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.

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.

Default mode network electrophysiological dynamics and causal role in creative thinking.

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally-directed cognition. The present study employs stereo-electroencephalography in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by a stronger increase in gamma band power (30-70 Hz) coupled with lower theta band power (4-8 Hz). The difference in activity between the two networks was especially strong during the mind wandering task. Within the DMN, we found that the tasks showed different dynamics, with the alternate uses task engaging the DMN more during the initial stage of the task, and mind wandering in the later stage. Gamma power changes were mainly driven by lateral DMN sites, while theta power displayed task-specific effects. During alternate uses task, theta changes did not show spatial differences within the DMN, while mind wandering was associated to an early lateral and late dorsomedial DMN engagement. Furthermore, causal manipulations of DMN regions using direct cortical stimulation preferentially decreased the originality of responses in the alternative uses task, without affecting fluency or mind wandering. Our results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in divergent thinking. These findings shed light on the neural constructs supporting different forms of cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts.

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.

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.

What's the n? On sample size vs. subject number for brain-behavior neurophysiology and neuromodulation.

Neurophysiology and neuromodulation strive to understand the neural basis of behavior through a one-to-one correspondence between a particular brain and its behavioral output. Within this framework, studies with few subjects but sufficient sample sizes can be both rigorous and impactful.

Miniature battery-free epidural cortical stimulators.

Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power and reliability for real-world operation by showing acute motor cortex activation in human patients and reliable chronic motor cortex activation for 30 days in a porcine model. This platform opens the possibility of simple surgical procedures for precise neuromodulation.

A biophysically constrained brain connectivity model based on stimulation-evoked potentials.

BACKGROUND: Single-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies. NEW METHOD: Using intracranial electrophysiology data recorded from a single patient undergoing stereo-electroencephalography (sEEG) evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a novel topology optimization method, modeling 3D electrical conductivity to infer neural pathways from stimulation sites. Additionally, PEP features were compared with tractography metrics, and model results were analyzed with respect to anatomical features. RESULTS: The proposed optimization model resolved conductivity paths with low error. Specific electrode contacts displaying high error correlated with anatomical complexities. The C1 component strongly correlated with additional PEP features and displayed stable, weak correlations with tractography measures. COMPARISON WITH EXISTING METHOD: Existing methods for estimating neural signal pathways are imaging-based and thus rely on anatomical inferences. CONCLUSIONS: These results demonstrate that informing topology optimization methods with human intracranial SPES data is a feasible method for generating 3D conductivity maps linking electrical pathways with functional neural ensembles. PEP-estimated effective connectivity is correlated with but distinguished from structural connectivity. Modeled conductivity resolves connectivity pathways in the absence of anatomical priors.

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.

Aberrant fast spiking interneuronal activity precedes seizure transitions in humans.

There is active debate regarding how GABAergic function changes during seizure initiation and propagation, and whether interneuronal activity drives or impedes the pathophysiology. Here, we track cell-type specific firing during spontaneous human seizures to identify neocortical mechanisms of inhibitory failure. Fast-spiking interneuron activity was maximal over 1 second before equivalent excitatory increases, and showed transitions to out-of-phase firing prior to local tissue becoming incorporated into the seizure-driving territory. Using computational modeling, we linked this observation to transient saturation block as a precursor to seizure invasion, as supported by multiple lines of evidence in the patient data. We propose that transient blocking of inhibitory firing due to selective fast-spiking interneuron saturation-resulting from intense excitatory synaptic drive-is a novel mechanism that contributes to inhibitory failure, allowing seizure propagation.

Benchmarking signal quality and spatiotemporal distribution of interictal spikes in prolonged human iEEG recordings using CorTec wireless brain interchange.

Neuromodulation through implantable pulse generators (IPGs) represents an important treatment approach for neurological disorders. While the field has observed the success of state-of-the-art interventions, such as deep brain stimulation (DBS) or responsive neurostimulation (RNS), implantable systems face various technical challenges, including the restriction of recording from a limited number of brain sites, power management, and limited external access to the assessed neural data in a continuous fashion. To the best of our knowledge, for the first time in this study, we investigated the feasibility of recording human intracranial EEG (iEEG) using a benchtop version of the Brain Interchange (BIC) unit of CorTec, which is a portable, wireless, and externally powered implant with sensing and stimulation capabilities. We developed a MATLAB/SIMULINK-based rapid prototyping environment and a graphical user interface (GUI) to acquire and visualize the iEEG captured from all 32 channels of the BIC unit. We recorded prolonged iEEG (~ 24 h) from three human subjects with externalized depth leads using the BIC and commercially available clinical amplifiers simultaneously in the epilepsy monitoring unit (EMU). The iEEG signal quality of both streams was compared, and the results demonstrated a comparable power spectral density (PSD) in all the systems in the low-frequency band (< 80 Hz). However, notable differences were primarily observed above 100 Hz, where the clinical amplifiers were associated with lower noise floor (BIC-17 dB vs. clinical amplifiers < - 25 dB). We employed an established spike detector to assess and compare the spike rates in each iEEG stream. We observed over 90% conformity between the spikes rates and their spatial distribution captured with BIC and clinical systems. Additionally, we quantified the packet loss characteristic in the iEEG signal during the wireless data transfer and conducted a series of simulations to compare the performance of different interpolation methods for recovering the missing packets in signals at different frequency bands. We noted that simple linear interpolation has the potential to recover the signal and reduce the noise floor with modest packet loss levels reaching up to 10%. Overall, our results indicate that while tethered clinical amplifiers exhibited noticeably better noise floor above 80 Hz, epileptic spikes can still be detected successfully in the iEEG recorded with the externally powered wireless BIC unit opening the road for future closed-loop neuromodulation applications with continuous access to brain activity.

Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered the stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.

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.

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.

Stereo-EEG-guided network modulation for psychiatric disorders: Interactive holographic planning.

BACKGROUND: Connectomic modeling studies are expanding understanding of the brain networks that are modulated by deep brain stimulation (DBS) therapies. However, explicit integration of these modeling results into prospective neurosurgical planning is only beginning to evolve. One challenge of employing connectomic models in patient-specific surgical planning is the inherent 3D nature of the results, which can make clinically useful data integration and visualization difficult. METHODS: We developed a holographic stereotactic neurosurgery research tool (HoloSNS) that integrates patient-specific brain models into a group-based visualization environment for interactive surgical planning using connectomic hypotheses. HoloSNS currently runs on the HoloLens 2 platform and it enables remote networking between headsets. This allowed us to perform surgical planning group meetings with study co-investigators distributed across the country. RESULTS: We used HoloSNS to plan stereo-EEG and DBS electrode placements for each patient participating in a clinical trial (NCT03437928) that is targeting both the subcallosal cingulate and ventral capsule for the treatment of depression. Each patient model consisted of multiple components of scientific data and anatomical reconstructions of the head and brain (both patient-specific and atlas-based), which far exceed the data integration capabilities of traditional neurosurgical planning workstations. This allowed us to prospectively discuss and evaluate the positioning of the electrodes based on novel connectomic hypotheses. CONCLUSIONS: The 3D nature of the surgical procedure, brain imaging data, and connectomic modeling results all highlighted the utility of employing holographic visualization to support the design of unique clinical experiments to explore brain network modulation with DBS.

Benefits of sharing neurophysiology data from the BRAIN Initiative Research Opportunities in Humans Consortium.

Sharing human brain data can yield scientific benefits, but because of various disincentives, only a fraction of these data is currently shared. We profile three successful data-sharing experiences from the NIH BRAIN Initiative Research Opportunities in Humans (ROH) Consortium and demonstrate benefits to data producers and to users.

A biophysically constrained brain connectivity model based on stimulation-evoked potentials.

Background: Single-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies. New Method: Using intracranial electrophysiology data recorded from a single patient undergoing sEEG evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a novel topology optimization method, modeling 3D conductivity propagation from stimulation sites. Additionally, PEP features were compared with tractography metrics, and model results were analyzed with respect to anatomical features. Results: The proposed optimization model resolved conductivity paths with low error. Specific electrode contacts displaying high error correlated with anatomical complexities. The C1 component strongly correlates with additional PEP features and displayed stable, weak correlations with tractography measures. Comparison with existing methods: Existing methods for estimating conductivity propagation are imaging-based and thus rely on anatomical inferences. Conclusions: These results demonstrate that informing topology optimization methods with human intracranial SPES data is a feasible method for generating 3D conductivity maps linking electrical pathways with functional neural ensembles. PEP-estimated effective connectivity is correlated with but distinguished from structural connectivity. Modeled conductivity resolves connectivity pathways in the absence of anatomical priors.

Pretrial predictors of conflict response efficacy in the human prefrontal cortex.

The ability to perform motor actions depends, in part, on the brain's initial state. We hypothesized that initial state dependence is a more general principle and applies to cognitive control. To test this idea, we examined human single units recorded from the dorsolateral prefrontal (dlPFC) cortex and dorsal anterior cingulate cortex (dACC) during a task that interleaves motor and perceptual conflict trials, the multisource interference task (MSIT). In both brain regions, variability in pre-trial firing rates predicted subsequent reaction time (RT) on conflict trials. In dlPFC, ensemble firing rate patterns suggested the existence of domain-specific initial states, while in dACC, firing patterns were more consistent with a domain-general initial state. The deployment of shared and independent factors that we observe for conflict resolution may allow for flexible and fast responses mediated by cognitive initial states. These results also support hypotheses that place dACC hierarchically earlier than dlPFC in proactive control.

Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.