A wearable platform for closed-loop stimulation and recording of single-neuron and local field potential activity in freely moving humans

Advances in technologies that can record and stimulate deep brain activity in humans have led to impactful discoveries within the field of neuroscience and contributed to the development of novel therapies for neurological and psychiatric disorders. Further progress, however, has been hindered by device limitations in that recording of single-neuron activity during freely moving behaviors in humans has not been possible. Additionally, implantable neurostimulation devices, currently approved for human use, have limited stimulation programmability and restricted full-duplex bidirectional capability. In this study, we developed a wearable bidirectional closed-loop neuromodulation system (Neuro-stack) and used it to record single-neuron and local field potential activity during stationary and ambulatory behavior in humans. Together with a highly flexible and customizable stimulation capability, the Neuro-stack provides an opportunity to investigate the neurophysiological basis of disease, develop improved responsive neuromodulation therapies, explore brain function during naturalistic behaviors in humans and, consequently, bridge decades of neuroscientific findings across species.

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March 2021
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Human research participants
Policy information about studies involving human research participants and Sex and Gender in Research.
Reporting on sex and gender Twelve participants (mean age 24 years, three males and nine females) took part in this study. Sex or gender information was not considered nor used for study design or experimental purposes, because the goal of the study was in-vivo validation of the proposed technical system, rather than an investigation of behavioral/cognitive effects in or differences between individuals. Information regarding the participants' sex or gender data was collected only for descriptive purposes during the recruitment process, according to an approved protocol.

Population characteristics
Twelve participants (mean age 24 years, three males and nine females) with pharmaco-resistant epilepsy and implanted depth electrodes for clinical monitoring in the hospital took part in this study. Electrode placements were determined solely based on clinical criteria.

Recruitment
During or before the scheduled hospital stay, participants were contacted in-person or via phone/e-Mail. They were given a detailed explanation of the study and were asked whether they would be willing to volunteer and consent to participate in the study. Participants were not offered compensation for their involvement in this research. Given that some of our experiments involved stimulation and physical walking, the participants were part of this experimental groups were always tested a day before or on the day of deplantation, while they were on medication. The participants were always informed in advance, during consent process, and during the experimental session about the experimental procedure. For the experiment with freely-walking participants, authors, in collaboration with the clinical team, specifically asked for participants, who were in good physical condition (i.e., able to walk freely) at the time of the experiment to avoid unnecessary risks (e.g., falling) in participants that were physically less fit. Brain stimulation was performed only in adult participants (>21 years of age) for ethical and safety reasons. However, these criteria were unlikely to impact the Neurostack's ability to record or stimulate, nor to substantially change the data and conclusions presented in the manuscript. Allocation to other experimental groups (stationary recording and verbal memory task) was not based on specific selection criteria.

Ethics oversight
All participants volunteered for the study by providing informed consent according to a protocol approved by the UCLA Medical Institutional Review Board (IRB) Note that full information on the approval of the study protocol must also be provided in the manuscript.

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Life sciences study design
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Sample size
Twelve participants (mean age 24 years, three males and nine females) with pharmaco-resistant epilepsy and implanted depth electrodes for clinical monitoring in the hospital took part in this study. No statistical methods were used to predetermine sample size. Since the main aim of this study was the validation of recording and stimulation capabilities of our developed Neuro-stack system, we chose sample sizes that are similar to (or larger than) previous studies, where similar recordings were performed with other similar technical systems ( Data exclusions Data from each participant were analyzed separately, but not all results or redundant conclusions about recording or stimulation signal quality were presented for each participant. Data from two participants (not included in the manuscript), who attempted to perform the stationary verbal memory task, were excluded from analysis, these participants did not complete the whole task procedure, but asked to stop the experiment after insufficient number of trials.
All methods used to perform this study are detailed in the Methods section. The Reproducibility subsection, within the Methods section, contains a statement about the reproducibility of this work. Data were analyzed for each individual participant separately. Selection of participants, assignment of participants to different experimental tasks (i.e., stationary recording, recording during ambulatory walking, stationary stimulation, or verbal memory), sample sizes per experimental tasks, and number of replications and task durations per participant were determined in close collaboration with the clinical stuff and were primarily based on the participant's clinical, cognitive, and physical condition. For example, only participants in good physical condition who were able to walk freely were asked to participate in the ambulatory walking experiment. Consequently, stationary recording, ambulatory recording, stationary stimulation, and stationary verbal memory task were successfully tested in 12, 6, 3, and 1 participants respectively. Hence, with the exception of the verbal memory task (described below), all experimental tasks were replicated in multiple participants. All attempts of stationary recordings and stimulation were of high quality and deemed successful. As reported in the manuscript, mobile recordings in the first 4 participants were used to determine and adjust technical parameters and the setup, and then remained constant for successful recordings in two more participants. The stationary verbal memory task was successfully completed in one participant, with two more attempts with participants (excluded from analysis) who did not wish to continue with the experiment before the artificial neural networks could be trained to provide meaningful results. While the main goal of this work was the technical system's human in-vivo validation rather than empirically characterizing neural effects related to participant's behavior and cognition, the aim of neural recordings during the verbal memory task was to showcase the technical feasibility of an automatic real-time analysis of the neural data, as an example use case of the Neuro-stack. This technical feasibility could be successfully demonstrated in one participant; however, behavioral/cognitive effects and conclusions regarding the verbal memory task were not replicated in this study and warrant future investigation. In-vitro recording and stimulation results were replicated and recorded 3 times independently prior to in-vivo experiments, in addition to numerous other in-vitro tests carried out as part of acquiring IRB approval, and as part of previous publications (Rozgic et al., 2017;Rozgic., et al 2018;Basir-Kazeruni et al., 2017;Chandrakumar et al., 2017;Alzuhair et al., 2018;Alzuhair et al., 2019). The delay measurements were performed twice independently with multiple measurements (50)  Randomization The Neuro-stack setup was the same for all tested participants, but the protocols differed for recording and stimulation tests as well as for resting state, stationary, and ambulatory tests. Recording and stimulation functionality were tested in twelve and three participants, respectively. During these tests, we varied, depending on the given participant's clinical, cognitive, and physical condition (in collaboration with their clinical team), the number of channels to record from as well as stimulation parameters (current, amplitude, etc.) in order to showcase stimulation programmability. The stationary verbal memory task was performed in one participant, and the ambulatory walking task was performed in six participants. Some of the participants were involved in multiple tests as stated in the manuscript.
Participants were asked to perform different experimental tasks (i.e., stationary recording, recording during ambulatory walking, stationary stimulation, or verbal memory), based on their physical, cognitive, and clinical condition. Thus, selection of participants, or assignment to different experimental tasks, sample sizes, and replication decisions were determined in close collaboration with the clinical staff and were primarily based on the participant's condition. For example, stationary stimulation required the presence of neurologists on-site for safety reasons (as per IRB and safety requirements), and only participants in good physical condition who were able to walk safely were asked to participate in the ambulatory walking task. For these reasons, full randomization and random assignment of participants to experimental tasks was not possible in this study. Given that the main aim of this work was the validation of the Neuro-stack recording and stimulation system, rather than empirical conclusions regarding cognitive or behavioral effects in individuals, it is the authors' opinion that this non-random assignment of participants to experimental tasks had minimal or no impact on the relevance of the work.