closed-loop-neurostimulation-for-biomarker-driven-personalized

Closed-Loop Neurostimulation for Biomarker-Driven, Personalized Treatment of Major Depressive Disorder

Deep brain stimulation involves the administration of electrical stimulation to targeted brain regions for therapeutic benefit. In the context of major ...

University of California, San Francisco

Castleman's disease is a rare lymphoproliferative disorder which occurs in localized and multicentric forms and can mimic lymphoma. Despite its well-known association with certain autoimmune diseases, including paraneoplastic pemphigus and myasthenia gravis, Castleman's disease has not previously been associated with limbic encephalitis.

Multicentric Castleman's disease with voltage-gated potassium channel antibody-positive limbic encephalitis: a case report.

Our cognitive abilities emerge from the coordinated activity of neurons in the brain. The average human brain contains 86 billion neurons that are richly interconnected through synapses, contact points for electrochemical communication. Patterns of synaptic connectivity create functional ensembles of neurons, called neural circuits, which mediate information processing in the brain. Neural circuits can be deconstructed further into basic motifs ('microcircuits') involving feedforward and feedback connections between different types of neurons that exert excitatory or inhibitory influence. At each level of neural circuitry, the opposing forces of excitation and inhibition are normally held in balance through a variety of homeostatic mechanisms.

Epilepsy.

Direct intracranial recording of human brain activity is an important approach for deciphering neural mechanisms of cognition. Such recordings, usually made in patients with epilepsy undergoing inpatient monitoring for seizure localization, are limited in duration and depend on patients' tolerance for the challenges associated with recovering from brain surgery. Thus, typical intracranial recordings, similar to most non-invasive approaches in humans, provide snapshots of brain activity in acute, highly constrained settings, limiting opportunities to understand long timescale and natural, real-world phenomena. A new device for treating some forms of drug-resistant epilepsy, the NeuroPace RNS® System, includes a cranially-implanted neurostimulator and intracranial electrodes that continuously monitor brain activity and respond to incipient seizures with electrical counterstimulation. The RNS System can record epileptic brain activity over years, but whether it can record meaningful, behavior-related physiological responses has not been demonstrated. Here, in a human subject with electrodes implanted over high-level speech-auditory cortex (Wernicke's area; posterior superior temporal gyrus), we report that cortical evoked responses to spoken sentences are robust, selective to phonetic features, and stable over nearly 1.5 years. In a second subject with RNS System electrodes implanted over frontal cortex (Broca's area, posterior inferior frontal gyrus), we found that word production during a naming task reliably evokes cortical responses preceding speech onset. The spatiotemporal resolution, high signal-to-noise, and wireless nature of this system's intracranial recordings make it a powerful new approach to investigate the neural correlates of human cognition over long timescales in natural ambulatory settings.

Chronic ambulatory electrocorticography from human speech cortex.

Responsive neurostimulation (RNS) has recently emerged as a safe and effective treatment for some patients with medically refractory focal epilepsy who are not candidates for surgical resection. Responsive neurostimulation involves an implanted neurostimulator and intracranial leads that detect incipient seizures and respond with electrical counterstimulation. Over 1800 patients have been treated with RNS since its FDA approval in 2013. Despite its widespread use, however, RNS presents distinct challenges for clinicians. What types of patients are most well-suited for treatment with RNS? Given the availability of two other neurostimulation modalities, vagus nerve stimulation (VNS) and thalamic deep brain stimulation (DBS), what patient characteristics favor or disfavor RNS? Once RNS candidates are identified, lead placement presents another challenge. Unlike VNS and thalamic DBS, which both involve prespecified electrode locations, RNS involves intracranial strip and/or depth electrodes that can be flexibly configured based on knowledge of the seizure onset zone. The efficacy of RNS may depend on optimal lead configuration, but there are few resources to guide clinicians in formulating lead placement strategies. Here, we address these challenges, first by reviewing clinical trial data supporting the safety and efficacy of RNS. Then, through a series of clinical vignettes from our center, we provide a framework for RNS patient selection. For each clinical scenario, we illustrate typical strategies for RNS lead placement. We outline considerations for choosing among available neurostimulation devices based on their intrinsic features. For example, a unique feature of RNS is that the neurostimulator provides chronic electrocorticography (ECoG), which has powerful diagnostic potential. We highlight emerging applications of chronic ECoG, and we discuss how the limitations of RNS will inform development of next-generation devices.

Responsive neurostimulation: Candidates and considerations.

Surgical resection of seizure-producing brain tissue is a gold standard treatment for drug-resistant focal epilepsy. However, several patient-specific factors can preclude resective surgery, including a spatially extensive ("regional") seizure-onset zone (SOZ). For such patients, responsive neurostimulation (RNS) represents a potential treatment, but its efficacy has not been investigated in this population.

Responsive neurostimulation for regional neocortical epilepsy.

Neurostimulation devices that deliver electrical impulses to the nervous system are widely used to treat seizures in patients with medically refractory epilepsy, but the effects of these therapies on sleep are incompletely understood. Vagus nerve stimulation can contribute to obstructive sleep apnea, and thalamic deep brain stimulation can cause sleep disruption. A device for brain-responsive neurostimulation (RNS System, NeuroPace, Inc) is well tolerated in clinical trials, but potential effects on sleep are unknown.

Sleep disruption is not observed with brain-responsive neurostimulation for epilepsy.

To study the pregnancy outcomes, including obstetric complications and fetal outcomes, in pregnant women with epilepsy (WWE) treated with direct brain-responsive neurostimulation (RNS System).

Pregnancy outcomes of refractory epilepsy patients treated with Brain-responsive neurostimulation.

Everyday tasks in social settings require humans to encode neural representations of not only their own spatial location, but also the location of other individuals within an environment. At present, the vast majority of what is known about neural representations of space for self and others stems from research in rodents and other non-human animals. However, it is largely unknown how the human brain represents the location of others, and how aspects of human cognition may affect these location-encoding mechanisms. To address these questions, we examined individuals with chronically implanted electrodes while they carried out real-world spatial navigation and observation tasks. We report boundary-anchored neural representations in the medial temporal lobe that are modulated by one's own as well as another individual's spatial location. These representations depend on one's momentary cognitive state, and are strengthened when encoding of location is of higher behavioural relevance. Together, these results provide evidence for a common encoding mechanism in the human brain that represents the location of oneself and others in shared environments, and shed new light on the neural mechanisms that underlie spatial navigation and awareness of others in real-world scenarios.

Boundary-anchored neural mechanisms of location-encoding for self and others.

Responsive neurostimulation (RNS) devices, able to detect imminent seizures and to rapidly deliver electrical stimulation to the brain, are effective in reducing seizures in some patients with focal epilepsy. However, therapeutic response to RNS is often slow, is highly variable, and defies prognostication based on clinical factors. A prevailing view holds that RNS efficacy is primarily mediated by acute seizure termination; yet, stimulations greatly outnumber seizures and occur mostly in the interictal state, suggesting chronic modulation of brain networks that generate seizures. Here, using years-long intracranial neural recordings collected during RNS therapy, we found that patients with the greatest therapeutic benefit undergo progressive, frequency-dependent reorganization of interictal functional connectivity. The extent of this reorganization scales directly with seizure reduction and emerges within the first year of RNS treatment, enabling potential early prediction of therapeutic response. Our findings reveal a mechanism for RNS that involves network plasticity and may inform development of next-generation devices for epilepsy.

Long-term brain network reorganization predicts responsive neurostimulation outcomes for focal epilepsy.

Responsive neurostimulation is a promising treatment for drug-resistant focal epilepsy; however, clinical outcomes are highly variable across individuals. The therapeutic mechanism of responsive neurostimulation likely involves modulatory effects on brain networks; however, with no known biomarkers that predict clinical response, patient selection remains empiric. This study aimed to determine whether functional brain connectivity measured non-invasively prior to device implantation predicts clinical response to responsive neurostimulation therapy. Resting-state magnetoencephalography was obtained in 31 participants with subsequent responsive neurostimulation device implantation between 15 August 2014 and 1 October 2020. Functional connectivity was computed across multiple spatial scales (global, hemispheric, and lobar) using pre-implantation magnetoencephalography and normalized to maps of healthy controls. Normalized functional connectivity was investigated as a predictor of clinical response, defined as percent change in self-reported seizure frequency in the most recent year of clinic visits relative to pre-responsive neurostimulation baseline. Area under the receiver operating characteristic curve quantified the performance of functional connectivity in predicting responders (≥50% reduction in seizure frequency) and non-responders (<50%). Leave-one-out cross-validation was furthermore performed to characterize model performance. The relationship between seizure frequency reduction and frequency-specific functional connectivity was further assessed as a continuous measure. Across participants, stimulation was enabled for a median duration of 52.2 (interquartile range, 27.0-62.3) months. Demographics, seizure characteristics, and responsive neurostimulation lead configurations were matched across 22 responders and 9 non-responders. Global functional connectivity in the alpha and beta bands were lower in non-responders as compared with responders (alpha, p < 0.001; beta, p < 0.001). The classification of responsive neurostimulation outcome was improved by combining feature inputs; the best model incorporated four features (i.e. mean and dispersion of alpha and beta bands) and yielded an area under the receiver operating characteristic curve of 0.970 (0.919-1.00). The leave-one-out cross-validation analysis of this four-feature model yielded a sensitivity of 86.3%, specificity of 77.8%, positive predictive value of 90.5%, and negative predictive value of 70%. Global functional connectivity in alpha band correlated with seizure frequency reduction (alpha,  = 0.010). Global functional connectivity predicted responder status more strongly, as compared with hemispheric predictors. Lobar functional connectivity was not a predictor. These findings suggest that non-invasive functional connectivity may be a candidate personalized biomarker that has the potential to predict responsive neurostimulation effectiveness and to identify patients most likely to benefit from responsive neurostimulation therapy. Follow-up large-cohort, prospective studies are required to validate this biomarker. These findings furthermore support an emerging view that the therapeutic mechanism of responsive neurostimulation involves network-level effects in the brain.

Network connectivity predicts effectiveness of responsive neurostimulation in focal epilepsy.

In classic speech network models, the primary auditory cortex is the source of auditory input to Wernicke's area in the posterior superior temporal gyrus (pSTG). Because resection of the primary auditory cortex in the dominant hemisphere removes inputs to the pSTG, there is a risk of speech impairment. However, recent research has shown the existence of other, nonprimary auditory cortex inputs to the pSTG, potentially reducing the risk of primary auditory cortex resection in the dominant hemisphere.

Intact speech perception after resection of dominant hemisphere primary auditory cortex for the treatment of medically refractory epilepsy: illustrative case.

Seizure emergencies and potential emergencies, ranging from seizure clusters to prolonged seizure and status epilepticus, may affect adults with epilepsy despite stable antiseizure therapy. Seizure action plans (SAPs) are designed for patients and their caregivers/care partners to provide guidance on the individualized treatment plan, including response to potential seizure emergencies and appropriate use of rescue therapy. The use of pediatric SAPs is common (typically required by schools), however, most adults with epilepsy do not have a plan. Patient-centered action plans are integral to care for other chronic conditions and may offer insights applicable to the care of adults with epilepsy. This review analyzes the potential benefits of action plans for medical conditions by exploring their utility in conditions such as asthma, diabetes, chronic obstructive pulmonary disease, heart disease, and opioid overdose. Evidence across these conditions substantiates the value of action plans for patients, and the benefits of adult SAPs in epilepsy are emerging. Because wide implementation of SAPs has faced barriers, other conditions may provide insights that are relevant to implementing SAPs in epilepsy. Based on these analyses, we propose concrete steps to improve the use of SAPs among adults. A recent consensus statement promoting the use of formal SAPs in epilepsy and advances in rescue therapy delivery methods provides support to engage patients around the value of SAPs. The precedent for use of SAPs for pediatric epilepsy patients serves as the foundation to support increased usage in adults. Seizure action plans in the context of improved clinical outcomes are expected to reduce healthcare utilization, improve patient quality of life, and optimize epilepsy management.

Article	Year
Multicentric Castleman's disease with voltage-gated potassium channel antibody-positive limbic encephalitis: a case report. BMC neurology\| PubMed ID: 25648431	2015
Epilepsy. Current biology : CB\| PubMed ID: 26325130	2015
Chronic ambulatory electrocorticography from human speech cortex. NeuroImage\| PubMed ID: 28396294	2017
Responsive neurostimulation: Candidates and considerations. Epilepsy & behavior : E&B\| PubMed ID: 30355456	2018
Responsive neurostimulation for regional neocortical epilepsy. Epilepsia\| PubMed ID: 31828780	2020
Sleep disruption is not observed with brain-responsive neurostimulation for epilepsy. Epilepsia open\| PubMed ID: 32524041	2020
Pregnancy outcomes of refractory epilepsy patients treated with Brain-responsive neurostimulation. Epilepsy research\| PubMed ID: 33360540	2021
Boundary-anchored neural mechanisms of location-encoding for self and others. Nature\| PubMed ID: 33361808	2021
Long-term brain network reorganization predicts responsive neurostimulation outcomes for focal epilepsy. Science translational medicine\| PubMed ID: 34433640	2021
Network connectivity predicts effectiveness of responsive neurostimulation in focal epilepsy. Brain communications\| PubMed ID: 35611310	2022
Intact speech perception after resection of dominant hemisphere primary auditory cortex for the treatment of medically refractory epilepsy: illustrative case. Journal of neurosurgery. Case lessons\| PubMed ID: 36443954	2022
Written seizure action plans for adult patients with epilepsy: Distilling insights from emergency action plans for other chronic conditions. Epilepsy & behavior : E&B\| PubMed ID: 36822041	2023

Vikram R. Rao

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