Closed-loop neurostimulation for the treatment of psychiatric disorders.

Despite increasing prevalence and huge personal and societal burden, psychiatric diseases still lack treatments which can control symptoms for a large fraction of patients. Increasing insight into the neurobiology underlying these diseases has demonstrated wide-ranging aberrant activity and functioning in multiple brain circuits and networks. Together with varied presentation and symptoms, this makes one-size-fits-all treatment a challenge. There has been a resurgence of interest in the use of neurostimulation as a treatment for psychiatric diseases. Initial studies using continuous open-loop stimulation, in which clinicians adjusted stimulation parameters during patient visits, showed promise but also mixed results. Given the periodic nature and fluctuations of symptoms often observed in psychiatric illnesses, the use of device-driven closed-loop stimulation may provide more effective therapy. The use of a biomarker, which is correlated with specific symptoms, to deliver stimulation only during symptomatic periods allows for the personalized therapy needed for such heterogeneous disorders. Here, we provide the reader with background motivating the use of closed-loop neurostimulation for the treatment of psychiatric disorders. We review foundational studies of open- and closed-loop neurostimulation for neuropsychiatric indications, focusing on deep brain stimulation, and discuss key considerations when designing and implementing closed-loop neurostimulation.

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 depressive disorder (MDD), most studies to date have administered continuous or open-loop stimulation with promising but mixed results. One factor contributing to these mixed results may stem from when the stimulation is applied. Stimulation administration specific to high-symptom states in a personalized and responsive manner may be more effective at reducing symptoms compared to continuous stimulation and may avoid diminished therapeutic effects related to habituation. Additionally, a lower total duration of stimulation per day is advantageous for reducing device energy consumption. This protocol describes an experimental workflow using a chronically implanted neurostimulation device to achieve closed-loop stimulation for individuals with treatment-refractory MDD. This paradigm hinges on determining a patient-specific neural biomarker that is related to states of high symptoms and programming the device detectors, such that stimulation is triggered by this read-out of symptom state. The described procedures include how to obtain neural recordings concurrent with patient symptom reports, how to use these data in a state-space model approach to differentiate low- and high-symptom states and corresponding neural features, and how to subsequently program and tune the device to deliver closed-loop stimulation therapy.

Intracranial electrical stimulation of corticolimbic sites modulates arousal in humans.

BACKGROUND: Humans routinely shift their sleepiness and wakefulness levels in response to emotional factors. The diversity of emotional factors that modulates sleep-wake levels suggests that the ascending arousal network may be intimately linked with networks that mediate mood. Indeed, while animal studies have identified select limbic structures that play a role in sleep-wake regulation, the breadth of corticolimbic structures that directly modulates arousal in humans remains unknown. OBJECTIVE: We investigated whether select regional activation of the corticolimbic network through direct electrical stimulation can modulate sleep-wake levels in humans, as measured by subjective experience and behavior. METHODS: We performed intensive inpatient stimulation mapping in two human participants with treatment resistant depression, who underwent intracranial implantation with multi-site, bilateral depth electrodes. Stimulation responses of sleep-wake levels were measured by subjective surveys (i.e. Stanford Sleepiness Scale and visual-analog scale of energy) and a behavioral arousal score. Biomarker analyses of sleep-wake levels were performed by assessing spectral power features of resting-state electrophysiology. RESULTS: Our findings demonstrated three regions whereby direct stimulation modulated arousal, including the orbitofrontal cortex (OFC), subgenual cingulate (SGC), and, most robustly, ventral capsule (VC). Modulation of sleep-wake levels was frequency-specific: 100Hz OFC, SGC, and VC stimulation promoted wakefulness, whereas 1Hz OFC stimulation increased sleepiness. Sleep-wake levels were correlated with gamma activity across broad brain regions. CONCLUSIONS: Our findings provide evidence for the overlapping circuitry between arousal and mood regulation in humans. Furthermore, our findings open the door to new treatment targets and the consideration of therapeutic neurostimulation for sleep-wake disorders.

Decoding naturalistic affective behaviour from spectro-spatial features in multiday human iEEG.

The neurological basis of affective behaviours in everyday life is not well understood. We obtained continuous intracranial electroencephalography recordings from the human mesolimbic network in 11 participants with epilepsy and hand-annotated spontaneous behaviours from 116 h of multiday video recordings. In individual participants, binary random forest models decoded affective behaviours from neutral behaviours with up to 93% accuracy. Both positive and negative affective behaviours were associated with increased high-frequency and decreased low-frequency activity across the mesolimbic network. The insula, amygdala, hippocampus and anterior cingulate cortex made stronger contributions to affective behaviours than the orbitofrontal cortex, but the insula and anterior cingulate cortex were most critical for differentiating behaviours with observable affect from those without. In a subset of participants (N = 3), multiclass decoders distinguished amongst the positive, negative and neutral behaviours. These results suggest that spectro-spatial features of brain activity in the mesolimbic network are associated with affective behaviours of everyday life.

Intracranial electroencephalographic biomarker predicts effective responsive neurostimulation for epilepsy prior to treatment.

OBJECTIVE: Despite the overall success of responsive neurostimulation (RNS) therapy for drug-resistant focal epilepsy, clinical outcomes in individuals vary significantly and are hard to predict. Biomarkers that indicate the clinical efficacy of RNS-ideally before device implantation-are critically needed, but challenges include the intrinsic heterogeneity of the RNS patient population and variability in clinical management across epilepsy centers. The aim of this study is to use a multicenter dataset to evaluate a candidate biomarker from intracranial electroencephalographic (iEEG) recordings that predicts clinical outcome with subsequent RNS therapy. METHODS: We assembled a federated dataset of iEEG recordings, collected prior to RNS implantation, from a retrospective cohort of 30 patients across three major epilepsy centers. Using ictal iEEG recordings, each center independently calculated network synchronizability, a candidate biomarker indicating the susceptibility of epileptic brain networks to RNS therapy. RESULTS: Ictal measures of synchronizability in the high-γ band (95-105 Hz) significantly distinguish between good and poor RNS responders after at least 3 years of therapy under the current RNS therapy guidelines (area under the curve = .83). Additionally, ictal high-γ synchronizability is inversely associated with the degree of therapeutic response. SIGNIFICANCE: This study provides a proof-of-concept roadmap for collaborative biomarker evaluation in federated data, where practical considerations impede full data sharing across centers. Our results suggest that network synchronizability can help predict therapeutic response to RNS therapy. With further validation, this biomarker could facilitate patient selection and help avert a costly, invasive intervention in patients who are unlikely to benefit.

Distributed Subnetworks of Depression Defined by Direct Intracranial Neurophysiology.

Major depressive disorder is a common and disabling disorder with high rates of treatment resistance. Evidence suggests it is characterized by distributed network dysfunction that may be variable across patients, challenging the identification of quantitative biological substrates. We carried out this study to determine whether application of a novel computational approach to a large sample of high spatiotemporal resolution direct neural recordings in humans could unlock the functional organization and coordinated activity patterns of depression networks. This group level analysis of depression networks from heterogenous intracranial recordings was possible due to application of a correlational model-based method for inferring whole-brain neural activity. We then applied a network framework to discover brain dynamics across this model that could classify depression. We found a highly distributed pattern of neural activity and connectivity across cortical and subcortical structures that was present in the majority of depressed subjects. Furthermore, we found that this depression signature consisted of two subnetworks across individuals. The first was characterized by left temporal lobe hypoconnectivity and pathological beta activity. The second was characterized by a hypoactive, but hyperconnected left frontal cortex. These findings have applications toward personalization of therapy.

Closed-loop neuromodulation in an individual with treatment-resistant depression.

Deep brain stimulation is a promising treatment for neuropsychiatric conditions such as major depression. It could be optimized by identifying neural biomarkers that trigger therapy selectively when symptom severity is elevated. We developed an approach that first used multi-day intracranial electrophysiology and focal electrical stimulation to identify a personalized symptom-specific biomarker and a treatment location where stimulation improved symptoms. We then implanted a chronic deep brain sensing and stimulation device and implemented a biomarker-driven closed-loop therapy in an individual with depression. Closed-loop therapy resulted in a rapid and sustained improvement in depression. Future work is required to determine if the results and approach of this n-of-1 study generalize to a broader population.

Effects of anterior thalamic nuclei stimulation on hippocampal activity: Chronic recording in a patient with drug-resistant focal epilepsy.

Implanted neurostimulation devices are gaining traction as palliative treatment options for certain forms of drug-resistant epilepsy, but clinical utility of these devices is hindered by incomplete mechanistic understanding of their therapeutic effects. Approved devices for anterior thalamic nuclei deep brain stimulation (ANT DBS) are thought to work at a network level, but limited sensing capability precludes characterization of neurophysiological effects outside the thalamus. Here, we describe a patient with drug-resistant temporal lobe epilepsy who was implanted with a responsive neurostimulation device (RNS System), involving hippocampal and ipsilateral temporal neocortical leads, and subsequently received ANT DBS. Over 1.5 years, RNS System electrocorticography enabled multiscale characterization of neurophysiological effects of thalamic stimulation. In brain regions sampled by the RNS System, ANT DBS produced acute, phasic, frequency-dependent responses, including suppression of hippocampal low frequency local field potentials. ANT DBS modulated functional connectivity between hippocampus and neocortex. Finally, ANT DBS progressively suppressed hippocampal epileptiform activity in relation to the extent of hippocampal theta suppression, which informs stimulation parameter selection for ANT DBS. Taken together, this unique clinical scenario, involving hippocampal recordings of unprecedented chronicity alongside ANT DBS, sheds light on the therapeutic mechanism of thalamic stimulation and highlights capabilities needed in next-generation devices.

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

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.

Evidence of state-dependence in the effectiveness of responsive neurostimulation for seizure modulation.

BACKGROUND: An implanted device for brain-responsive neurostimulation (RNS® System) is approved as an effective treatment to reduce seizures in adults with medically-refractory focal epilepsy. Clinical trials of the RNS System demonstrate population-level reduction in average seizure frequency, but therapeutic response is highly variable. HYPOTHESIS: Recent evidence links seizures to cyclical fluctuations in underlying risk. We tested the hypothesis that effectiveness of responsive neurostimulation varies based on current state within cyclical risk fluctuations. METHODS: We analyzed retrospective data from 25 adults with medically-refractory focal epilepsy implanted with the RNS System. Chronic electrocorticography was used to record electrographic seizures, and hidden Markov models decoded seizures into fluctuations in underlying risk. State-dependent associations of RNS System stimulation parameters with changes in risk were estimated. RESULTS: Higher charge density was associated with improved outcomes, both for remaining in a low seizure risk state and for transitioning from a high to a low seizure risk state. The effect of stimulation frequency depended on initial seizure risk state: when starting in a low risk state, higher stimulation frequencies were associated with remaining in a low risk state, but when starting in a high risk state, lower stimulation frequencies were associated with transition to a low risk state. Findings were consistent across bipolar and monopolar stimulation configurations. CONCLUSION: The impact of RNS on seizure frequency exhibits state-dependence, such that stimulation parameters which are effective in one seizure risk state may not be effective in another. These findings represent conceptual advances in understanding the therapeutic mechanism of RNS, and directly inform current practices of RNS tuning and the development of next-generation neurostimulation systems.

Early seizure spread and epilepsy surgery: A systematic review.

OBJECTIVE: A fundamental question in epilepsy surgery is how to delineate the margins of cortex that must be resected to result in seizure freedom. Whether and which areas showing seizure activity early in ictus must be removed to avoid postoperative recurrence of seizures is an area of ongoing research. Seizure spread dynamics in the initial seconds of ictus are often correlated with postoperative outcome; there is neither a consensus definition of early spread nor a concise summary of the existing literature linking seizure spread to postsurgical seizure outcomes. The present study is intended to summarize the literature that links seizure spread to postoperative seizure outcome and to provide a framework for quantitative assessment of early seizure spread. METHODS: A systematic review was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A Medline search identified clinical studies reporting data on seizure spread measured by intracranial electrodes, having at least 10 subjects and reporting at least 1-year postoperative outcome in the English literature from 1990 to 2019. Studies were evaluated regarding support for a primary hypothesis: Areas of early seizure spread represent cortex with seizure-generating potential. RESULTS: The search yielded 4562 studies: 15 studies met inclusion criteria and 7 studies supported the primary hypothesis. The methods and metrics used to describe seizure spread were heterogenous. The timeframe of seizure spread associated with seizure outcome ranged from 1-14 seconds, with large, well-designed, retrospective studies pointing to 3-10 seconds as most likely to provide meaningful correlates of postoperative seizure freedom. SIGNIFICANCE: The complex correlation between electrophysiologic seizure spread and the potential for seizure generation needs further elucidation. Prospective cohort studies or trials are needed to evaluate epilepsy surgery targeting cortex involved in the first 3-10 seconds of ictus.

Functional brain network reconfiguration during learning in a dynamic environment.

When learning about dynamic and uncertain environments, people should update their beliefs most strongly when new evidence is most informative, such as when the environment undergoes a surprising change or existing beliefs are highly uncertain. Here we show that modulations of surprise and uncertainty are encoded in a particular, temporally dynamic pattern of whole-brain functional connectivity, and this encoding is enhanced in individuals that adapt their learning dynamics more appropriately in response to these factors. The key feature of this whole-brain pattern of functional connectivity is stronger connectivity, or functional integration, between the fronto-parietal and other functional systems. Our results provide new insights regarding the association between dynamic adjustments in learning and dynamic, large-scale changes in functional connectivity across the brain.

Model-based design for seizure control by stimulation.

OBJECTIVE: Current brain stimulation paradigms are largely empirical rather than theoretical. An opportunity exists to improve upon their modest effectiveness in closed-loop control strategies with the development of theoretically grounded, model-based designs. APPROACH: Inspired by this need, here we couple experimental data and mathematical modeling with a control-theoretic strategy for seizure termination. We begin by exercising a dynamical systems approach to model seizures (n = 94) recorded using intracranial EEG (iEEG) from 21 patients with medication-resistant, localization-related epilepsy. MAIN RESULTS: Although each patient's seizures displayed unique spatial and temporal patterns, their evolution can be parsimoniously characterized by the same model form. Idiosyncracies of the model can inform individualized intervention strategies, specifically in iEEG samples with well-localized seizure onset zones. Temporal fluctuations in the spatial profiles of the oscillatory modes show that seizure onset marks a transition into a regime in which the underlying system supports prolonged rhythmic and focal activity. Based on these observations, we propose a control-theoretic strategy that aims to stabilize ictal activity using static output feedback for linear time-invariant switching systems. Finally, we demonstrate in silico that our proposed strategy allows us to dampen the emerging focal oscillatory sources using only a small set of electrodes. SIGNIFICANCE: Our integrative study informs the development of modulation and control algorithms for neurostimulation that could improve the effectiveness of implantable, closed-loop anti-epileptic devices.

Emerging roles of network analysis for epilepsy.

In recent years there has been increasing interest in applying network science tools to EEG data. At the 2018 American Epilepsy Society conference in New Orleans, LA, the yearly session of the Engineering and Neurostimulation Special Interest Group focused on emerging, translational technologies to analyze seizure networks. Each speaker demonstrated practical examples of how network tools can be utilized in clinical care and provide additional data to help care for patients with intractable epilepsy. The groups presented advances using tools from functional connectivity, control theory, and graph theory to analyze human EEG data. These tools have great potential to augment clinical interpretation of EEG signals.

Virtual resection predicts surgical outcome for drug-resistant epilepsy.

Patients with drug-resistant epilepsy often require surgery to become seizure-free. While laser ablation and implantable stimulation devices have lowered the morbidity of these procedures, seizure-free rates have not dramatically improved, particularly for patients without focal lesions. This is in part because it is often unclear where to intervene in these cases. To address this clinical need, several research groups have published methods to map epileptic networks but applying them to improve patient care remains a challenge. In this study we advance clinical translation of these methods by: (i) presenting and sharing a robust pipeline to rigorously quantify the boundaries of the resection zone and determining which intracranial EEG electrodes lie within it; (ii) validating a brain network model on a retrospective cohort of 28 patients with drug-resistant epilepsy implanted with intracranial electrodes prior to surgical resection; and (iii) sharing all neuroimaging, annotated electrophysiology, and clinical metadata to facilitate future collaboration. Our network methods accurately forecast whether patients are likely to benefit from surgical intervention based on synchronizability of intracranial EEG (area under the receiver operating characteristic curve of 0.89) and provide novel information that traditional electrographic features do not. We further report that removing synchronizing brain regions is associated with improved clinical outcome, and postulate that sparing desynchronizing regions may further be beneficial. Our findings suggest that data-driven network-based methods can identify patients likely to benefit from resective or ablative therapy, and perhaps prevent invasive interventions in those unlikely to do so.

White Matter Network Architecture Guides Direct Electrical Stimulation through Optimal State Transitions.

Optimizing direct electrical stimulation for the treatment of neurological disease remains difficult due to an incomplete understanding of its physical propagation through brain tissue. Here, we use network control theory to predict how stimulation spreads through white matter to influence spatially distributed dynamics. We test the theory's predictions using a unique dataset comprising diffusion weighted imaging and electrocorticography in epilepsy patients undergoing grid stimulation. We find statistically significant shared variance between the predicted activity state transitions and the observed activity state transitions. We then use an optimal control framework to posit testable hypotheses regarding which brain states and structural properties will efficiently improve memory encoding when stimulated. Our work quantifies the role that white matter architecture plays in guiding the dynamics of direct electrical stimulation and offers empirical support for the utility of network control theory in explaining the brain's response to stimulation.

Functional control of electrophysiological network architecture using direct neurostimulation in humans.

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

Integrating EEG and MEG Signals to Improve Motor Imagery Classification in Brain-Computer Interface.

We adopted a fusion approach that combines features from simultaneously recorded electroencephalogram (EEG) and magnetoencephalogram (MEG) signals to improve classification performances in motor imagery-based brain-computer interfaces (BCIs). We applied our approach to a group of 15 healthy subjects and found a significant classification performance enhancement as compared to standard single-modality approaches in the alpha and beta bands. Taken together, our findings demonstrate the advantage of considering multimodal approaches as complementary tools for improving the impact of noninvasive BCIs.