Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Cortical signatures of sleep are altered following effective deep brain stimulation for depression.

Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep-slow-wave activity (SWA, 0.5-4.5 Hz) and sleep spindles-in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep.

Leveraging Physiological Markers to Quantify the Transient Effects of Traumatic Stress and Non-Invasive Neuromodulation.

Millions around the world suffer from traumatic stress (stress caused by traumatic memories). Transcutaneous cervical vagus nerve stimulation (tcVNS) has been shown to counteract physiological changes associated with traumatic stress. However, little is known regarding the approximate timecourse of tcVNS effects. This knowledge of how quickly tcVNS takes effect is needed to optimize closed-loop tcVNS systems that can mitigate traumatic stress in a timely manner. To address this gap, we studied N=26 participants with history of prior trauma. Participants wore electrocardiogram, photoplethysmogram, seismocardiogram, and respiratory effort sensors throughout a double-blind protocol involving traumatic stress and active tcVNS (n=12) or sham stimulation (n=14). From the physiological signals, we extracted cardiovascular and respiratory markers and studied their dynamics during the traumatic stress and stimulation conditions. We decoupled the short-term transient responses from longer-term cumulative changes by centering each condition's response with respect to data immediately prior to the condition. We thereby elucidate a diverse set of transient physiological responses to tcVNS and traumatic stress. These responses demonstrate that tcVNS-induced changes occur within seconds and have the potential to reduce acute physiological manifestations of traumatic stress.Clinical relevance- Traumatic stress can overpower an individual within seconds and often occurs outside the clinic. This analysis focuses on transient physiological responses to traumatic memories and tcVNS captured using multimodal physiological sensing. We demonstrate that tcVNS-induced changes occur within seconds and have the potential to mitigate some of the short-term effects of traumatic stress.

Neuroethics guidance documents: principles, analysis, and implementation strategies.

Innovations in neurotechnologies have ignited conversations about ethics around the world, with implications for researchers, policymakers, and the private sector. The human rights impacts of neurotechnologies have drawn the attention of United Nations bodies; nearly 40 states are tasked with implementing the Organization for Economic Co-operation and Development's principles for responsible innovation in neurotechnology; and the United States is considering placing export controls on brain-computer interfaces. Against this backdrop, we offer the first review and analysis of neuroethics guidance documents recently issued by prominent government, private, and academic groups, focusing on commonalities and divergences in articulated goals; envisioned roles and responsibilities of different stakeholder groups; and the suggested role of the public. Drawing on lessons from the governance of other emerging technologies, we suggest implementation and evaluation strategies to guide practitioners and policymakers in operationalizing these ethical norms in research, business, and policy settings.

Cingulate dynamics track depression recovery with deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD)1. However, achieving stable recovery is unpredictable2, typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting3. We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment.

Pain is reduced by transcutaneous cervical vagus nerve stimulation and correlated with cardiorespiratory variability measures in the context of opioid withdrawal.

Over 100,000 individuals in the United States lost their lives secondary to drug overdose in 2021, with opioid use disorder (OUD) being a leading cause. Pain is an important component of opioid withdrawal, which can complicate recovery from OUD. This study's objectives were to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS), a technique shown to reduce sympathetic arousal in other populations, on pain during acute opioid withdrawal and to study pain's relationships with objective cardiorespiratory markers. Twenty patients with OUD underwent opioid withdrawal while participating in a two-hour protocol. The protocol involved opioid cues to induce opioid craving and neutral conditions for control purposes. Adhering to a double-blind design, patients were randomly assigned to receive active tcVNS (n = 9) or sham stimulation (n = 11) throughout the protocol. At the beginning and end of the protocol, patients' pain levels were assessed using the numerical rating scale (0-10 scale) for pain (NRS Pain). During the protocol, electrocardiogram and respiratory effort signals were measured, from which heart rate variability (HRV) and respiration pattern variability (RPV) were extracted. Pre- to post- changes (denoted with a Δ) were computed for all measures. Δ NRS Pain scores were lower (P = 0.045) for the active group (mean ± standard deviation: -0.8 ± 2.4) compared to the sham group (0.9 ± 1.0). A positive correlation existed between Δ NRS pain scores and Δ RPV (Spearman's ρ = 0.46; P = 0.04). Following adjustment for device group, a negative correlation existed between Δ HRV and Δ NRS Pain (Spearman's ρ = -0.43; P = 0.04). This randomized, double-blind, sham-controlled pilot study provides the first evidence of tcVNS-induced reductions in pain in patients with OUD experiencing opioid withdrawal. This study also provides the first quantitative evidence of an association between breathing irregularity and pain. The correlations between changes in pain and changes in objective physiological markers add validity to the data. Given the clinical importance of reducing pain non-pharmacologically, the findings support the need for further investigation of tcVNS and wearable cardiorespiratory sensing for pain monitoring and management in patients with OUD.

Time-frequency signatures evoked by single-pulse deep brain stimulation to the subcallosal cingulate.

Precision targeting of specific white matter bundles that traverse the subcallosal cingulate (SCC) has been linked to efficacy of deep brain stimulation (DBS) for treatment resistant depression (TRD). Methods to confirm optimal target engagement in this heterogenous region are now critical to establish an objective treatment protocol. As yet unexamined are the time-frequency features of the SCC evoked potential (SCC-EP), including spectral power and phase-clustering. We examined these spectral features-evoked power and phase clustering-in a sample of TRD patients (n = 8) with implanted SCC stimulators. Electroencephalogram (EEG) was recorded during wakeful rest. Location of electrical stimulation in the SCC target region was the experimental manipulation. EEG was analyzed at the surface level with an average reference for a cluster of frontal sensors and at a time window identified by prior study (50-150 ms). Morlet wavelets generated indices of evoked power and inter-trial phase clustering. Enhanced phase clustering at theta frequency (4-7 Hz) was observed in every subject and was significantly correlated with SCC-EP magnitude, but only during left SCC stimulation. Stimulation to dorsal SCC evinced stronger phase clustering than ventral SCC. There was a weak correlation between phase clustering and white matter density. An increase in evoked delta power (2-4 Hz) was also coincident with SCC-EP, but was less consistent across participants. DBS evoked time-frequency features index mm-scale changes to the location of stimulation in the SCC target region and correlate with structural characteristics implicated in treatment optimization. Results also imply a shared generative mechanism (inter-trial phase clustering) between evoked potentials evinced by electrical stimulation and evoked potentials evinced by auditory/visual stimuli and behavioral tasks. Understanding how current injection impacts downstream cortical activity is essential to building new technologies that adapt treatment parameters to individual differences in neurophysiology.

Passively Captured Interpersonal Social Interactions and Motion From Smartphones for Predicting Decompensation in Heart Failure: Observational Cohort Study.

BACKGROUND: Heart failure (HF) is a major cause of frequent hospitalization and death. Early detection of HF symptoms using smartphone-based monitoring may reduce adverse events in a low-cost, scalable way. OBJECTIVE: We examined the relationship of HF decompensation events with smartphone-based features derived from passively and actively acquired data. METHODS: This was a prospective cohort study in which we monitored HF participants' social and movement activities using a smartphone app and followed them for clinical events via phone and chart review and classified the encounters as compensated or decompensated by reviewing the provider notes in detail. We extracted motion, location, and social interaction passive features and self-reported quality of life weekly (active) with the short Kansas City Cardiomyopathy Questionnaire (KCCQ-12) survey. We developed and validated an algorithm for classifying decompensated versus compensated clinical encounters (hospitalizations or clinic visits). We evaluated models based on single modality as well as early and late fusion approaches combining patient-reported outcomes and passive smartphone data. We used Shapley additive explanation values to quantify the contribution and impact of each feature to the model. RESULTS: We evaluated 28 participants with a mean age of 67 years (SD 8), among whom 11% (3/28) were female and 46% (13/28) were Black. We identified 62 compensated and 48 decompensated clinical events from 24 and 22 participants, respectively. The highest area under the precision-recall curve (AUCPr) for classifying decompensation was with a late fusion approach combining KCCQ-12, motion, and social contact features using leave-one-subject-out cross-validation for a 2-day prediction window. It had an AUCPr of 0.80, with an area under the receiver operator curve (AUC) of 0.83, a positive predictive value (PPV) of 0.73, a sensitivity of 0.77, and a specificity of 0.88 for a 2-day prediction window. Similarly, the 4-day window model had an AUC of 0.82, an AUCPr of 0.69, a PPV of 0.62, a sensitivity of 0.68, and a specificity of 0.87. Passive social data provided some of the most informative features, with fewer calls of longer duration associating with a higher probability of future HF decompensation. CONCLUSIONS: Smartphone-based data that includes both passive monitoring and actively collected surveys may provide important behavioral and functional health information on HF status in advance of clinical visits. This proof-of-concept study, although small, offers important insight into the social and behavioral determinants of health and the feasibility of using smartphone-based monitoring in this population. Our strong results are comparable to those of more active and expensive monitoring approaches, and underscore the need for larger studies to understand the clinical significance of this monitoring method.

Proceedings of the Ninth Annual Deep Brain Stimulation Think Tank: Advances in Cutting Edge Technologies, Artificial Intelligence, Neuromodulation, Neuroethics, Pain, Interventional Psychiatry, Epilepsy, and Traumatic Brain Injury.

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. 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 deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury.

Constrained brain volume in an efficient coding model explains the fraction of excitatory and inhibitory neurons in sensory cortices.

The number of neurons in mammalian cortex varies by multiple orders of magnitude across different species. In contrast, the ratio of excitatory to inhibitory neurons (E:I ratio) varies in a much smaller range, from 3:1 to 9:1 and remains roughly constant for different sensory areas within a species. Despite this structure being important for understanding the function of neural circuits, the reason for this consistency is not yet understood. While recent models of vision based on the efficient coding hypothesis show that increasing the number of both excitatory and inhibitory cells improves stimulus representation, the two cannot increase simultaneously due to constraints on brain volume. In this work, we implement an efficient coding model of vision under a constraint on the volume (using number of neurons as a surrogate) while varying the E:I ratio. We show that the performance of the model is optimal at biologically observed E:I ratios under several metrics. We argue that this happens due to trade-offs between the computational accuracy and the representation capacity for natural stimuli. Further, we make experimentally testable predictions that 1) the optimal E:I ratio should be higher for species with a higher sparsity in the neural activity and 2) the character of inhibitory synaptic distributions and firing rates should change depending on E:I ratio. Our findings, which are supported by our new preliminary analyses of publicly available data, provide the first quantitative and testable hypothesis based on optimal coding models for the distribution of excitatory and inhibitory neural types in the mammalian sensory cortices.

Transcutaneous Cervical Vagus Nerve Stimulation Reduces Respiratory Variability in the Context of Opioid Withdrawal.

Opioid withdrawal's physiological effects are a major impediment to recovery from opioid use disorder (OUD). Prior work has demonstrated that transcutaneous cervical vagus nerve stimulation (tcVNS) can counteract some of opioid withdrawal's physiological effects by reducing heart rate and perceived symptoms. The purpose of this study was to assess the effects of tcVNS on respiratory manifestations of opioid withdrawal - specifically, respiratory timings and their variability. Patients with OUD (N = 21) underwent acute opioid withdrawal over the course of a two-hour protocol. The protocol involved opioid cues to induce opioid craving and neutral conditions for control purposes. Patients were randomly assigned to receive double-blind active tcVNS (n = 10) or sham stimulation (n = 11) throughout the protocol. Respiratory effort and electrocardiogram-derived respiration signals were used to estimate inspiration time (Ti), expiration time (Te), and respiration rate (RR), along with each measure's variability quantified via interquartile range (IQR). Comparing the active and sham groups, active tcVNS significantly reduced IQR(Ti) - a variability measure - compared to sham stimulation (p = .02). Relative to baseline, the active group's median change in IQR(Ti) was 500 ms less than the sham group's median change in IQR(Ti). Notably, IQR(Ti) was found to be positively associated with post-traumatic stress disorder symptoms in prior work. Therefore, a reduction in IQR(Ti) suggests that tcVNS downregulates the respiratory stress response associated with opioid withdrawal. Although further investigations are necessary, these results promisingly suggest that tcVNS - a non-pharmacologic, non-invasive, readily implemented neuromodulation approach - can serve as a novel therapy to mitigate opioid withdrawal symptoms.

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.

Sparse Coding Using the Locally Competitive Algorithm on the TrueNorth Neurosynaptic System.

The Locally Competitive Algorithm (LCA) is a biologically plausible computational architecture for sparse coding, where a signal is represented as a linear combination of elements from an over-complete dictionary. In this paper we map the LCA algorithm on the brain-inspired, IBM TrueNorth Neurosynaptic System. We discuss data structures and representation as well as the architecture of functional processing units that perform non-linear threshold, vector-matrix multiplication. We also present the design of the micro-architectural units that facilitate the implementation of dynamical based iterative algorithms. Experimental results with the LCA algorithm using the limited precision, fixed-point arithmetic on TrueNorth compare favorably with results using floating-point computations on a general purpose computer. The scaling of the LCA algorithm within the constraints of the TrueNorth is also discussed.

PatcherBot: a single-cell electrophysiology robot for adherent cells and brain slices.

OBJECTIVE: Intracellular patch-clamp electrophysiology, one of the most ubiquitous, high-fidelity techniques in biophysics, remains laborious and low-throughput. While previous efforts have succeeded at automating some steps of the technique, here we demonstrate a robotic 'PatcherBot' system that can perform many patch-clamp recordings sequentially, fully unattended. APPROACH: Comprehensive automation is accomplished by outfitting the robot with machine vision, and cleaning pipettes instead of manually exchanging them. MAIN RESULTS: the PatcherBot can obtain data at a rate of 16 cells per hour and work with no human intervention for up to 3 h. We demonstrate the broad applicability and scalability of this system by performing hundreds of recordings in tissue culture cells and mouse brain slices with no human supervision. Using the PatcherBot, we also discovered that pipette cleaning can be improved by a factor of three. SIGNIFICANCE: The system is potentially transformative for applications that depend on many high-quality measurements of single cells, such as drug screening, protein functional characterization, and multimodal cell type investigations.

Stabilizing embedology: Geometry-preserving delay-coordinate maps.

Delay-coordinate mapping is an effective and widely used technique for reconstructing and analyzing the dynamics of a nonlinear system based on time-series outputs. The efficacy of delay-coordinate mapping has long been supported by Takens' embedding theorem, which guarantees that delay-coordinate maps use the time-series output to provide a reconstruction of the hidden state space that is a one-to-one embedding of the system's attractor. While this topological guarantee ensures that distinct points in the reconstruction correspond to distinct points in the original state space, it does not characterize the quality of this embedding or illuminate how the specific parameters affect the reconstruction. In this paper, we extend Takens' result by establishing conditions under which delay-coordinate mapping is guaranteed to provide a stable embedding of a system's attractor. Beyond only preserving the attractor topology, a stable embedding preserves the attractor geometry by ensuring that distances between points in the state space are approximately preserved. In particular, we find that delay-coordinate mapping stably embeds an attractor of a dynamical system if the stable rank of the system is large enough to be proportional to the dimension of the attractor. The stable rank reflects the relation between the sampling interval and the number of delays in delay-coordinate mapping. Our theoretical findings give guidance to choosing system parameters, echoing the tradeoff between irrelevancy and redundancy that has been heuristically investigated in the literature. Our initial result is stated for attractors that are smooth submanifolds of Euclidean space, with extensions provided for the case of strange attractors.

Cell Membrane Tracking in Living Brain Tissue Using Differential Interference Contrast Microscopy.

Differential interference contrast (DIC) microscopy is widely used for observing unstained biological samples that are otherwise optically transparent. Combining this optical technique with machine vision could enable the automation of many life science experiments; however, identifying relevant features under DIC is challenging. In particular, precise tracking of cell boundaries in a thick ( ) slice of tissue has not previously been accomplished. We present a novel deconvolution algorithm that achieves the state-of-the-art performance at identifying and tracking these membrane locations. Our proposed algorithm is formulated as a regularized least squares optimization that incorporates a filtering mechanism to handle organic tissue interference and a robust edge-sparsity regularizer that integrates dynamic edge tracking capabilities. As a secondary contribution, this paper also describes new community infrastructure in the form of a MATLAB toolbox for accurately simulating DIC microscopy images of in vitro brain slices. Building on existing DIC optics modeling, our simulation framework additionally contributes an accurate representation of interference from organic tissue, neuronal cell-shapes, and tissue motion due to the action of the pipette. This simulator allows us to better understand the image statistics (to improve algorithms), as well as quantitatively test cell segmentation and tracking algorithms in scenarios, where ground truth data is fully known.

Matched Filtering for Heart Rate Estimation on Compressive Sensing ECG Measurements.

OBJECTIVE: Compressive sensing (CS) has recently been applied as a low-complexity compression framework for long-term monitoring of electrocardiogram (ECG) signals using wireless body sensor networks. Long-term recording of ECG signals can be useful for diagnostic purposes and to monitor the evolution of several widespread diseases. In particular, beat-to-beat intervals provide important clinical information, and these can be derived from the ECG signal by computing the distance between QRS complexes (R-peaks). Numerous methods for R-peak detection are available for uncompressed ECG. However, in the case of compressed sensed data, signal reconstruction can be performed with relatively complex optimization algorithms, which may require significant energy consumption. This paper addresses the problem of heart rate estimation from CS ECG recordings, avoiding the reconstruction of the entire signal. METHODS: We consider a framework, where the ECG signals are represented under the form of CS linear measurements. The QRS locations are estimated in the compressed domain by computing the correlation of the compressed ECG and a known QRS template. RESULTS: Experiments on actual ECG signals show that our novel solution is competitive with methods applied to the reconstructed signals. CONCLUSION: Avoiding the reconstruction procedure, the proposed method proves to be very convenient for real-time low-power applications.

Outcome measures based on classification performance fail to predict the intelligibility of binary-masked speech.

To date, the most commonly used outcome measure for assessing ideal binary mask estimation algorithms is based on the difference between the hit rate and the false alarm rate (H-FA). Recently, the error distribution has been shown to substantially affect intelligibility. However, H-FA treats each mask unit independently and does not take into account how errors are distributed. Alternatively, algorithms can be evaluated with the short-time objective intelligibility (STOI) metric using the reconstructed speech. This study investigates the ability of H-FA and STOI to predict intelligibility for binary-masked speech using masks with different error distributions. The results demonstrate the inability of H-FA to predict the behavioral intelligibility and also illustrate the limitations of STOI. Since every estimation algorithm will make errors that are distributed in different ways, performance evaluations should not be made solely on the basis of these metrics.

Cochlear implant speech intelligibility outcomes with structured and unstructured binary mask errors.

It has been shown that intelligibility can be improved for cochlear implant (CI) recipients with the ideal binary mask (IBM). In realistic scenarios where prior information is unavailable, however, the IBM must be estimated, and these estimations will inevitably contain errors. Although the effects of both unstructured and structured binary mask errors have been investigated with normal-hearing (NH) listeners, they have not been investigated with CI recipients. This study assesses these effects with CI recipients using masks that have been generated systematically with a statistical model. The results demonstrate that clustering of mask errors substantially decreases the tolerance of errors, that incorrectly removing target-dominated regions can be as detrimental to intelligibility as incorrectly adding interferer-dominated regions, and that the individual tolerances of the different types of errors can change when both are present. These trends follow those of NH listeners. However, analysis with a mixed effects model suggests that CI recipients tend to be less tolerant than NH listeners to mask errors in most conditions, at least with respect to the testing methods in each of the studies. This study clearly demonstrates that structure influences the tolerance of errors and therefore should be considered when analyzing binary-masking algorithms.