Advances in Deep Brain Stimulation: From Mechanisms to Applications.

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Cost-effectiveness and threshold analysis of deep brain stimulation vs. treatment-as-usual for treatment-resistant depression.

Treatment-resistant depression (TRD) affects approximately 2.8 million people in the U.S. with estimated annual healthcare costs of $43.8 billion. Deep brain stimulation (DBS) is currently an investigational intervention for TRD. We used a decision-analytic model to compare cost-effectiveness of DBS to treatment-as-usual (TAU) for TRD. Because this therapy is not FDA approved or in common use, our goal was to establish an effectiveness threshold that trials would need to demonstrate for this therapy to be cost-effective. Remission and complication rates were determined from review of relevant studies. We used published utility scores to reflect quality of life after treatment. Medicare reimbursement rates and health economics data were used to approximate costs. We performed Monte Carlo (MC) simulations and probabilistic sensitivity analyses to estimate incremental cost-effectiveness ratios (ICER; USD/quality-adjusted life year [QALY]) at a 5-year time horizon. Cost-effectiveness was defined using willingness-to-pay (WTP) thresholds of $100,000/QALY and $50,000/QALY for moderate and definitive cost-effectiveness, respectively. We included 274 patients across 16 studies from 2009-2021 who underwent DBS for TRD and had ≥12 months follow-up in our model inputs. From a healthcare sector perspective, DBS using non-rechargeable devices (DBS-pc) would require 55% and 85% remission, while DBS using rechargeable devices (DBS-rc) would require 11% and 19% remission for moderate and definitive cost-effectiveness, respectively. From a societal perspective, DBS-pc would require 35% and 46% remission, while DBS-rc would require 8% and 10% remission for moderate and definitive cost-effectiveness, respectively. DBS-pc will unlikely be cost-effective at any time horizon without transformative improvements in battery longevity. If remission rates ≥8-19% are achieved, DBS-rc will likely be more cost-effective than TAU for TRD, with further increasing cost-effectiveness beyond 5 years.

Beta activity in human anterior cingulate cortex mediates reward biases.

The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12-30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit.

Insula uses overlapping codes for emotion in self and others.

In daily life, we must recognize others' emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.

Disruption of neural periodicity predicts clinical response after deep brain stimulation for obsessive-compulsive disorder.

Recent advances in surgical neuromodulation have enabled chronic and continuous intracranial monitoring during everyday life. We used this opportunity to identify neural predictors of clinical state in 12 individuals with treatment-resistant obsessive-compulsive disorder (OCD) receiving deep brain stimulation (DBS) therapy ( NCT05915741 ). We developed our neurobehavioral models based on continuous neural recordings in the region of the ventral striatum in an initial cohort of five patients and tested and validated them in a held-out cohort of seven additional patients. Before DBS activation, in the most symptomatic state, theta/alpha (9 Hz) power evidenced a prominent circadian pattern and a high degree of predictability. In patients with persistent symptoms (non-responders), predictability of the neural data remained consistently high. On the other hand, in patients who improved symptomatically (responders), predictability of the neural data was significantly diminished. This neural feature accurately classified clinical status even in patients with limited duration recordings, indicating generalizability that could facilitate therapeutic decision-making.

Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

Pulsation artifact removal from intra-operatively recorded local field potentials using sparse signal processing and data-specific dictionary.

Neural recordings frequently get contaminated by ECG or pulsation artifacts. These large amplitude components can mask the neural patterns of interest and make the visual inspection process difficult. The current study describes a sparse signal representation strategy that targets to denoise pulsation artifacts in local field potentials (LFPs) recorded intraoperatively. To estimate the morphology of the artifact, we first detect the QRS-peaks from the simultaneously recorded ECG trace as an anchor point. After the LFP data has been epoched with respect to each beat, a pool of raw data segments of a specific length is generated. Using the K-singular value decomposition (K-SVD) algorithm, we constructed a data-specific dictionary to represent each contaminated LFP epoch in a sparse fashion. Since LFP is aligned to each QRS complex and the background neural activity is uncorrelated to the anchor points, we assumed that constructed dictionary will be formed to mainly represent the pulsation artifact. In this scheme, we performed an orthogonal matching pursuit to represent each LFP epoch as a linear combination of the dictionary atoms. The denoised LFP data is thus obtained by calculating the residual between the raw LFP and its approximation. We discuss and demonstrate the improvements in denoised data and compare the results with respect to principal component analysis (PCA). We noted that there is a comparable change in the signal for visual inspection to observe various oscillating patterns in the alpha and beta bands. We also see a noticeable compression of signal strength in the lower frequency band (<13 Hz), which was masked by the pulsation artifact, and a strong increase in the signal-to-noise ratio (SNR) in the denoised data.Clinical Relevance- Pulsation artifact can mask relevant neural activity patterns and make their visual inspection difficult. Using sparse signal representation, we established a new approach to reconstruct the quasiperiodic pulsation template and computed the residue signal to achieve noise-free neural activity.

Decoding Depression Severity From Intracranial Neural Activity.

BACKGROUND: Disorders of mood and cognition are prevalent, disabling, and notoriously difficult to treat. Fueling this challenge in treatment is a significant gap in our understanding of their neurophysiological basis. METHODS: We recorded high-density neural activity from intracranial electrodes implanted in depression-relevant prefrontal cortical regions in 3 human subjects with severe depression. Neural recordings were labeled with depression severity scores across a wide dynamic range using an adaptive assessment that allowed sampling with a temporal frequency greater than that possible with typical rating scales. We modeled these data using regularized regression techniques with region selection to decode depression severity from the prefrontal recordings. RESULTS: Across prefrontal regions, we found that reduced depression severity is associated with decreased low-frequency neural activity and increased high-frequency activity. When constraining our model to decode using a single region, spectral changes in the anterior cingulate cortex best predicted depression severity in all 3 subjects. Relaxing this constraint revealed unique, individual-specific sets of spatiospectral features predictive of symptom severity, reflecting the heterogeneous nature of depression. CONCLUSIONS: The ability to decode depression severity from neural activity increases our fundamental understanding of how depression manifests in the human brain and provides a target neural signature for personalized neuromodulation therapies.

Stereo-EEG-guided network modulation for psychiatric disorders: Surgical considerations.

BACKGROUND: Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. OBJECTIVE: /Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. METHODS: We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. RESULTS: Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). CONCLUSION: This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders.

PELP: Accounting for Missing Data in Neural Time Series by Periodic Estimation of Lost Packets.

Recent advances in wireless data transmission technology have the potential to revolutionize clinical neuroscience. Today sensing-capable electrical stimulators, known as "bidirectional devices", are used to acquire chronic brain activity from humans in natural environments. However, with wireless transmission come potential failures in data transmission, and not all available devices correctly account for missing data or provide precise timing for when data losses occur. Our inability to precisely reconstruct time-domain neural signals makes it difficult to apply subsequent neural signal processing techniques and analyses. Here, our goal was to accurately reconstruct time-domain neural signals impacted by data loss during wireless transmission. Towards this end, we developed a method termed Periodic Estimation of Lost Packets (PELP). PELP leverages the highly periodic nature of stimulation artifacts to precisely determine when data losses occur. Using simulated stimulation waveforms added to human EEG data, we show that PELP is robust to a range of stimulation waveforms and noise characteristics. Then, we applied PELP to local field potential (LFP) recordings collected using an implantable, bidirectional DBS platform operating at various telemetry bandwidths. By effectively accounting for the timing of missing data, PELP enables the analysis of neural time series data collected via wireless transmission-a prerequisite for better understanding the brain-behavior relationships underlying neurological and psychiatric disorders.

Artifact characterization and mitigation techniques during concurrent sensing and stimulation using bidirectional deep brain stimulation platforms.

Bidirectional deep brain stimulation (DBS) platforms have enabled a surge in hours of recordings in naturalistic environments, allowing further insight into neurological and psychiatric disease states. However, high amplitude, high frequency stimulation generates artifacts that contaminate neural signals and hinder our ability to interpret the data. This is especially true in psychiatric disorders, for which high amplitude stimulation is commonly applied to deep brain structures where the native neural activity is miniscule in comparison. Here, we characterized artifact sources in recordings from a bidirectional DBS platform, the Medtronic Summit RC + S, with the goal of optimizing recording configurations to improve signal to noise ratio (SNR). Data were collected from three subjects in a clinical trial of DBS for obsessive-compulsive disorder. Stimulation was provided bilaterally to the ventral capsule/ventral striatum (VC/VS) using two independent implantable neurostimulators. We first manipulated DBS amplitude within safe limits (2-5.3 mA) to characterize the impact of stimulation artifacts on neural recordings. We found that high amplitude stimulation produces slew overflow, defined as exceeding the rate of change that the analog to digital converter can accurately measure. Overflow led to expanded spectral distortion of the stimulation artifact, with a six fold increase in the bandwidth of the 150.6 Hz stimulation artifact from 147-153 to 140-180 Hz. By increasing sense blank values during high amplitude stimulation, we reduced overflow by as much as 30% and improved artifact distortion, reducing the bandwidth from 140-180 Hz artifact to 147-153 Hz. We also identified artifacts that shifted in frequency through modulation of telemetry parameters. We found that telemetry ratio changes led to predictable shifts in the center-frequencies of the associated artifacts, allowing us to proactively shift the artifacts outside of our frequency range of interest. Overall, the artifact characterization methods and results described here enable increased data interpretability and unconstrained biomarker exploration using data collected from bidirectional DBS devices.

Honeycomb: a template for reproducible psychophysiological tasks for clinic, laboratory, and home use.

OBJECTIVE: To improve the ability of psychiatry researchers to build, deploy, maintain, reproduce, and share their own psychophysiological tasks. Psychophysiological tasks are a useful tool for studying human behavior driven by mental processes such as cognitive control, reward evaluation, and learning. Neural mechanisms during behavioral tasks are often studied via simultaneous electrophysiological recordings. Popular online platforms such as Amazon Mechanical Turk (MTurk) and Prolific enable deployment of tasks to numerous participants simultaneously. However, there is currently no task-creation framework available for flexibly deploying tasks both online and during simultaneous electrophysiology. METHODS: We developed a task creation template, termed Honeycomb, that standardizes best practices for building jsPsych-based tasks. Honeycomb offers continuous deployment configurations for seamless transition between use in research settings and at home. Further, we have curated a public library, termed BeeHive, of ready-to-use tasks. RESULTS: We demonstrate the benefits of using Honeycomb tasks with a participant in an ongoing study of deep brain stimulation for obsessive compulsive disorder, who completed repeated tasks both in the clinic and at home. CONCLUSION: Honeycomb enables researchers to deploy tasks online, in clinic, and at home in more ecologically valid environments and during concurrent electrophysiology.

Periodic Artifact Removal With Applications to Deep Brain Stimulation.

Deep brain stimulation (DBS) therapies have shown clinical success in the treatment of a number of neurological illnesses, including obsessive-compulsive disorder, epilepsy, and Parkinson's disease. An emerging strategy for increasing the efficacy of DBS therapies is to develop closed-loop, adaptive DBS systems that can sense biomarkers associated with particular symptoms and in response, adjust DBS parameters in real-time. The development of such systems requires extensive analysis of the underlying neural signals while DBS is on, so that candidate biomarkers can be identified and the effects of varying the DBS parameters can be better understood. However, DBS creates high amplitude, high frequency stimulation artifacts that prevent the underlying neural signals and thus the biological mechanisms underlying DBS from being analyzed. Additionally, DBS devices often require low sampling rates, which alias the artifact frequency, and rely on wireless data transmission methods that can create signal recordings with missing data of unknown length. Thus, traditional artifact removal methods cannot be applied to this setting. We present a novel periodic artifact removal algorithm for DBS applications that can accurately remove stimulation artifacts in the presence of missing data and in some cases where the stimulation frequency exceeds the Nyquist frequency. The numerical examples suggest that, if implemented on dedicated hardware, this algorithm has the potential to be used in embedded closed-loop DBS therapies to remove DBS stimulation artifacts and hence, to aid in the discovery of candidate biomarkers in real-time. Code for our proposed algorithm is publicly available on Github.

Intraoperative valence testing to adjudicate between ventral capsule/ventral striatum and bed nucleus of the stria terminalis target selection in deep brain stimulation for obsessive-compulsive disorder.

OBJECTIVE: Deep brain stimulation (DBS) is an accepted therapy for severe, treatment-refractory obsessive-compulsive disorder (trOCD). The optimal DBS target location within the anterior limb of the internal capsule, particularly along the anterior-posterior axis, remains elusive. Empirical evidence from several studies in the past decade has suggested that the ideal target lies in the vicinity of the anterior commissure (AC), either just anterior to the AC, above the ventral striatum (VS), or just posterior to the AC, above the bed nucleus of the stria terminalis (BNST). Various methods have been utilized to optimize target selection for trOCD DBS. The authors describe their practice of planning trajectories to both the VS and BNST and adjudicating between them with awake intraoperative valence testing to individualize permanent target selection. METHODS: Eight patients with trOCD underwent awake DBS with trajectories planned for both VS and BNST targets bilaterally. The authors intraoperatively assessed the acute effects of stimulation on mood, energy, and anxiety and implanted the trajectory with the most reliable positive valence responses and least stimulation-induced side effects. The method of intraoperative target adjudication is described, and the OCD outcome at last follow-up is reported. RESULTS: The mean patient age at surgery was 41.25 ± 15.1 years, and the mean disease duration was 22.75 ± 10.2 years. The median preoperative Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was 39 (range 34-40). Two patients had previously undergone capsulotomy, with insufficient response. Seven (44%) of 16 leads were moved to the second target based on intraoperative stimulation findings, 4 of them to avoid strong negative valence effects. Three patients had an asymmetric implant (1 lead in each target). All 8 patients (100%) met full response criteria, and the mean Y-BOCS score reduction across the full cohort was 51.2% ± 12.8%. CONCLUSIONS: Planning and intraoperatively testing trajectories flanking the AC-superjacent to the VS anteriorly and to the BNST posteriorly-allowed identification of positive valence responses and acute adverse effects. Awake testing helped to select between possible trajectories and identify individually optimized targets in DBS for trOCD.

Proceedings of the 10th annual deep brain stimulation think tank: Advances in cutting edge technologies, artificial intelligence, neuromodulation, neuroethics, interventional psychiatry, and women in neuromodulation.

The deep brain stimulation (DBS) Think Tank X was held on August 17-19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation. Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the "trough of disillusionment." DBS for depression was considered as "re-emerging" and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS.

Decoding Human Cognitive Control Using Functional Connectivity of Local Field Potentials.

Many patients with mental illnesses characterized by impaired cognitive control have no relief from gold-standard clinical treatments resulting in a pressing need for new alternatives. This paper develops a neural decoder to detect task engagement in ten human subjects during a conflict-based behavioral task known as the multi-source interference task (MSIT). Task engagement is of particular interest here because closed-loop brain stimulation during those states can augment decision-making. The functional connectivity patterns of the electrodes are extracted. A principal component analysis of these patterns is carried out and the ranked principal components are used as inputs to train subject-specific linear support vector machine classifiers. In this paper, we show that task engagement can be differentiated from background brain activity with a median accuracy of 89.7%. This was accomplished by constructing distributed functional networks from local field potentials recording during the task performance. A further challenge is that goal-directed efforts take place over higher temporal resolution. Task engagement must thus be detected at a similar rate for proactive intervention. We show that our algorithms can detect task engagement from neural recordings in less than 2 seconds; this can be further improved using an application-specific device.

Spectral Features Based Decoding of Task Engagement: The Role of Theta and High Gamma Bands in Cognitive Control.

This paper analyzes local field potentials (LFP) from 10 human subjects to discover frequency-dependent biomarkers of cognitive conflict. We utilize cortical and sub-cortical LFP recordings from the subjects during a cognitive task known as the Multi-Source Interference Task (MSIT). We decode the task engagement and discover biomarkers that may facilitate closed-loop neuromodulation to enhance cognitive control. First, we show that spectral power features in predefined frequency bands can be used to classify task and non-task segments with a median accuracy of 88.1%. Here the features are first ranked using the Bayes Factor and then used as inputs to subject-specific linear support vector machine classifiers. Second, we show that theta (4-8 Hz) band, and high gamma (65-200 Hz) band oscillations are modulated during the task performance. Third, by isolating time-series from specific brain regions of interest, we observe that a subset of the dorsolateral prefrontal cortex features is sufficient to decode the task states. The paper shows that cognitive control evokes robust neurological signatures, especially in the prefrontal cortex (PFC).

How do packet losses affect measures of averaged neural signalsƒ.

Recent advances in implanted device development have enabled chronic streaming of neural data to external devices allowing for long timescale, naturalistic recordings. However, characteristic data losses occur during wireless transmission. Estimates for the duration of these losses are typically uncertain reducing signal quality and impeding analyses. To characterize the effect of these losses on recovery of averaged neural signals, we simulated neural time series data for a typical event-related potential (ERP) experiment. We investigated how the signal duration and the degree of timing uncertainty affected the offset of the ERP, its duration in time, its amplitude, and the ability to resolve small differences corresponding to different task conditions. Simulations showed that long timescale signals were generally robust to the effects of packet losses apart from timing offsets while short timescale signals were significantly delocalized and attenuated. These results provide clarity on the types of signals that can be resolved using these datasets and provide clarity on the restrictions imposed by data losses on typical analyses.

Region-Level Functional and Effective Network Analysis of Human Brain During Cognitive Task Engagement.

Mental disorders are a major source of disability, with few effective treatments. It has recently been argued that these diseases might be effectively treated by focusing on decision-making, and specifically remediating decision-making deficits that act as "ingredients" in these disorders. Prior work showed that direct electrical brain stimulation can enhance human cognitive control, and consequently decision-making. This raises a challenge of detecting cognitive control lapses directly from electrical brain activity. Here, we demonstrate approaches to overcome that challenge. We propose a novel method, referred to as maximal variance node merging (MVNM), that merges nodes within a brain region to construct informative inter-region brain networks. We employ this method to estimate functional (correlational) and effective (causal) networks using local field potentials (LFP) during a cognitive behavioral task. The effective networks computed using convergent cross mapping differentiate task engagement from background neural activity with 85% median classification accuracy. We also derive task engagement networks (TENs): networks that constitute the most discriminative inter-region connections. Subsequent graph analysis illustrates the crucial role of the dorsolateral prefrontal cortex (dlPFC) in task engagement, consistent with a widely accepted model for cognition. We also show that task engagement is linked to prefrontal cortex theta (4-8 Hz) oscillations. We, therefore, identify objective biomarkers associated with task engagement. These approaches may generalize to other cognitive functions, forming the basis of a network-based approach to detecting and rectifying decision deficits.

Uncovering biomarkers during therapeutic neuromodulation with PARRM: Period-based Artifact Reconstruction and Removal Method.

Advances in therapeutic neuromodulation devices have enabled concurrent stimulation and electrophysiology in the central nervous system. However, stimulation artifacts often obscure the sensed underlying neural activity. Here, we develop a method, termed Period-based Artifact Reconstruction and Removal Method (PARRM), to remove stimulation artifacts from neural recordings by leveraging the exact period of stimulation to construct and subtract a high-fidelity template of the artifact. Benchtop saline experiments, computational simulations, five unique in vivo paradigms across animal and human studies, and an obscured movement biomarker are used for validation. Performance is found to exceed that of state-of-the-art filters in recovering complex signals without introducing contamination. PARRM has several advantages: (1) it is superior in signal recovery; (2) it is easily adaptable to several neurostimulation paradigms; and (3) it has low complexity for future on-device implementation. Real-time artifact removal via PARRM will enable unbiased exploration and detection of neural biomarkers to enhance efficacy of closed-loop therapies.