Levetiracetam Prevents Neurophysiological Changes and Preserves Cognitive Function in the Human Immunodeficiency Virus (HIV)-1 Transactivator of Transcription Transgenic Mouse Model of HIV-Associated Neurocognitive Disorder.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the central nervous system and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. SIGNIFICANCE STATEMENT: Approximately half of people living with human immunodeficiency virus (HIV) also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein transactivator of transcription (TAT) causes toxicity that is thought to contribute to HAND. Here, the antiepileptic drug levetiracetam (LEV) prevented synaptic and cognitive impairments in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-mediated neuroprotection in HAND.

Optimization of closed-loop electrical stimulation enables robust cerebellar-directed seizure control.

Additional treatment options for temporal lobe epilepsy are needed, and potential interventions targeting the cerebellum are of interest. Previous animal work has shown strong inhibition of hippocampal seizures through on-demand optogenetic manipulation of the cerebellum. However, decades of work examining electrical stimulation-a more immediately translatable approach-targeting the cerebellum has produced very mixed results. We were therefore interested in exploring the impact that stimulation parameters may have on seizure outcomes. Using a mouse model of temporal lobe epilepsy, we conducted on-demand electrical stimulation of the cerebellar cortex, and varied stimulation charge, frequency and pulse width, resulting in over 1000 different potential combinations of settings. To explore this parameter space in an efficient, data-driven, manner, we utilized Bayesian optimization with Gaussian process regression, implemented in MATLAB with an Expected Improvement Plus acquisition function. We examined three different fitting conditions and two different electrode orientations. Following the optimization process, we conducted additional on-demand experiments to test the effectiveness of selected settings. Regardless of experimental setup, we found that Bayesian optimization allowed identification of effective intervention settings. Additionally, generally similar optimal settings were identified across animals, suggesting that personalized optimization may not always be necessary. While optimal settings were effective, stimulation with settings predicted from the Gaussian process regression to be ineffective failed to provide seizure control. Taken together, our results provide a blueprint for exploration of a large parameter space for seizure control and illustrate that robust inhibition of seizures can be achieved with electrical stimulation of the cerebellum, but only if the correct stimulation parameters are used.

The cerebellum's understated role and influences in the epilepsies.

Approximately 1 in 26 people will develop epilepsy in their lifetime, but current treatment options leave as many as half of all epilepsy patients with uncontrolled seizures. In addition to the burden of the seizures themselves, chronic epilepsy can be associated with cognitive deficits, structural changes, and devastating negative outcomes such as sudden unexpected death in epilepsy (SUDEP). Thus, major challenges in epilepsy research surround the need to both develop new therapeutic targets for intervention as well as shed light on the mechanisms by which chronic epilepsy can lead to comorbidities and negative outcomes. Despite not being traditionally associated with epilepsy or seizures, the cerebellum has emerged as not only a brain region that can serve as an important target for seizure control, but one that may also be profoundly impacted by chronic epilepsy. Here, we discuss targeting the cerebellum for potential therapeutic intervention and discuss pathway insights gained from recent optogenetic studies. We then review observations of cerebellar alterations during seizures and in chronic epilepsy, as well as the potential for the cerebellum to be a seizure focus. Cerebellar alterations in epilepsy may be critical to patient outcomes, highlighting the need for a more comprehensive understanding and appreciation of the cerebellum in the epilepsies.

Distinct Fastigial Output Channels and Their Impact on Temporal Lobe Seizures.

Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear whether this broad targeting underlies seizure suppression, or whether a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely nonoverlapping populations of neurons that send collaterals to unique sets of additional, somewhat overlapping, thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures. Our results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. More broadly, our data highlight the concept of specific cerebellar output channels, whereby discrete cerebellar nucleus neurons project to specific aggregates of downstream targets, with important consequences for therapeutic interventions.SIGNIFICANCE STATEMENT The cerebellum has an emerging relationship with nonmotor systems and may represent a powerful target for therapeutic intervention in temporal lobe epilepsy. We find, as previously reported, that fastigial neurons project to numerous brain regions via largely segregated output channels, and that projection targets cannot be predicted simply by somatic locations within the nucleus. We further find that on-demand optogenetic excitation of fastigial neurons projecting to the central lateral nucleus of the thalamus-but not fastigial neurons projecting to the reticular formation, superior colliculus, or ventral lateral thalamus-is sufficient to attenuate hippocampal seizures.

HippoBellum: Acute Cerebellar Modulation Alters Hippocampal Dynamics and Function.

Here we examine what effects acute manipulation of the cerebellum, a canonically motor structure, can have on the hippocampus, a canonically cognitive structure. In male and female mice, acute perturbation of the cerebellar vermis (lobule 4/5) or simplex produced reliable and specific effects in hippocampal function at cellular, population, and behavioral levels, including evoked local field potentials, increased hippocampal cFos expression, and altered CA1 calcium event rate, amplitudes, and correlated activity. We additionally noted a selective deficit on an object location memory task, which requires objection-location pairing. We therefore combined cerebellar optogenetic stimulation and CA1 calcium imaging with an object-exploration task, and found that cerebellar stimulation reduced the representation of place fields near objects, and prevented a shift in representation to the novel location when an object was moved. Together, these results clearly demonstrate that acute modulation of the cerebellum alters hippocampal function, and further illustrates that the cerebellum can influence cognitive domains.SIGNIFICANCE STATEMENT The cerebellum, a canonically motor-related structure, is being increasingly recognized for its influence on nonmotor functions and structures. The hippocampus is a brain region critical for cognitive functions, such as episodic memory and spatial navigation. To investigate how modulation of the cerebellum may impact the hippocampus, we stimulated two sites of the cerebellar cortex and examined hippocampal function at multiple levels. We found that cerebellar stimulation strongly modulates hippocampal activity, disrupts spatial memory, and alters object-location processing. Therefore, a canonically cognitive brain area, the hippocampus, is sensitive to cerebellar modulation.

The cerebellum and epilepsy.

Epilepsy is the fourth most common neurological disorder, but current treatment options provide limited efficacy and carry the potential for problematic adverse effects. There is an immense need to develop new therapeutic interventions in epilepsy, and targeting areas outside the seizure focus for neuromodulation has shown therapeutic value. While not traditionally associated with epilepsy, anatomical, clinical, and electrophysiological studies suggest the cerebellum can play a role in seizure networks, and importantly, may be a potential therapeutic target for seizure control. However, previous interventions targeting the cerebellum in both preclinical and clinical studies have produced mixed effects on seizures. These inconsistent results may be due in part to the lack of specificity inherent with open-loop electrical stimulation interventions. More recent studies, using more targeted closed-loop optogenetic approaches, suggest the possibility of robust seizure inhibition via cerebellar modulation for a range of seizure types. Therefore, while the mechanisms of cerebellar inhibition of seizures have yet to be fully elucidated, the cerebellum should be thoroughly revisited as a potential target for therapeutic intervention in epilepsy. This article is part of the Special Issue "NEWroscience 2018.

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures.

KEY POINTS: On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy. In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures. On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures. Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity. ABSTRACT: Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells - the fastigial nucleus - in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.

Selective loss of the GABAAα1 subunit from Purkinje cells is sufficient to induce a tremor phenotype.

Previously, an essential tremor-like phenotype has been noted in animals with a global knockout of the GABAAα1 subunit. Given the hypothesized role of the cerebellum in tremor, including essential tremor, we used transgenic mice to selectively knock out the GABAAα1 subunit from cerebellar Purkinje cells. We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of tremor. Purkinje cell specific knockout of the GABAAα1 subunit abolished all GABAA-mediated inhibition in Purkinje cells, while leaving GABAA-mediated inhibition to cerebellar molecular layer interneurons intact. Selective loss of GABAAα1 from Purkinje cells did not produce deficits on the accelerating rotarod, nor did it result in decreased survival rates. However, a tremor phenotype was apparent, regardless of sex or background strain. This tremor mimicked the tremor seen in animals with a global knockout of the GABAAα1 subunit, and, like essential tremor in patients, was responsive to ethanol. These findings indicate that reduced inhibition to Purkinje cells is sufficient to induce a tremor phenotype, highlighting the importance of the cerebellum, inhibition, and Purkinje cells in tremor.NEW & NOTEWORTHY Animals with a global knockout of the GABAAα1 subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABAAα1 from Purkinje cells is sufficient to produce a tremor phenotype, although this tremor is less severe than seen in animals with a global knockout. These findings illustrate that the cerebellum can play a key role in the genesis of the observed tremor phenotype.

Axonal sprouting in commissurally projecting parvalbumin-expressing interneurons.

Previous research has shown that in vivo on-demand optogenetic stimulation of inhibitory interneurons expressing parvalbumin (PV) is sufficient to suppress seizures in a mouse model of temporal lobe epilepsy (TLE). Surprisingly, this intervention was capable of suppressing seizures when PV-expressing interneurons were stimulated ipsilateral or contralateral to the presumed seizure focus, raising the possibility of commissural inhibition in TLE. There are mixed reports regarding commissural PV interneuron projections in the healthy hippocampus, and it was previously unknown whether these connections would be maintained or modified following the network reorganization associated with TLE. Using retrograde labeling and viral vector technology in both sexes and the intrahippocampal kainate mouse model of TLE, we therefore examined these issues. Our results reveal that healthy controls possess a population of commissurally projecting hippocampal PV interneurons. Two weeks post kainate injection, we observed a slight, but not statistically significant decrease in retrogradely labeled PV interneurons in the hippocampus contralateral to kainate and tracer injection. By 6 months post kainate, however, there was a significant increase in retrogradely labeled PV interneurons, suggesting commissural inhibitory axonal sprouting. Using viral green fluorescent protein expression selectively in PV neurons, we demonstrated sprouting of commissural PV projections in the dentate gyrus of the kainate-injected hippocampus 6 months post kainate. These findings indicate that PV interneurons supply direct inhibition to the contralateral hippocampus and undergo sprouting in a mouse model of TLE. © 2017 Wiley Periodicals, Inc.

In vivo evaluation of the dentate gate theory in epilepsy.

The dentate gyrus is a region subject to intense study in epilepsy because of its posited role as a 'gate', acting to inhibit overexcitation in the hippocampal circuitry through its unique synaptic, cellular and network properties that result in relatively low excitability. Numerous changes predicted to produce dentate hyperexcitability are seen in epileptic patients and animal models. However, recent findings question whether changes are causative or reactive, as well as the pathophysiological relevance of the dentate in epilepsy. Critically, direct in vivo modulation of dentate 'gate' function during spontaneous seizure activity has not been explored. Therefore, using a mouse model of temporal lobe epilepsy with hippocampal sclerosis, a closed-loop system and selective optogenetic manipulation of granule cells during seizures, we directly tested the dentate 'gate' hypothesis in vivo. Consistent with the dentate gate theory, optogenetic gate restoration through granule cell hyperpolarization efficiently stopped spontaneous seizures. By contrast, optogenetic activation of granule cells exacerbated spontaneous seizures. Furthermore, activating granule cells in non-epileptic animals evoked acute seizures of increasing severity. These data indicate that the dentate gyrus is a critical node in the temporal lobe seizure network, and provide the first in vivo support for the dentate 'gate' hypothesis.

How might novel technologies such as optogenetics lead to better treatments in epilepsy?

Recent technological advances open exciting avenues for improving the understanding of mechanisms in a broad range of epilepsies. This chapter focuses on the development of optogenetics and on-demand technologies for the study of epilepsy and the control of seizures. Optogenetics is a technique which, through cell-type selective expression of light-sensitive proteins called opsins, allows temporally precise control via light delivery of specific populations of neurons. Therefore, it is now possible not only to record interictal and ictal neuronal activity, but also to test causality and identify potential new therapeutic approaches. We first discuss the benefits and caveats to using optogenetic approaches and recent advances in optogenetics related tools. We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research.

Distinct functional classes of CA1 hippocampal interneurons are modulated by cerebellar stimulation in a coordinated manner.

There is mounting evidence that the cerebellum impacts hippocampal functioning, but the impact of the cerebellum on hippocampal interneurons remains obscure. Using miniscopes in freely behaving animals, we find optogenetic stimulation of Purkinje cells alters the calcium activity of a large percentage of CA1 interneurons. This includes both increases and decreases in activity. Remarkably, this bidirectional impact occurs in a coordinated fashion, in line with interneurons' functional properties. Specifically, CA1 interneurons activated by cerebellar stimulation are commonly locomotion-active, while those inhibited by cerebellar stimulation are commonly rest-active interneurons. We additionally find that subsets of CA1 interneurons show altered activity during object investigations, suggesting a role in the processing of objects in space. Importantly, these neurons also show coordinated modulation by cerebellar stimulation: CA1 interneurons that are activated by cerebellar stimulation are more likely to be activated, rather than inhibited, during object investigations, while interneurons that show decreased activity during cerebellar stimulation show the opposite profile. Therefore, CA1 interneurons play a role in object processing and in cerebellar impacts on the hippocampus, providing insight into previously noted altered CA1 processing of objects in space with cerebellar stimulation. We examined two different stimulation locations (IV/V Vermis; Simplex) and two different stimulation approaches (7Hz or a single 1s light pulse) - in all cases, the cerebellum induces similar coordinated CA1 interneuron changes congruent with an explorative state. Overall, our data show that the cerebellum impacts CA1 interneurons in a bidirectional and coordinated fashion, positioning them to play an important role in cerebello-hippocampal communication. Significance Statement: Acute manipulation of the cerebellum can affect the activity of cells in CA1, and perturbing normal cerebellar functioning can affect hippocampal-dependent spatial processing, including the processing of objects in space. Despite the importance of interneurons on the local hippocampal circuit, it was unknown how cerebellar activation impacts CA1 inhibitory neurons. We find that stimulating the cerebellum robustly affects multiple populations of CA1 interneurons in a bidirectional, coordinated manner, according to their functional profiles during behavior, including locomotion and object investigations. Our work also provides support for a role of CA1 interneurons in spatial processing of objects, with populations of interneurons showing altered activity during object investigations.

LINCs Are Vulnerable to Epileptic Insult and Fail to Provide Seizure Control via On-Demand Activation.

Temporal lobe epilepsy (TLE) is notoriously pharmacoresistant, and identifying novel therapeutic targets for controlling seizures is crucial. Long-range inhibitory neuronal nitric oxide synthase-expressing cells (LINCs), a population of hippocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABAA-mediated and GABAB-mediated postsynaptic inhibition. We therefore hypothesized that LINCs could be an effective target for seizure control. LINCs were optogenetically activated for on-demand seizure intervention in the intrahippocampal kainate (KA) mouse model of chronic TLE. Unexpectedly, LINC activation at 1 month post-KA did not substantially reduce seizure duration in either male or female mice. We tested two different sets of stimulation parameters, both previously found to be effective with on-demand optogenetic approaches, but neither was successful. Quantification of LINCs following intervention revealed a substantial reduction of LINC numbers compared with saline-injected controls. We also observed a decreased number of LINCs when the site of initial insult (i.e., KA injection) was moved to the amygdala [basolateral amygdala (BLA)-KA], and correspondingly, no effect of light delivery on BLA-KA seizures. This indicates that LINCs may be a vulnerable population in TLE, regardless of the site of initial insult. To determine whether long-term circuitry changes could influence outcomes, we continued testing once a month for up to 6 months post-KA. However, at no time point did LINC activation provide meaningful seizure suppression. Altogether, our results suggest that LINCs are not a promising target for seizure inhibition in TLE.

The little brain and the seahorse: Cerebellar-hippocampal interactions.

There is a growing appreciation for the cerebellum beyond its role in motor function and accumulating evidence that the cerebellum and hippocampus interact across a range of brain states and behaviors. Acute and chronic manipulations, simultaneous recordings, and imaging studies together indicate coordinated coactivation and a bidirectional functional connectivity relevant for various physiological functions, including spatiotemporal processing. This bidirectional functional connectivity is likely supported by multiple circuit paths. It is also important in temporal lobe epilepsy: the cerebellum is impacted by seizures and epilepsy, and modulation of cerebellar circuitry can be an effective strategy to inhibit hippocampal seizures. This review highlights some of the recent key hippobellum literature.

TRPM7 kinase mediates hypomagnesemia-induced seizure-related death.

Hypomagnesemia (HypoMg) can cause seizures and death, but the mechanism is unknown. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function. In this study, we focused on the kinase role of TRPM7 in HypoMg-induced seizures and death. Wild type C57BL/6J mice and transgenic mice with a global homozygous mutation in the TRPM7 kinase domain (TRPM7K1646R, with no kinase function) were fed with control diet or a HypoMg diet. After 6 weeks of HypoMg diet, mice had significantly decreased serum Mg, elevated brain TRPM7, and a significant rate of death, with females being most susceptible. Deaths were immediately preceded by seizure events. TRPM7K1646R mice showed resistance to seizure-induced death. HypoMg-induced brain inflammation and oxidative stress were suppressed by TRPM7K1646R. Compared to their male counterparts, HypoMg female mice had higher levels of inflammation and oxidative stress in the hippocampus. We concluded that TRPM7 kinase function contributes seizure-induced deaths in HypoMg mice and that inhibiting the kinase reduced inflammation and oxidative stress.

Ivy and neurogliaform interneurons are a major target of µ-opioid receptor modulation.

µ-Opioid receptors (µORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin-expressing, basket cells express µORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by µORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by µORs. Ivy and neurogliaform cells are not only numerous but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABA(B) response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that, across all layers of CA1, activation of µORs hyperpolarizes Ivy and neurogliaform cells. Furthermore, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by µOR activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking parvalbumin basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by µOR activation. Together, these findings identify a major, previously unrecognized, target of µOR modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications.

Intrinsic functional neuron-type selectivity of transcranial focused ultrasound neuromodulation.

Transcranial focused ultrasound (tFUS) is a promising neuromodulation technique, but its mechanisms remain unclear. We hypothesize that if tFUS parameters exhibit distinct modulation effects in different neuron populations, then the mechanism can be understood through identifying unique features in these neuron populations. In this work, we investigate the effect of tFUS stimulation on different functional neuron types in in vivo anesthetized rodent brains. Single neuron recordings were separated into regular-spiking and fast-spiking units based on their extracellular spike shapes acquired through intracranial electrophysiological recordings, and further validated in transgenic optogenetic mice models of light-excitable excitatory and inhibitory neurons. We show that excitatory and inhibitory neurons are intrinsically different in response to ultrasound pulse repetition frequency (PRF). The results suggest that we can preferentially target specific neuron types noninvasively by tuning the tFUS PRF. Chemically deafened rats and genetically deafened mice were further tested for validating the directly local neural effects induced by tFUS without potential auditory confounds.

Stimulating Solutions for Intractable Epilepsy.

Implantable devices for controlling medically intractable seizures nondestructively are rapidly advancing. These offer reversible, potentially, restorative options beyond traditional, surgical procedures, which rely, largely on resection or ablation of selected brain sites. Several lines of, investigation aimed at improving efficacy of these devices are discussed, ranging from identifying novel subcortical, white matter, or cell-type specific targets to engineering advances for adaptive techniques based- on continuous, dynamic system analysis.

From Point A to Point B, and What it Means for Epilepsy.

[Box: see text].