We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer’s disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank. The Eighth Annual deep brain stimulation (DBS) Think Tank meeting was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The DBS Think Tank presenters pooled data and determined that DBS has expanded in its scope and has been applied to multiple brain disorders. There have now been an estimated 208,000 DBS devices implanted for neurological and neuropsychiatric disorders worldwide. The DBS Think Tank was founded in 2012 and provides a space where clinicians, engineers, clinical-researchers, basic researchers and scientists from both industry and academia engage in discussions on current and emerging DBS technologies as well as tackle logistical and ethical issues facing the field. The DBS Think Tank has an emphasis on cutting edge research and collaboration which is aimed to more rapidly advance the DBS field.The DBS Think Tank meeting was focused on advances in the following areas:(1)optogenetics as a tool for comprehending the neurobiology of diseases and on optogenetically inspired DBS,(2)the cutting edge of emerging DBS technologies,(3)ethical issues affecting DBS research and access to care,(4)neuromodulatory approaches for depression,(5)advancing novel hardware, software and imaging methodologies,(6)the use of neurophysiological signals in adaptive neurostimulation,(7)the use of more advanced technologies to improve DBS clinical outcomes,(8)the use of novel techniques such as INTRSECT ,(9)an updated survey of 178 attendees which is performed each year to track trends in the field.These proceedings will summarize the Eighth Annual DBS Think Tank meeting.Optogenetics has advanced our comprehension of the pathophysiology and neurobiology of disease, and continues to bring promise to our fundamental comprehension of the role of specific cell types, and even single cells, in the brain. Channelrhodopsins are naturally occurring light-gated ion channels in algae, which have become important in neuroscience research for targeted control of specific circuit elements with optogenetic techniques. Here we discuss how optogenetics as a research tool can be used to uncover underlying circuitry and to motivate new approaches for applying DBS into the human population.It was Francis Crick who first suggested the rather far-fetched idea that light could be a useful tool for the investigation of neural function and that it could be used in a targeted manner. Since then, converging advances in genetics, optics and engineering have collectively shown substantial promise for the investigation of neurological diseases. Current neuromodulation methods (achieved via DBS) tend to stimulate all neurons in a certain volume of tissue, which may include cells not involved in disease and thus likely result in undesirable side-effects. Hence, controlling the activity of specific neurons has significant potential to advance the field of neuromodulation. Cell specific excitation (or inhibition) of neurons can be achieved using light via microbial opsins, which encode all-in-one proteins including ion channels called channelrhodopsins that transduce photons into electrical current , enablinRecruitment of opsins to modulate neuronal circuitry at the single cell level in living mammals was initially achieved via two photon activation of neurons . This ulTM) to implement chronically sensed brain signals, these opportunities for clinical value have become available more broadly. Very early evidence  beginning early in 2021. The Percept PCTM platform has also been architected to unlock other advanced capabilities with appropriate regulatory approvals for research, including novel stimulation waveforms, network connectivity, and directional sensing with DBS leads bearing segmented electrodes. Research-enabled commercial device platforms such as the Percept PCTM are poised to enable more rapid research translation through faster access to technological innovations and also offer fewer tradeoffs to clinical researchers and to research subjects.Over the past years, chronically sensed brain signals have been established as an important new opportunity for advancing the standard of care (SOC) in DBS therapies. Historically, access to such signals has been available on a limited basis via investigational devices specialized for such recordings, which have collectively allowed constrained exploration of such signals in research contexts. However, these signals were the impetus of significant scientific and technological discoveries in the DBS space. In the research literature, it has been shown that such signals are robust and chronically present over months to years , that thevidence  suggestsAdvancement of DBS device technology has made it possible to have multiple combinations of DBS programming settings in an effort to deliver better outcomes. Device programming on the other hand has only become more complicated. The development of a computer-guided closed-loop based programming algorithm could potentially make DBS programming easier for clinicians. In this context, Boston Scientific Neuromodulation (BSN) is working to improve tools to aid the clinical DBS workflow. These tools broadly include computer-aided programming (using objective outcome measurements), as well as stimulation field modeling with specificity to patient anatomy, which has been pursued through Boston Scientific’s CLOVER Study. CLOVER (NCT03037398) is a multi-center study which uses direct and objective symptom measures, such as from PD-validated, commercial finger-worn accelerometers, and integrates these measurements with a BSN-developed search and optimization algorithm. After three starting measurements, this algorithm iteratively suggests the next settings to test, until an optimum setting is found. Such an algorithm could assist both in-clinic and in remote programmers. BSN has recently updated the CLOVER algorithm to support programming of their directional leads. The preliminary results indicate that the new algorithm is able to converge in a single visit on stimulation settings that result in UPDRS motor score reductions (as compared to the baseline scores) that are statistically equivalent to multi-visit SOC programming (as defined by the clinician in the study) .Programming may also be aided using patient imaging data paired with three-dimensional stimulation models in the Guide XT software, developed in collaboration with BrainLab. When available, the combination of surgical, imaging, and stimulation response (such as aggregated therapy sweet spots) with real-time clinical response may further assist DBS programmers. BSN is working toward tools to enable large scale, group studies to further investigate the relationships between stimulation locations and clinical outcomes, including using population statistics in order to build probabilistic maps of stimulation. The results of these population-based analyses could be used to inform programming software. More research is needed to further explore the predictive value of these maps and their potential use in routine clinical DBS programming practices.1 and remote support technologies2 have been established in other Class 3 active implantable technologies. Remote programming of DBS systems has been enabled by China-based manufacturers but is not yet available in countries requiring CE or FDA approvals  reported by subjects within three weeks of a programming session which was conducted using the remote programming feature. Ten subjects connected with their treating clinician through the secure remote programming feature. No serious AEs were reported in this study and anticipated, non-serious AEs that were reported for 1 subject resolved without sequalae. Evaluation of such remote programming features will likely advance the field towards low-burden therapy options for patients and clinicians in the rapidly emerging digital health realm.Real-world analyses of claims data have previously shown a higher rate of DBS revision/removal procedures than typically recognized . The imppprovals . Abbott With the increased investigation and subsequent use of novel DBS therapies, there has been a simultaneous growth in ethical issues and considerations. One important issue that has been emerging is continued device access after the conclusion of a research study, which is generally considered to be ethically appropriate and desirable. Ascertaining whether researchers and industry sponsors are ethically obligated to facilitate continued access to those participants whose benefit requires a dialogue and engagement of all the relevant stakeholders. Additionally, the potential of DBS technologies for off-label use and the ethics surrounding this, specifically in vulnerable patient populations, must also be developed and subsequently reviewed.The use of various forms of neurotechnologies and techniques to define and model loci for possible interventional neuromodulation is opening new vistas of “on target,” and (yet still) off-label uses of DBS , 2019 seThat DBS affords effective clinical benefit can be seen as only an initial component (and hurdle) of successful care. Indeed, there have been—and remain—ethical and policy challenges regarding post-trial management of brain implant devices . Brain imay be covered by health insurance providers, such coverage is not obligated (and therefore is routinely not provided) for those indications that are experimental (insure) post-trial continuity of clinical care for those patients/subjects for whom therapeutic benefits are achieved. Public and private research sponsors, device manufacturers, researchers—and the institutions in which this research occurs—can, and we believe should, play active roles in facilitating both the discourse as well as the resources required to assure these patients’ continued access to successful clinical care.Patients who participate in these trials have severe and treatment-resistant neuropsychiatric conditions. Axiomatically, patients with “treatment-resistant” disorders who benefit from an experimental DBS intervention during a trial have no other effective treatment alternatives; and guaranteed provision of services and resources to assure maintenance of DBS devices upon completion of such trials is lacking. To be sure, such continued maintenance may incur significant costs. While sustainability of these devices for extant (CPT-code listed) indications rimental . The sigOf additional interest, particularly for experimental  uses of DBS are potential side effects that can occur in either the short, intermediate, or long-term. Provocative questions have arisen whether closed-loop neuromodulation could induce changes to a patients’ sense of identity and agency. Ongoing discussions in the literature have been equivocal, noting a paucity of data and arguing that such concerns may be overdrawn . To addrAn unexpected finding was that the ability to view the neural recordings collected by the device was regarded as highly meaningful and personally significant to patients and caregivers; in some cases, independent of the device’s stimulation algorithm and/or effect(s). Notably, patients reported that neural recordings enabled visual demonstration of the disease process in ways that affected their understanding of the disorder, and themselves. These are the first such empirically obtained findings from clinical populations undergoing closed-loop neuromodulation, which we believe illustrate—and support—how empirical studies can and should inform the conceptual neuroethics literature.Major depressive disorder (MDD) is a prevalent disease, and one of the leading causes of disability worldwide . A failuDeep brain stimulation for severe, treatment-resistant depression (TRD) is an investigational therapy. Previous studies have shown heterogeneous results, with early open-label studies demonstrating promise ; howeverWe report the results from the first patient in this trial (NCT03437928), which is funded by the NIH BRAIN Initiative . This trial was approved by the FDA (IDE G180300) and IRB. We gathered a plethora of data during the intracranial phase that helped to create a model of the relationship between imaging, neurophysiology, and behavioral/symptomatic response. We used this information to create three parameter sets, which we tested in the outpatient phase. Implementing these individualized parameter sets across the four DBS leads led to a steady reduction in symptom scores, such that the subject achieved symptom remission by 22 weeks.We propose that “sEEG-guided DBS” is a useful platform for developing a network understanding of disorders and that this approach will provide sufficient information to optimize neuromodulatory therapies such as DBS. Future challenges include balancing the competing drives of optimizing previously studied DBS targets versus exploring new targets, properly interpreting acute results for chronic use, and translating this paradigm so that in the future, inpatient intracranial recordings will not be needed.MDD is a common and highly disabling disorder worldwide. While the majority of patients respond well to medication and psychotherapy, a substantial number of patients remain refractory to all available treatments. DBS is a highly promising therapy for this subset of patients with treatment resistant disease. However, results from randomized controlled studies of DBS for depression have not been consistent, suggesting that novel strategies in DBS treatment are needed. Three approaches toward DBS optimization in depression are currently underway by groups at Mt. Sinai, Baylor and UCSF. They include enhanced target engagement through tractography and biomarker development, DBS parameter optimization through individualized network targeting, and development of a personalized closed-loop paradigm.® System) is implanted in sensing and stimulation targets identified in the discovery stage. An open label period follows where a biomarker-based detection algorithm is developed and integrated into closed-loop therapy and then tested through a randomized controlled study. In this talk, we discuss the rationale behind a closed-loop DBS approach. We discuss the conceptualization of depression in a closed-loop model, implications for patient selection, and a strategy for personalized clinical mapping that integrates clinical responses with functional and structural connectivity mapping. We highlight differences of our approach in comparison to the approaches at Mt. Sinai and Baylor and suggest strategies for integration of the three complementary efforts  region . InitialThis standardized method for reproducible lead implantation and contact selection for chronic stimulation has been further verified by robust and reproducible intraoperative behavioral effects associated with unilateral and bilateral therapeutic stimulation at the predefined targets . With thTo this point, preliminary studies have demonstrated that following 2 months of therapeutic SCC DBS, machine learning models of facial expression and vocal inflection drawn from unstructured patient interviews can reliably predict 6-month outcomes, outperforming classical depression severity rating scales . HoweverAdvances in MRI technology has made it feasible to visualize brain networks in a manner previously thought to be impossible. The Human Connectome Project has enabled the generation of publicly available normative connectomes, which has proven invaluable for neuromodulation research . Neuroimansotomy for treatment of Parkinsonian tremor  cohort  cohort .In the future, a similar methodology could be used to define symptom-specific circuitopathies that may ultimately facilitate personalization of DBS targets to a somatotopic domain and to a symptom-spectrum of individual patients. Furthermore, advanced imaging technology will likely continue to enter the operation room in an effort to integrate surgical targets with a variety of neuroimaging data.Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by tics and often associated with psychiatric comorbidities, such as obsessive-compulsive behavior (OCB). DBS is an effective therapy for select patients with severe, treatment-refractory TS. However, patient responses to DBS are variable and there are currently no reliable predictors of symptom improvement. One contributing factor to the variability in clinical outcomes is the uncertainty into how to optimally target stimulation to improve tics or OCB. Progress toward identifying predictors of symptom improvement and effective neuroanatomical structures for stimulation has been limited by the relative paucity of TS cases implanted at individual centers. The International TS DBS Registry and Database  was estaUsing multicenter data from the registry, recent studies have aimed to identify the neuroanatomical structures associated with improvement in tics and comorbid OCB in patients who have undergone DBS for TS. Image-based computational models were constructed based on patient-specific lead locations and on individual stimulation settings to visualize the active contact locations across patients and to identify the structural networks and local fiber pathways modulated by DBS . The resDeep brain stimulation is an effective treatment for PD, but its efficacy depends heavily on selection of optimal stimulation parameters for each individual patient. DBS programming is frequently time consuming and burdensome for patients, caregivers, and clinicians. We recently conducted a multi-center study (NCT02474459) to test if the integration of the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, into the DBS programming process could transform the care model by enabling home health nurses to effectively manage patients at home. We conducted two open-label, 1:1 randomized, controlled, clinical trials. The first trial, which was conducted at six expert DBS centers across the United States, compared 6 months of SOC to 6 months of MAP DBS-aided programming. The primary outcome was the total time spent on DBS programming over all clinical visits during the study period. In the second trial, we compared 6 months of SOC to 6 months of home health postoperative DBS management. The home health postoperative management was conducted by a home health nurse who chose DBS settings with the aid of the MAP DBS system. By design, the home health nurse had no prior experience providing DBS care. The primary outcome was the number of times each patient traveled to the movement disorders clinic during the study period. In both studies, the secondary outcomes were changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (motor score), the total UPDRS (sum of parts I through IV), the 39-question Parkinson’s disease rating scale (PDQ-39), the Multidimensional Caregiver Strain Index (MCSI), and levodopa equivalent daily doses (LEDD) between the baseline and six-month outcomes visit. We analyzed 72  patients in the first trial (Phase I). In the second trial  we analyzed 42 patients . The study results are in submission but will help us to understand how tools like MAP DBS can be used to enhance the experience of non-expert home health nurses. Additionally, this data will be used to design and pilot a study of home health nurse driven telemedicine in DBS.Seminal papers on adaptive neuromodulation and brain sensing have been primarily demonstrated in clinic or in postoperative settings . While tHowever, if we want to achieve optimal aDBS outcomes, not only will electrode location and biomarker sensing be key, but also, the type of control algorithm used will ultimately affect the outcome and success of any aDBS paradigm. Previous control algorithms for PD have used a pre-specified threshold on beta  or gammaInvasive neural recordings in humans have shown promise for understanding physiological signatures or “biomarkers” of specific motor and non-motor signs of PD. Until recently, most recordings were performed for short durations from externalized brain leads in hospital settings. The availability of bidirectional (sense and stimulate) neural interfaces has launched a new approach: chronic invasive brain sensing at home. This approach offers many advantages over brief recordings: validation in the “real world” of biomarkers identified at rest with externalized leads in defined medication states, identification of “personalized” biomarkers based on chronic recordings over many exacerbations and remissions of a specific sign or symptom within a single subject, understanding effects of chronic DBS on neural circuits, and implementation of aDBS. Here, we highlight several uses of chronic brain recordings in PD at UCSF. Using an investigational first-generation bidirectional interface, the Activa PC + S (Medtronic) in four patients, we identified prefrontal cortical beta band activity as a possible signature of anxiety and depression. More recently we have used a second-generation bidirectional interface, Summit RC + S (Medtronic). This device has the capability for high volume wireless data streaming at home over many hours, improved signal to noise ratios, and better management of stimulation artifacts as compared to its precursor device. Five PD patients streamed bilateral 4-channel motor cortex and basal ganglia field potentials at home for over 2,600 h. Recordings were paired with wearable monitors for the neural decoding of motor fluctuations at home . We valiElectrical brain stimulation (EBS) is an effective therapy for neurological and psychiatric diseases. Currently available systems, however, do not provide a bi-directional interface suitable for ambulatory biomarker tracking, patient reporting, or adaptive therapy. While regulatory challenges exist, integrating EBS implants with off-the-body computing devices, like a smart phone, can enable tracking, analyzing, and modulating brain activity in ambulatory subjects while also providing real-time behavioral data via phones and wearable sensors. The bi-directional interface between ambulatory patients, their brain activity, as well as the local and distributed computing environments creates a powerful platform for therapy optimization and neuroscience discovery.Current FDA approved EBS devices for epilepsy do not utilize adaptive therapy, take years for therapy optimization, and do not track seizures or treat common comorbidities like mood, sleep, and cognition. Here, we describe a Digital Epilepsy Management System for drug resistant epilepsy that integrates a brain stimulation and sensing implant with off-the-body devices and cloud computing enabled ambulatory tracking of seizures, biomarkers, behavior, sleep, cognition, and mood that can all possibly drive adaptive therapy .Pre-clinical work at the Mayo Clinic was completed in research and pet canines with epilepsy using an investigational Medtronic Summit RC + S  sensing and stimulation implantable device integrated with a tablet computer and cloud-based system for streaming data acquisition from the brain and wearable sensors, patient and device triggered tablet annotations, data analytics, and visualization.The system is currently deployed in a person with epilepsy and 2 pet dogs with epilepsy living with their owners. We have demonstrated automated seizure catalogs, interictal biomarker tracking, sleep staging, and patient mood and cognition testing in the naturalistic settings. The Digital Epilepsy Management System provides an interactive interface between patient and physicians and should be useful for optimizing adaptive EBS therapy in patients with epilepsy.A diverse array of chronic pain syndromes is refractory to almost all treatment modalities; however, they involve pathological activity in similar brain regions. This finding suggests therapeutic potential for DBS to treat pain, but despite early promise, long-term efficacy is lacking. Prior DBS approaches have been limited in anatomical reach, targeting brain regions underlying only single dimensions of pain (such as somatosensation). Further, DBS therapy has been bluntly applied in an open-loop, continuous fashion without regard to underlying physiology. As a result of these shortcomings, DBS for pain is frequently ineffective or shows diminished effect over time. DBS could be significantly improved by seeking individually optimized brain targets or by using neural biomarkers of pain to selectively control stimulation when it is needed (closed-loop DBS). This type of approach may help avert tolerance and may provide prolonged pain relief.Using personalized neural signatures of acute and chronic pain states over long-time scales (weeks to months), we at UCSF are developing a closed-loop DBS technology to treat chronic pain. In our first cohort of four subjects with chronic pain, we have implanted electrodes in the anterior cingulate and orbitofrontal cortices. Using machine learning methods, we have successfully decoded high versus low pain states and identified personalized biomarkers of clinically relevant chronic pain states. The stimulation of anterior cingulate cortex (ACC) and orbital frontal cortex (OFC) has been variably analgesic with inconsistent results over time. In a newer study, we are using sEEG to perform a temporary stimulation trial of multiple brain targets that underlie the somatosensory, affective, and cognitive dimensions of pain. Based on this trial period, we can identify personalized brain targets for each subject to maximize both stimulation-induced pain relief and pain biomarker detection. These pain biomarkers can then be used as a next step and be embedded into closed-loop DBS control algorithms to provide long term pain relief.As DBS has proven successful in well-selected patients for the treatment of movement disorders, such as PD and essential tremor, its indications are expanding to include intractable or severe neuropsychiatric conditions such as post-traumatic stress disorder PTSD; , OCD Go, and imp® System , sEEG electrodes for seizure evaluation, or intra-operative recording electrodes implanted prior to DBS placement in a patient with PTSD. A subset of the participants was diagnosed with PTSD and/or generalized anxiety disorder (GAD). Results yielded low and high frequency oscillatory biomarkers that were and will be used to trigger responsive neurostimulation in PTSD patients as part of an ongoing NIH UH3 funded clinical trial. Future studies will focus on characterizing amygdala-hippocampal-prefrontal circuit mechanisms underlying fear-related memory and improve the ecological validity of laboratory-based tasks using virtual reality, simultaneous physiological  and iEEG activity combined with intracranial electrical stimulation .Ventral striatum (VS) DBS for treatment of intractable OCD benefits approximately 50–60% of cases, leaving room for improvement in both clinical outcomes and reduction of DBS-induced behavioral side effects, notably hypomania. An adaptive DBS (aDBS) system may improve efficacy of DBS for OCD by facilitating the titration of stimulation parameters in response to neural biomarkers of hypomania and in response to OCD-related distress. In an NIH UH3  for aDBS in OCD, five participants underwent DBS surgery; two with the Medtronic Activa PC + S, and three with the Medtronic Summit RC + S. Participants returned to clinic for DBS programming and to conduct neural recordings [local field potentials (LFPs) and scalp EEG], video and heart rate monitoring, as well as behavioral tasks, all measured on a bi-weekly to monthly basis. Early evidence from one participant suggested an increase in the left vs delta-band power over a timeline of weeks since the DBS ON condition. This increase in power preceded symptom improvement, which occurred after an increase in pulse width from 90 to 120 μs that elicited a mirthful response. In addition to in-clinic data collection, we captured data in the participants’ home environments. The Summit RC + S device enabled streaming of neural data at home during natural fluctuations in OCD symptom intensity and hypomania, as well as during exposure response therapy. There were 228 h of neural data streamed from one Summit RC + S participant during a range of behavioral states and tasks. The majority of LFP data was collected during active DBS therapy. To better understand underlying neural activity, we developed a novel stimulation artifact removal paradigm, termed Period-based Artifact Reconstruction and Removal Method (PARRM). PARRM is applicable to various neurostimulation paradigms beyond DBS, is superior in signal recovery, low complexity, and requires minimal onboard storage. Next, we plan to examine behavioral and neural data collected across various behavioral states to identify biomarkers that can be deployed in an effort to enable aDBS for OCD.® System . Eligible participants must have treatment-refractory obesity with a body mass index (BMI) 40–60 kg/m2.Loss of control (LOC) is a pervasive feature of eating disorders and contributes significantly to the epidemic of obesity. Responsive DBS that is guided by low-frequency changes in the nucleus accumbens (NAc), was previously observed to block binge-eating behavior in mice . FollowiThere are three participants currently enrolled. Electrophysiological signals of LOC will be characterized in humans using ambulatory recording capabilities and controlled, in-clinic behavioral tasks. We have developed novel behavioral tasks and we will utilize virtual reality and eye-tracking to capture anticipatory signals for LOC eating during intraoperative testing and in the laboratory. Using eye-tracking and remote telemetry communication, we captured real-time electrophysiological signals during naturalistic eating behaviors in the clinic. We assess LOC eating in the clinic by introducing participants to a validated multi-item buffet task where they are given a standard breakfast and lunch , and following a brief LOC priming period with mood provocation, participants are presented a buffet of preferred, high fat-caloric food . Further, we utilize ambulatory data collection via magnet swiping which is paired with ecological momentary surveys, food diaries, and wearables to capture real-world LOC cravings and eating episodes. Initial piloting of these tasks and assessments were used for feasibility in the initial pilot study and analysis for a LOC-responsive biomarker study. Collectively, these preliminary results demonstrate the usefulness of long-term, objective neural recordings in naturalistic environments and the potential of individualized biomarkers of pathology or symptoms for the potential successful employment of aDBS.New techniques for the application of DBS have emerged with the advent of imaging, which has resulted in a paradigm shift toward targeted modulation of a particular network . AnotherInitially, DBS was thought to mimic the effect of lesioning through neuromodulation of neuronal activity within the area surrounding the stimulating electrode. However, current physiological concepts imply, that DBS has multiple, time-dependent effects on the cellular, local neuronal circuitry and also at the large-scale network level. These changes may influence the dysfunctional activity within symptom specific neural circuits. Axons originating or terminating within the stimulation volume or bypassing it are the key elements potentially mediating multiple clinical responses . Therefo•should be flexible in stimulating only a small volume of interest,•should preferentially stimulate axons mediating benefit,•should avoid stimulation of axons or other excitable elements resulting in adverse effects,•should eliminate the neuronal signal mediating a network dysfunction ,•should not interfere with normal  network function.Recent methodological advances addressing these needs include segmented electrode designs and an expanded pulse parameter space  for more precise delineation of the stimulation volume and for selective stimulation of particular fiber pathways of interest. Another advance includes sensing capability using either brain signals or peripheral kinematic sensors to adapt stimulation to fluctuating symptom severity and to the underlying dynamics of neural circuits. Finally, future advances include the rapidly advancing field of digital innovations for clinical response prediction which may inform and substantially shorten programming times for DBS.Several open source and commercial software have facilitated visualization of the volume of tissue activated (VTA) based on axon cable models in patient specific anatomical models (derived from MRI and CT imaging). Aggregated data from large patient cohorts have facilitated the creation of probabilistic maps of clinical responses, which in turn can be used to train machine learning algorithms for predicting a clinical  response with a given electrode location and a particular stimulation setting . We hopeDespite the vital role of brain network studies to predict disease trajectories in patients with movement disorders, their analysis and modeling are often difficult to interpret due to complexity, uniqueness, test-retest issues and group or single subject validity of the data. Of distinct importance for the comprehension of the analytical framework is to note, that network interactions occur at specific spatial locations within regions (space) over distinct time dimensions (state). With this in mind, we hypothesize that brain networks have instantaneous state and space properties at each level. Proper identification and association of features (within and between brain regions) from these critical variables at different time scales can be modeled by newly proposed computational approaches  that canIn a recent review, we comprehensively describe the causal interrogations and modulations of network states using neuroimaging and electrophysiology . Using sOver the last decade, we and others have used the access to deep brain nuclei in patients undergoing DBS not only for treatment of motor symptoms, but also to record neuronal activity in order to understand the underlying pathophysiology of movement disorders. We could show that the temporal pattern of neuronal output is highly important to understanding network disorders. The oscillatory activity pattern is different in bradykinetic and hyperkinetic disorders, i.e., dynamic changes in the network related to a specific motor state of the patient. Best known is the increased subthalamic oscillatory beta (13–35 Hz) band activity which has been shown to be a potential electrophysiological signature of bradykinetic motor signs in patients with PD . DopaminIn several studies, a significant correlation between parkinsonian symptom severity and beta synchronization has been reported , 2008, eOur first experience with PERCEPT has revealed that a stepwise increase of stimulation amplitude was mirrored in the sequential decrease of beta oscillatory activity, which occurred in parallel with the improvement in bradykinesia. Mean beta band (13–20 Hz) activity correlated significantly with the UPDRS scores during DBS. Further studies using chronic sensing will likely reveal circadian fluctuations in oscillatory patterns. This will also likely be useful for application to aDBS in real life situations. This finding may also be important to future clinical development.This section describes the advances in the field of neurotechnology as applicable to DBS research. This includes real-time neural recordings, remote DBS programming, optimization of electrode configurations, and model-based algorithms, which can all be developed to further incorporate physiological signals in the optimization process. Finally, we address issues surrounding chronic implantation and utilization of neural micro-devices, which have the potential to provide sensory information feedback, and how to mitigate these issues.With sensing-enabled deep brain stimulators, chronically monitoring neural activities in the deep brain has become a reality. This capability could play a key role in clinical neuroscience and neuromodulation technology. We developed a DBS system with the capability of chronic recording . We inveIn addition to this change we also observed combinations of alpha, beta and gamma bands which could be used as chronic biomarkers for the classification of different sleep stages . The resIn the past five years, remote programming technology has been widely expanding in large medical centers specifically in an effort to improve access, and particularly for those residing in remote locations. At the beginning of the COVID-19 pandemic, many patients were secluded from standard medical services due to social distancing, quarantine, and lockdowns. For patients with PD, efficient programming could be safely achieved by a remote tele-programming system. We have developed a DBS programming technology using a Bluetooth communication interface. We reported the application of the device during the pandemic, particularly for PD patients with freezing of gait (FOG) who were able to be programmed with a complex variable frequency stimulation VFS;  paradigmOur remote programming system provides a promising approach for the control of a wide range of implantable medical devices. We anticipate that telemedicine for remote DBS programming will be an important trend in future DBS management.Computational models of DBS have provided significant insight into the regions and pathways involved in treatment and side effect induction with DBS therapy. To date much of the research has focused on retrospective analysis in which previously collected clinical outcomes are matched with model predictions of the regions or pathways activated by clinically optimized or suboptimal stimulation settings that may or may not induce side effects. As we continue to pursue these retrospective studies, the knowledge gained provides an opportunity to build data-driven algorithms for identifying therapeutic electrode configurations prospectively and on an individual subject basis.Several targeting algorithms have been developed in recent years including neural network classification based on VTA morphologies , convex Model-based algorithms can also be extended to incorporate physiological signals in the optimization process. Examples of these approaches include adaptive closed-loop strategies that integrate a response surface model to intelligently guide and update stimulation parameters. One recent example is the development of Bayesian adaptive dual control that balances exploitation of DBS settings that are known to be therapeutic with the exploration of settings that may yield a better outcome . As teleThe loss of sensorimotor function has devastating consequences on quality of life. One approach to restoring lost sensorimotor abilities is to supply patients with implants that provide a direct interface with the central nervous system. For an amputee or tetraplegic patient, this interfacing could allow a patient’s desired limb movement to be executed by a prosthetic limb, and to convey to the patient, sensory information about the consequences of these movements. Highly sophisticated robotic limbs have been developed, as have algorithms to decode motor commands from the brain. However, somatosensory feedback is critically important in activities of daily living. Furthermore, touch is important in emotional communication and in embodiment of our limbs. Without touch, the dexterity of the prostheses will be limited, as will the degree to which they are incorporated into the self-image. Given the importance of touch, upper limb neuroprostheses may not be clinically viable until these devices provide informative tactile feedback.Direct interfacing of micro-devices with the brain has the potential to provide sensory information feedback. However, chronic implantation and utilization of neural micro-devices can result in a reactive tissue response that both functionally isolates the device from the tissue as well as triggers neuronal apoptosis or migration. The goal of our research is to understand and to mitigate this limited functionality. Our research seeks to determine the interdependent effects of device design, electrophysiological recording, electrical stimulation, and the reactive tissue response on the efficacy of neural interfaces. We: (1) conduct psychophysical experiments using multi-channel cortical implants in the cortex, (2) collect longitudinal electrochemical and electrophysiological recordings, (3) investigate mitigation strategies, and (4) use advanced histological approaches to evaluate the device-tissue interface. Our lab studies these various approaches and their implications for reliable chronic neural interfacing via micro-devices. We expect that these data will enable further neuroprosthetic development for many neural interfaces’ potential applications.The Eighth Annual DBS Think Tank meeting provided scientific insight into the most current commercially available technologies and also facilitated important dialogue as to how clinical outcomes may be influenced The topics included (1) closed-loop and adaptive DBS for the treatment of multiple emerging indications, (2) improved imaging techniques which could expand our understanding of brain circuitry and improve DBS outcomes by offering more personalized targeting, (3) optogenetics to elucidate the fundamental roles of various cell types in the neurobiology of disease and could lead to a better understanding of pathological brain circuitries, and (4) the use of chronic neural recordings to define symptom-specific, individualized biomarkers. The Think Tank also addressed a multitude of emerging ethical issues arising from research and from the application of these aforementioned technologies, especially when DBS is successfully applied for off-label uses. We discussed the ethical implications of post-trial management. Furthermore, attendees of the DBS Think Tank completed a questionnaire and 178 participants responded. The participants were primarily scientists or clinicians at academic institutions/universities. The weighted-mean experience in the field of neurotechnology of the participants was 12.3 years. Within the last year, DBS for essential tremor and PD remain at the slope of enlightenment, with mean scores of 5.38 and 5.36, respectively. Additionally, cochlear implants have joined the slope of enlightenment this year. Optogenetics for clinical neural interfaces remains as a technology trigger. Several DBS indications  have moved from technology trigger to peak of inflated expectations, corresponding to the expanding research and clinical trials. Results indicated that some uses and techniques of DBS remained on the trough of disillusionment  or moved to the trough of disillusionment .These proceedings present the latest advances in the field of neuromodulation and emerging challenges that will require international collaboration to more rapidly advance DBS therapy.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the individual academic institutions. All participants provided their written informed consent prior to participation in the studies. The animal study was reviewed and approved by individual institutional animal welfare committees at the respective academic institutions.All authors fulfilled authorship criteria by substantial contributions to the conception of the work, providing data for the work, revisiting it critically for important intellectual content, approving the final version, and agreeing to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.SG and MM were employed by the companies Medtronic and Boston Scientific Neuromodulation, respectively. Research devices for Dr. Goodman’s NIH funded study were donated by Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Idiopathic intracranial hypertension (IIH) is a debilitating condition that has traditionally been difficult to treat. In recent years, there has been increasing focus on the role of intracranial venous hypertension in the pathophysiology of IIH. Based on increased understanding of this pathophysiology, venous sinus stenting (VSS) has emerged as a safe and reliable treatment for a certain population of patients with IIH. Stratifying patients with IIH based on the status of their venous outflow can provide insight into which patients may enjoy reduction in their symptoms after VSS and provides information regarding why some patients may have symptom recurrence. The traditional view of IIH as a disease due to obesity in young women has been cast into doubt as the understanding of the role of intracranial venous hypertension has improved. Idiopathic intracranial hypertension (IIH), previously referred to as pseudotumor cerebri, or more recently chronic intracranial venous hypertension syndrome (CIVHS) , is a coWhile VSS was first reported as a successful treatment for IIH in 2002 , only reThe modern understanding of IIH as result of pathophysiologic impaired cranial venous drainage has its basis in a good understanding of intracranial pressure (ICP), dural venous outflow, and venous manometry. Recent calls for a new nomenclature system identifying IIH as CIVHS are also clarified with a deepened understanding of intracranial venous hypertension. In this manuscript, we aim to synthesize selected literature on these topics to provide a commentary on the modern evaluation and management of patients with IIH, the utility of VSS in their treatment, and areas of future research.Intracranial CSF pressures and intracranial venous pressures are coupled by arachnoid granulations, which exist predominantly in the superior sagittal sinus (SSS). Animal studies have demonstrated that unidirectional flow of CSF from the subarachnoid space into the venous sinuses through these granulations occurs at a pressure gradient of 3–5 mmHg . This un2 = 0.34, significant). While outliers were present , in general, OP and torcular pressures were consistently and reliably correlated. Importantly these values correlated across the OP spectrum regardless of whether the OP was in their teens or in their 50′s indicating that the correlation between OP and torcular pressures exists regardless of gender, body mass index (BMI), or presence/absence of venous sinus stenosis.While animal models have provided insight on the theoretical coupling of ICP and venous pressure, there is now robust literature demonstrating this relationship in human patients. One study of nearly 50 IIH patients correlating concomitant intracranial venous sinus pressures (in mmHg) with LP OP (in cm of water) in the lateral decubitus position  found thFurther corroborating the relationship between venous sinus pressures and ICP are studies showing immediate reduction in ICP with procedures lowering venous pressures. This has been shown objectively in two separate studies in which patients who underwent simultaneous ICP monitoring and VSS demonstrated an immediate decrease in venous pressures and ICP after placement of the stent ,9.If patients with IIH have elevated OP secondary to high intracranial venous pressures, how do we define normal intracranial venous pressures? Remarkably, quite little is known about what normal venous sinus pressures should be; in fact, no studies exist measuring venous sinus pressures in humans in the absence of disease. We can, however, infer what we have learned by studying venous pressures in patients with symptoms of IIH with OP that are on the lower end of the OP spectrum.Many patients presenting with symptoms of IIH now undergo venous manometry as part of the work-up to determine candidacy for VSS. Under light sedation, a guide catheter is usually advanced through the femoral vein into the internal jugular vein (IJ) and then a microcatheter is maneuvered into the SSS. Pressure is measured at the tip of the catheter through the fluid column within the microcatheter. The microcatheter is then withdrawn through the sinuses and pressures are measured at specific landmarks, terminating at the superior vena cava (SVC) to measure central venous pressure (CVP).Studies of venous pressures in patients with IIH can provide some information on venous physiology and pressures in patients with normal OP. In one recent study, 104 patients presenting for evaluation of IIH underwent venous manometry [More recently, a study evaluating ICP and venous pressures in patients with IIH included 17 patients with OP of less than 20 cm of water [As the understanding of the relationship between intracranial venous hypertension and ICP has deepened, it has become clear that IIH is not idiopathic at all . We now A new nomenclature and classification scheme has recently been proposed, calling for the name of the disease be changed to CIVHS  and to sCentral-type patients have elevated CVP without concomitant venous sinus stenosis, whereby morbid obesity or cardiorespiratory disease results in significant CVP elevations with subsequent elevations in intracranial venous pressures. These patients account for about 25% of patients with IIH, are not candidates for VSS, and tend to respond to weight loss or furosemide to reduce central venous volume and therefore CVP. Craniocervical-type patients demonstrate pathologic venous sinus stenosis with low-moderate CVP, wherein the venous outflow obstruction at the venous stenosis manifests as the primary driver of elevated intracranial venous pressures. These patients are often excellent candidates for VSS. Mixed-type patients are the largest subset of patients and demonstrate both pathologic venous sinus stenosis as well as moderate to high CVP, wherein both are independent and additive drivers of high intracranial venous pressures. Post-thrombotic patients demonstrate impaired intracranial venous outflow due to chronic venous sinus thrombosis and are the rarest.Importantly, this nomenclature also describes “CIVHS spectrum disorder”, which is a condition wherein patients demonstrate LP OP of 15–24 cm of water but have serious symptoms of CIVHS that respond to pressure-lowering therapies, usually CSF diversion. This group accounts for about 15% of patients in the senior author’s practice. This group is not universally accepted among specialists and often have associated connective tissue disorders (most commonly Ehlers-Danlos syndrome) characterized by hyper-sensitivity to pressure. They are less commonly candidates for stenting as they often do not have a pathologic stenosis or TSPG, as would be predicted based on their lower OP and therefore lower venous sinus pressures.The longest-acknowledged pathophysiologic mechanism regarding patients with IIH has been obesity-related increased intra-abdominal pressure resulting in elevated CVP and upstream impairment of cranial venous outflow. As CVP forms the foundation in intracranial venous pressures, weight-related elevations in CVP will naturally cause higher intracranial venous pressures. However, CVP is rarely ever measured to be greater than 20 mmHg, even in the largest patients. In fact, it has been shown that CVP and BMI correlate in a linear fashion up to CVP of 20 mmHg . As intrThe most common site of venous stenosis in patients with IIH is at the transverse sinus ,12. TranWhy does this positive feedback loop occur? The most reasonable hypothesis centers around several core principles: (1) There is an inherent predisposition that some people have to develop stenosis at the transverse sinus from extramural compression, which is probably related to the anatomy of the transverse sinus at that location; (2) elevations in ICP have a diffuse effect on venous sinus calibers, but the transverse sinus is most susceptible to becoming compressed; and (3) high ICP events must occur to precipitate this process. Most patients with IIH are overweight, and it is likely that nocturnal, episodic ICP elevations associated with obesity and sleep apnea instigate the positive feedback loop to occur in a recurrent manner, explaining why patients have only temporary relief following CSF removal.Importantly, a small fraction of IIH patients are discovered to have venous outflow obstruction from intramural sinus stenosis. These patients often have large arachnoid granulations that have the appearance of round masses narrowing the sinuses. These granulations obstruct venous outflow, generate a TSPG, and can result in a similar clinical syndrome but behave differently than extramural compression from elevated ICP.Treatments for IIH should now be considered based upon the way they influence ICP (and IIH symptoms) based on the described pathophysiologic mechanism. While carbonic anhydrase inhibitors continue to reduce ICP through reduction in CSF production, diuretics are effective through loss of volume and lowering of CVP, thereby reducing intracranial venous pressures. Weight loss similarly reduces CVP through lowering of intra-abdominal and intra-thoracic pressures, thereby lowering the foundation through which intracranial venous pressures arise. Furthermore, weight loss and correction of sleep apnea potentially reduce nocturnal ICP elevations that instigate venous sinus stenosis feedback loops.CSF shunting procedures lower ICP through diversion of CSF out of the intracranial compartment and may mitigate dramatic elevations in venous sinus pressure by preventing the occurrence of venous sinus stenosis. However, once the shunt fails to drain appropriately, ICP increases, and symptoms return. VSS, on the other hand, is designed to disrupt the positive feedback loop by reinforcing the venous wall and preventing extramural compression. VSS therefore does not correct underlying elevations in CVP that are driving high venous pressures, but it corrects pathological stenoses that may result in dramatic elevations in OP.While guidelines for VSS candidacy are scarce, most practitioners offer VSS to patients with a TSPG of at least 8 mmHg . Based oThe stent reinforces the walls of the transverse sinus and increases its resistance to extramural compression, restoring a more physiologic gradient of venous outflow. This helps lower ICP by preventing the development of upstream venous congestion. There are a few studies that quantified the reduction in CSF-OP with VSS. A study in 2019, which quantified this in 63 patients over 6 years, found that the average pre-treatment CSF-OP was with 37 cm of water, and post-treatment was 20.2 cm of water . The aveMultiple studies have sought to identify the rate of symptom recurrence and the rate of treatment failure after VSS. Meta-analyses, predominantly studying small retrospective series with short follow-up, suggest high rates of headache, tinnitus, and visual improvement. Nicholson et al. reported that nearly 80% of patients had improved headache, 90% had an improvement in tinnitus, and nearly 94% had improvement in papilledema . The samA more realistic study was published in 2020 reporting on 81 patients that underwent VSS and used validated quality of life and headache scores . Over haThe recurrence of headache symptoms that occur after VSS is often in spite of the fact that OP is significantly lower than pre-stenting. We have labeled this observation the “re-equilibration” phenomenon . Other pThe traditional understanding of IIH has focused on elevated intra-abdominal and intra-pleural pressures due to obesity. The increase in intracranial venous pressure and increase in CSF pressure results in headaches and papilledema, which can further lead to vision loss. Multiple treatment strategies have been employed to address these specific components of IIH, including bariatric surgery, CSF diversion via ventriculo-peritoneal shunting or lumbo-peritoneal shunting (VPS/LPS), and optic nerve sheath fenestration (ONSF). While there are no randomized trials to date to directly compare any of these procedures to each other or VSS, a recent systematic review provides some insight into the outcomes of these procedures . ONSF isFuture study is required in a number of areas. There are no cadaveric studies to demonstrate the hypothesized differential susceptibility of the TS to extramural compression in patients with IIH. A study to evaluate the relative elasticity or compliance in this population would provide much needed insight. A prospective FDA study evaluating a novel stent designed specifically for transverse sinus stenting  is underway. Historically, a number of medications  have been linked to the development of IIH. How and why these medications affect venous pressures remain poorly understood. VSS is only one of a few surgical treatments available for patients with IIH. This list includes optic nerve sheath fenestration, CSF diversion via either VPS or LPS, and bariatric surgery. While systematic reviews have summarized the outcomes of these procedures , there aResearch conducted over the past 20 years has provided new insight into the connection between intracranial venous pressure and ICP and how pathologic elevation of intracranial venous pressures results in the clinical syndrome of IIH. Thinking of IIH as a disease resulting from obesity in young women is antiquated and does not take into account venous drivers of the condition. VSS addresses one of the major pathophysiologic mechanisms of IIH, and it is worthwhile to include investigation of intracranial venous pressures to ensure that a potentially appropriate therapy is offered. While many physicians do consider VSS to be a possible first-line therapy for IIH, there still remain many unanswered questions regarding patient selection, surgical technique, and management of symptom recurrence. Future efforts will help answer these questions and provide insight into appropriate patient selection for the investigation and treatment of venous drivers of IIH.


This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients.Epilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca Epilepsy is a prevalent neurological disorder impacting quality of life for 50 million people worldwide. Patients suffer from recurrent seizures caused by excessive firing of neurons in the brain which can often lead to hippocampal sclerosis and further deterioration. Around 30% of patients are refractory to treatment, current antiepileptic drugs often create unpleasant side effects and there are no preventative or disease-modifying epilepsy therapies. The most common type of epilepsy in adults is temporal lobe epilepsy, but acquired epilepsy is also a common result of a stroke in elderly people. Other causes are traumatic brain injury, infection or hypoxia during birth. The process of acquiring or developing epilepsy is called epileptogenesis. During epileptogenesis, the homeostatic mechanisms which protect against hyperexcitability in healthy neurons become unbalanced as the initial insult alters gene expression patterns. This is accompanied by excitotoxicity and neuronal degeneration, aberrant mossy fibre sprouting, and astrocyte-mediated inflammation  kindling model, kindling is induced by an injection of a subconvulsive dose of the GABAEpileptogenesis alters patterns of gene expression within affected brain regions. One gene of interest which is differentially regulated in epilepsy is the transcription factor Repressor Element 1-Silencing Transcription factor (REST)/Neuron Restrictive Silencer Factor (NRSF). REST is a widespread transcriptional repressor which binds to a 21-bp Repressor Element 1 (RE1)/Neural Restrictive Silencer Element (NRSE) region on its target genes via its zinc finger domain  in animals can be induced by a high dose injection, or a few lower dose injections of a chemoconvulsant, or a high frequency train of electrical stimulation. After the induced SE is a latent period leading to the development of spontaneous seizures. The most commonly used inducer of SE is kainate; a glutamate analog, and agonist of kainate receptors. Seizures and hippocampal damage from kainate injection was first described by Ben-Ari and colleagues  channels , with REST overexpression causing reduced transcript expression of the receptor , synaptic genes  and genes involved in control of excitatory and inhibitory currents   is an established binding target of REST  has been implicated as an important driver of epileptogenesis and is activated by the BDNF TrkB pathway in pilocarpine and kindling mouse models  to inhibit glycolysis as a mimic for the ketogenic diet. In 2006 the Roopra group showed that 2DG application blocked epileptogenesis in a rat electrical kindling model and prevented post-seizure upregulation of BDNF and TrkB mRNA, through enhanced repression by REST and the REST co-repressor C-terminal-Binding Protein 1 (CtBP). Glycolytic inhibition enhanced REST recruitment of the NADH-sensitive CtBP. This interaction was disrupted by increasing NADH levels as would occur during glycolysis, suggesting glycolytic inhibition allows REST to bind CtBP more strongly through a reduction of NADH and provide an enhanced level of gene repression   activator pyrvinium pamoate. CK1 phosphorylates REST, targeting it for proteasomal degradation. As well as blocking REST increase, CK1 activation also rescued neurons from cell death . The latent period is particularly relevant for the process of epileptogenesis, and the mossy fibre sprouting and hippocampal sclerosis are common pathological hallmarks of TLE. SE leads to an increase in mossy fiber sprouting, neuron death, and increases in NMDA and AMPA receptor expression, compared to kindled rats , as this does not appear to have been looked at. TBI is more likely than ischemic injury to result in epilepsy. Like ischemia and SE, TBI leads to excitotoxicity and cell death, inflammation and blood brain barrier dysfunction (Sande and West Epileptogenesis involves a selection of cellular and molecular changes following an initial brain insult and a latent phase, which make neurons more susceptible to hyperexcitability and spontaneous seizures. However, we are far from understanding the mechanisms responsible and knowledge of such mechanisms may help identify therapeutic strategies. In addition to larger structural changes such as the loss of inhibitory interneurons and aberrant axonal sprouting, changes at the mRNA and protein levels have also been explored to uncover some molecular pathways involved in seizure progression. The abundance of data implicating REST in the process of epileptogenesis makes it a strong candidate as a master switch, triggering a cascade of downstream events to modulate excitability of each individual neuron. Sirt1 activity increases after insult, likely by sensing an increased metabolic demand in the cell, and this represses miR-124, which allows upregulation of REST (Chen et al.


Apis mellifera L.) remains apparent amongst beekeepers in both Europe and North America, and is of widespread public, scientific, and agricultural concern. Academically, interest from numerous fields including veterinary sciences has led to many exemplary reviews of the parasites of honey bees and the treatment options available. However, summaries of current research frontiers in treating both novel and long-known parasites of managed honey bees are lacking. This review complements the currently comprehensive body of literature summarizing the effectiveness of parasite control in managed honey bees by outlining where significant gaps in development, implementation, and uptake lie, including integration into IPM frameworks and separation of cultural, biological, and chemical controls. In particular, I distinguish where challenges in identifying appropriate controls exist in the lab compared to where we encounter hurdles in technology transfer due to regulatory, economic, or cultural contexts. I overview how exciting frontiers in honey bee parasite control research are clearly demonstrated by the abundance of recent publications on novel control approaches, but also caution that temperance must be levied on the applied end of the research engine in believing that what can be achieved in a laboratory research environment can be quickly and effectively marketed for deployment in the field.Demand for better control of certain parasites in managed western honey bees (  •Comprehensive, contemporary overviews of parasite control in beekeeping exist.•Research in parasite control beekeeping is a lively, thriving field.•Challenges can be separated into lab/research and regulatory/market.•IPM concepts are apparent in beekeeping, but are arguably still in their infancy. Reflect1.2The parasite burden placed on managed bees by pests and pathogens impacts the beekeeping industry directly, but is also a wider problem for agriculture in parts of the world where honeybees provide pollination services . This maMounting contemporary evidence supports the assertion that treating bees for their parasites makes for better colony health , this is1.3Current treatment approaches to the litany of parasites which infect honey bees will differ between regulatory environments, with the USA typically being the slowest to approve novel treatments. Of note is the recent emphasis on requiring veterinarian involvement in honey bee health, related to their classification as livestock in parts of the world and tighter regulations on antibiotic use. Correspondingly, there are abundant recent efforts to summarize effective treatments for a variety of honey bee parasite infestations or infections including 2Vairimorpha . Manages honey bees in the U.S. are often supplementarily fed by beekeepers  and whil2.4Box 1Integrative pest management (IPM) in beekeeping remains culturally popular amongst many hobbyist or sideline beekeepers, although its influence varies between practitioners. The core principles of IPM rely on a hierarchical approach to pest management where cultural and mechanical controls take precedence as preventative measures, followed by biological controls, reserving chemical treatments (organic or synthetic) as a last resort responsive control tactic; use of these acute approaches is based on monitoring of parasite prevalence, treating curatively only once parasite pressure surpasses some economic threshold. Preventative, prophylactic chemical control application is avoided, and control chemicals are in addition rotated to help reduce the rate at which parasites evolve resistance to control chemicals. In beekeeping, I highlight here two illustrative examples of where IPM intersects with bee parasite control: European foulbrood management and varroa control.In the case of European foulbrood, historical recommendations in some parts of the world spanning back to the 1980's advised that beekeepers prophylactically treat with antibiotics  as part of standard management to help control all foulbrood pathogens. Gradual change in policy from removing this recommendation towards actively discouraging antibiotic use, for example by requiring veterinarian approval , represeVarroa control is the current dominant concern in honey bee parasite control, including whether IPM approaches are suitable in beekeeping; IPM approaches for varroa control were recently reviewed in detail by Alt-text: Box 1Box 2Negative results are underreported broadly in science; in applied sciences, this presents as a problem when ineffective treatments are not sufficiently and widely reported as inadequate. Repeating high-investment work is a gross inefficiency, and tracking ineffective treatments requires better compilation of the literature. Parasite control in beekeeping is not lacking in productive research lines which, unfortunately, did not yield promising actionable recommendations. These failures in developing effective parasite controls span across IPM framework techniques ; here, I highlight examples from the challenging arena of varroa control, where initially promising control methods have ultimately proven insufficient. It remains an important part of extension and scientist/practitioner communication to explain when approaches have been found to be ineffective.Mechanical control: An early concept in reducing varroa reproductive potential was the idea that a ‘small cell’ restricts the physical space available to varroa to move and feed on developing bees, and that providing bees with frames imprinted with small cell patterning could impede varroa population growth. This intuitively appealing idea ultimately proved ineffective .Biological control: A old adage cites in biocontrol is that ‘the enemy of my enemy is my friend’ - this has been pursued in varroa control with initially promising prospects of using predatory pseudoscorpions to actively hunt varroa mites . DespiteChemical controls: Across chemical prospecting papers exploring bee-safe acaricides is the abundant reporting of chemicals that are too dangerous to bees for deployment in the field or are simply ineffective acaricides. For example numerous potential acaricides screened by Alt-text: Box 2Many methods of control are context-dependent in their effectiveness. This is particularly the case for those relating to varroa. Numerous reviews either could be or already are dedicated purely to the effectiveness of different methods of control of varroa in honey bee colonies see . Varroa Other  options for varroa control are often limited due to the environment they are deployed in . For exa3Efforts continue to address some of the unmet challenges in parasite control in beekeeping, with efforts to better combine current treatment approaches and improve efficiencies of already approved control tactics, particularly by combining multiple forms of control see . In addi3.1In response to the inadequacy of particular non-synthetic controls in specific environments and the evolution of resistance to synthetic controls in parasite populations, namely varroa in both instances, significant effort both by practitioners and by researchers has been invested in improving or combining treatment options and regimes to achieve adequate parasite control without requiring the development of entirely new products. Illustratively, investigations into increasing the dose of oxalic acid , develop3.2Biological controls remain a high-demand research priority for beekeepers in treating all manner of parasites in honey bees, although the conceptualization of what counts as a biological compared to chemical control in beekeeping is a possible disconnect between practitioners and scientists; for example, beekeepers may cite organic or reduced-risk chemical controls as biological controls, counter to the typical paradigm within which IPM and wider regulatory systems typically operate. Regardless, research in these spheres remains active and in some cases already have formulated products on the market. Supplementary feeding of phytochemicals  mirrorinLactobacillus spp. . However, this would significantly reduce the damage inflicted by the mite, as varroa populations without circulating vectored DWV seem to lead to low overall impact on their associated infected colonies  and thecha spp. ). The la5.2The emergence of new epidemic viruses, similar to the recent re-emergence of DWV  and argu5.3Lotmaria passim (Lactobacillus spp. (Bombella apis (Vairimorpha section 2.0 and section 4.2) we require prospective treatment that reflects our lack of understanding of effective antimicrobials across neglected parasitic taxa in nature; however gains are being made on this frontier in beekeeping as discussed across this review spanning biotechnology approaches to plant extracts (New bacteria, fungi, microsporidia, trypanosomes, and others are continually identified in honey bees, with some correlatively linked to colony decline but their possible pathological roles broadly uncharacterized, for example the recent investigations into the seemingly ubiquitous trypanosome a passim . The emea passim . In the a passim ; this isa passim . For funlus spp.  and Bomblla apis . For lesextracts .6Efforts to improve parasite control in beekeeping will continue to gather momentum as current and future threats imperil managed honey bees. Open frontiers remain in identifying new control measures for a variety of challenging parasites that are likely to be developed by manufacturers, approved by regulators, and adopted by beekeepers. Macroparasites such as varroa still pose a serious unmet challenge to honey bee health, and microparasites such as viruses, microsporidia, and trypanosomes act as current arenas of innovative biological research. The increasingly large body of work on certain parasites and control approaches, as well the involvement of veterinary sciences, has prompted numerous strong summative reviews of aspects of parasite control in honey bees. However, more can be done to better synthesise some of the larger topics of research in this field.The sole author has no conflicts of interest to declare. No external funding was used to support this manuscript.


College students often hold negative attitudes toward elders and rank this area of practice at the bottom of their future professional life; colleges and universities have an important role to play in changing attitudes and attracting more professionals to work with older adults. This study examined factors contributing to students’ attitudes toward older adults to provide suggestions for pedagogical intervention. Data was collected from 195 undergraduates participating in an online survey with questions on the quality of relationships with a grandparent and other nonfamilial older adults, previous experience and future interest in pursuing a career in an aging-related field, and The Fabroni Scale of Ageism . Path analyses using hierarchical multiple regression revealed that high quality relationships with older adults  was associated with less negative attitudes and more interest in pursuing a future career in age-related jobs/internships. Although both types of relationship quality were significant in the model (p<.05), path coefficients demonstrated that relationships with nonfamilial elders have a greater impact on participants’ attitudes . Previous working/internship experiences with older adults also predicted a greater willingness to pursue a future career in an aging-related field . Findings suggest that colleges could increase students’ interest in pursuing aging-related careers with multiple interventions, such as developing opportunities to interact and build relationships with older adults in the community, updating information on job opportunities, pay scales, and advancement opportunities, and providing more gerontological course or modules.


Since the first isolation of mesenchymal stem cells from lipoaspirate in the early 2000s, adipose tissue has been a darling of regenerative medicine. It is abundant, easy to access, and contains high concentrations of stem cells (ADSCs) exhibiting multipotency, proregenerative paracrine signaling, and immunomodulation—a winning combination for stem cell-based therapeutics. While basic science, preclinical and clinical findings back up the translational potential of ADSCs, the vast majority of these used cells from a single location—subcutaneous abdominal fat. New data highlight incredible diversity in the adipose morphology and function in different anatomical locations or depots. Even in isolation, ADSCs retain a memory of this diversity, suggesting that the optimal adipose source material for ADSC isolation may be application specific. This review discusses our current understanding of the heterogeneity in the adipose organ, how that heterogeneity translates into depot-specific ADSC characteristics, and how atypical ADSC populations might be harnessed for regenerative medicine applications. While our understanding of the breadth of ADSC heterogeneity is still in its infancy, clear trends are emerging for application-specific sourcing to improve regenerative outcomes. This is especially true of adult stem cells. These cells, which can be derived from the patient's own body and applied without the ethical challenges of embryonic stem cells (ESCs) or the technical hurdles of induced pluripotent stem cells (iPSCs), have pushed a new frontier of stem cell-based therapies. The hematopoietic and mesenchymal stem cells (MSCs) have been the most successful translationally, with over four thousand clinical trials and millions of patients treated . While hematopoietic stem cells are generally restricted to the myeloid and lymphoid lineages, MSCs exhibit plasticity toward a number of adult tissues such as bone, cartilage, adipose, muscle, and even nerve, making them promising candidates for treatment across a spectrum of injury and disease. MSCs are currently under development for the treatment of dozens of conditions from osteoarthritis to infertility.Since its modern inception, the field of regenerative medicine has dedicated itself to harnessing the power of stem cells. Viewed broadly, the progress is staggering. From organ-in-a-dish models of disease to biomaterial scaffolds to direct stem cell fate Mesenchymal stem cells are now recognized to be a highly heterogeneous population. Not only are there variations in proliferative capacity and multipotency between clones of a single isolationIn this review, we will discuss the morphological and functional heterogeneity among adipose depots and review the evidence for differential regenerative capacity among their resident ADSC populations. While heterogeneity in adipose depots has long been recognized to influence ADSC regenerative potential, this review moves beyond the traditional abdominal adipose sources to consider specific organ- and tissue-associated depots that could be harnessed to improve regeneration in specialized applications. We will discuss emerging data on the unique properties of ADSCs isolated from these depots and novel strategies to enhance their potential for clinical translation.While stem cells have long been the holy grail of regenerative medicine as the body's natural source of regeneration, they are difficult to harness therapeutically. Since the discovery of hematopoietic stem cells in the 1960s and embryonic stem cells (ESCs) in the 1980s, scientists have devoted significant effort to utilize their therapeutic potential in tissue repair and regeneration. Three major issues currently challenge stem cell-based therapies: (1) accessing sufficient quantities of cells, (2) directing those cells to enhance regeneration, and (3) preventing rejection by the body. ESCs have the most regenerative potential in terms of differentiation capacity, but ethical issues concerning their sourcing limit their translational potential. Furthermore, because of their pluripotency and allogenic origin, ESCs have the potential to cause both immune rejection and tumor generation. The potency of ESCs can be regained without the ethical or immune issues in induced pluripotent stem cells (iPSCs) by genetic modification of a patient's own cells, but the expense and low rate of conversion currently limit the translational potential of these cells as well. Adult, or somatic, stem cells avoid the ethical and practical issues with ESCs and iPSCs but have faced other challenges.in vitro multipotency and low morbidity during cell culture, the painful harvesting process and relatively low yield limit their potential in clinical applications. Zuk et al. were the first to isolate and characterize a similar population of multipotent cells from lipoaspirate.Adult mesenchymal stem cells (MSCs) combine multipotency  with low immunogenicity (because they can be derived from the patient's own tissues).Application of ADSCs in preclinical models of disease has shown significant regenerative benefits including improvements in cardiac ejection fraction post-infarction,in vitro and their role in maintaining tissue homeostasis in vivo, it is natural to conclude that they contribute to tissue regeneration by differentiating into target cells. However, few reports demonstrate direct contribution of injected MSCs to injured tissue, and they are now thought to elicit therapeutic effects primarily through paracrine signaling and immunomodulation  on tissue regeneration is not well characterized. In fact, substantial argument still exists regarding what these cells actually are .Originally considered an inert storage depot for energy, our understanding of the role of adipose tissue has greatly expanded to now being considered the largest endocrine organ of the body.Historically, adipose tissue is subdivided into two types: white adipose tissue (WAT) and brown adipose tissue (BAT). These two types are differentiated by gross appearance, cellular composition, gene expression signature, and developmental lineage . Generally speaking, they have significant similarities: they both are stable in culture, exhibit similar degrees of pluripotency, and share a surface marker profile.in vitro.ADSCs can also be derived from BAT in humans and rodents and exhibit similar characteristics in culture to their WAT counterparts: fibroblastic morphology, stable expansion, multipotency, and mesenchymal surface marker expression,in vitro. Generally, ADSCs isolated from the IPFP resemble those isolated from SAT in the surface marker profile, proliferative capacity, and potency—though reports vary as to which source exhibits higher proliferation and osteogenic capacity.A handful of studies have explored the unique features and regenerative potential of ADSCs isolated from depots outside the classical WAT and BAT described above . The mosADSCs derived from the cardiac-associated depots—epicardial and pericardial fat—have also been examined for their potential in cardiac regeneration. Epicardial fat is adjacent to the myocardium without a fascial division, while pericardial fat lies on the outer surface of the fibrous pericardium. ADSCs from both depots exhibit a typical mesenchymal morphology, surface marker profile, and potency,in vitro compared with subject-matched SAT ADSCs and are able to directly contribute to regenerating muscle in vivo.in vitro or in vivo,A similar but less characterized depot of fat can also be found around some skeletal muscles—most notably the muscles of the rotator cuff. Rotator cuff epimuscular fat sits on the superior surface of the supraspinatus muscle, outside the fascial boundary of the muscle. Human ADSCs derived from this fat exhibit increased myogenic potency in vitro characterization, perirenal ADSCs have been applied therapeutically in preclinical models of disease with promising results. In a rabbit model of acute pyelonephritis, injection of autologous perirenal ADSCs enhanced histopathological outcomes and significantly improved the cortical function compared with neck subcutaneous ADSCs.ADSCs derived from perirenal adipose tissue likewise exhibit an MSC-associated surface marker profile and are capable of trilineage differentiation in rodents and humans.in vitro and evaluated in regenerative therapies in vivo, the contribution of this specific subpopulation has yet to be defined. Identification of unique surface markers could enable purification of these cells to harness their proregenerative paracrine signaling for regenerative therapies.The progenitor cells that give rise to the adipocytes in the bone marrow are a unique subpopulation within the MSCs derived from the bone marrow.in vitro and in vivo to maximize survival and senescence-free expansion and direct differentiation and adipokine secretion to maximize the pro-regenerative impact of stem cell-based therapies. Harnessing these strategies could make any adipose depot a realistic source for therapeutic ADSCs.While extensive characterization is lacking and there may be a literature bias toward pairing ADSCs derived from specific auxiliary depots with regenerative therapies targeting the associated organ/tissue, what evidence exists suggests that selective ADSC sourcing could improve regenerative medicine strategies. Importantly, not only does there appear to be a propensity for ADSCs to support regeneration in the organ/tissue with which they are associated, but also these ADSCs are frequently accessible during the surgical treatment of that organ/tissue. For example, the IPFP is accessible during knee osteotomy, pericardial fat is accessible during open heart surgery, and epimuscular fat is accessible during rotator cuff repair. In each of these scenarios, surgical success will depend on the degree of tissue regeneration and healing over subsequent months, and thus, post-surgical adjuvant treatment with ADSCs isolated during the surgery is an intuitive and feasible approach to improve outcomes. However, such strategies will face biological and technical challenges. Most significant among them is the limited source material. In comparison to abdominal SAT, these auxiliary depots are very small, which will likely necessitate culture expansion of ADSCs to generate sufficient numbers to achieve therapeutic benefits. Second, as mentioned previously, most of these depots undergo pathologic changes in response to disease in their associated organ/tissue and may even contribute to the organ/tissue pathology. It may not be beneficial to directly apply ADSCs isolated from the diseased fat to the diseased organ. However, part of the therapeutic potential of ADSCs lies in their plasticity and ability to be redirected by environmental cues. Significant advances have been made in tissue engineering to recreate healthy environmental cues in vitro to promote quiescence or senescence-free expansion or to direct differentiation prior to in vivo applications. Alternatively, they can be applied with ADSCs to promote survival, reduce dispersion, and direct differentiation in vivo. Cytokine delivery approaches seek to direct ADSC behavior using soluble factors in the microenvironment and are frequently used in combination with engineered scaffolds to combine physical and chemical cues. Most of the current strategies either deliver growth factors to promote cell survival or deliver inflammatory cytokines to enhance the immunomodulatory effects of ADSCs. Genetic engineering can be used to elicit a stronger and more sustained survival and directed differentiation response by editing apoptotic genes and the transcription factors that control pluripotency. Finally, culture conditions are continually being optimized to improve ADSC survival and performance in diseased microenvironments. Two major strategies are hypoxic preconditioning and 3D spheroid culture. Both strategies are designed to better mimic the ADSC native microenvironment and have been shown to improve the viability and survival of transplanted ADSCs.The field of tissue engineering has been working for over a decade to optimize ADSC-based therapeutics. The breadth of innovative strategies and designs has filled several reviews,In vitro, induced osteogenic differentiation of epicardial ADSCs is improved with culture on electrospun collagen.in vivo, thereby requiring fewer ADSCs to elicit a therapeutic effect.These strategies were developed and optimized with ADSCs derived from abdominal SAT, but they have clear potential for improving the translational potential of ADSCs derived from other depots . The limChronic diseases such as aging and diabetes impair both the potency and immunomodulatory functions of SAT ADSCs.in vitro using a combination of hypoxic preconditioning, biochemical cues, and biophysical cues.et al. were able to identify a surface marker to sort the proregenerative ADSCs to maximize the therapeutic benefit of cell injection.However, IPFP ADSCs isolated from arthritic knees can still be conditioned to generate tissue engineered cartilaginous grafts ADSC based therapies sourcing from these nontraditional depots may also be able to capitalize on some new engineering strategies targeting beige and brown fat. While studies have yet to fully differentiate the regenerative potential—and heterogeneity—of ADSCs derived from the nonwhite fats, many have hypothesized that their paracrine effects are modifiable by adrenergic (browning) stimuli. Positive selection of progenitors that are sensitive to browning stimuli, priming with browning stimuli prior to cell delivery and delivery of cells in conjunction with browning stimuli all have the potential to further direct the regenerative action of beige fat derived ADSCs. While current engineering strategies are focused on generating and transplanting mature BAT,As our understanding of the diversity of ADSCs expands, population-specific engineering will likely play a significant role in expanding the use of ADSCs in regenerative medicine. However, a word of caution is warranted as much remains to be done at the preclinical and clinical levels before ADSCs can be effectively used in therapeutically. A heterogeneous stromal vascular fraction (SVF) containing ADSCs has become a popular therapy, sometimes discussed as a “cure-all” despite a lack of careful characterization and consistent documentation of clinical efficacy. Variability in outcomes across clinical trials, and in clinics, no doubt reflects a lack of uniformity in isolation and delivery, as well as a limited understanding of the factors that influence the transplanted ADSC behavior. A step back to fundamentally understand these cells and their heterogeneity will enable guided, targeted ADSC-based therapeutics with consistent and positive outcomes.There is incredible diversity in function across adipose depots, and data support the concept that each depot is specialized to play a specific role in homeostasis and disease. At least some of this specialization is retained in isolated ADSCs. Preferential potencies, different cytokine secretion profiles, and varied immunomodulatory capacities suggest that ADSCs from specific sources may be optimal for specific applications. While much more characterization and comparative data are needed, work to date strongly suggests that improving methodologies to utilize ADSCs from multiple depots could significantly improve regenerative medicine outcomes.C.G. and J.P. contributed equally to this work.