation of a clinical system for deep brain stimulation and recording of neural network activity.

BACKGROUND/AIMS: In conjunction with therapeutic stimulation, next-generation deep brain stimulation (DBS) devices may offer the ability to record and analyze neural signals, providing for unprecedented insight into DBS effects on neural networks. This work was conducted to evaluate an implantable, clinical-grade system that permits concurrent stimulation and recording using a large animal (ovine) model recently developed to study DBS for epilepsy. METHODS: Following anesthesia and 1.5-tesla MRI acquisition, unilateral anterior thalamic and hippocampal DBS leads were implanted (n = 3) using a frameless stereotactic system. Chronic, awake recordings of evoked potentials (EPs) and local field potentials were collected with the implanted device and analyzed off-line. RESULTS: Hippocampal EPs were stable over long-term (>1 year) recording and consistent in morphology and latency with prior acute results. Thalamic and hippocampal DBS produced both excitatory and inhibitory network effects that were stimulation site and parameter dependent. Free roaming recordings illustrated periods of highly correlated activity between these two structures within the circuit of Papez. CONCLUSIONS: These results provide further insight into mechanisms of DBS therapy for epilepsy and an encouraging demonstration of the capabilities of this new technology, which in the future, may afford unique opportunities to study human brain function and neuromodulation mechanism of action.

In vivo electrical stimulation of rabbit retina with a microfabricated array: strategies to maximize responses for prospective assessment of stimulus efficacy and biocompatibility.

PURPOSE: Our primary goal was to assess the effects of varying stimulus parameters on the electrically evoked cortical potentials (EECPs) in rabbits, which we intend to use as one measure of biocompatibility of implanted retinal prosthetic devices. We also sought to exclude contamination of waveforms recorded over the occipital cortex from electrical activity from the retina and the degree of reproducibility of EECP recordings. METHODS: A concentric bipolar platinum electrode or microfabricated 5x5 electrode array delivered current to the retina of 43 Dutch-belted rabbits while the EECP was recorded from extradural electrodes over the occipital cortex. Electroretinogram (ERG) and visual evoked cortical potential (VECP) recordings were routinely obtained. Verification that occipital cortical recordings were not heavily contaminated by electrical potentials from the retina (i.e. the "validity" of the cortical recordings) was made by recording retinal and brain responses before and after intravitreal injection of tetrodotoxin. Electrical stimulation of the retina was performed with monopolar (with distant return) or bipolar electrode configurations. Cortical responses were computer-averaged over 100-500 stimulations. The effect of variation in stimulus current, charge, duration, frequency, polarity and spatial orientation of stimulating electrodes on cortical responses was studied. RESULTS: Progressive reduction of responses toward the anterior skull and abolition of posterior recordings by tetrodotoxin indicated that retinal activity did not significantly contaminate EECP recordings. Reproducibility testing revealed that inter-animal variability within the first hour of testing across all animals was not significantly greater than that found during prolonged testing of a single animal. The lowest current that yielded a reproducible EECP with monopolar stimulation was 75 microA (total current through 21 electrodes) using 200 microsec pulses, which yielded a 45 microV cortical response. Strength-duration curves were generally flat for fixed charge stimulation and linear for fixed current stimulation, at least up to a saturation point, which occurred at very high charge. Over 0.5-16 Hz stimulus frequencies, ERGs varied little but evoked potential responses showed a monotonic decline in amplitude at higher frequencies. Large negative-going initial pulses of a biphasic pair yielded the largest cortical amplitudes. EECP amplitudes varied significantly with the orientation of stimulating electrodes on the retina. CONCLUSIONS: This study provides novel data on the reproducibility of EECP recordings, and insight into stimulation parameters that affect retinal and cortical responses. This information can be used to improve the yield of retinal and evoked potential recordings, which will enhance the prospective assessment of the efficacy of stimulation and health of the stimulated tissues following.