Electrophysiological sweet spot mapping in deep brain stimulation for Parkinson's disease patients.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is a well-established therapy to treat Parkinson's disease (PD). However, the STN-DBS sub-target remains debated. Recently, a white matter tract termed the hyperdirect pathway (HDP), directly connecting the motor cortex to STN, has gained interest as HDP stimulation is hypothesized to drive DBS therapeutic effects. Previously, we have investigated EEG-based evoked potentials (EPs) to better understand the neuroanatomical origins of the DBS clinical effect. We found a 3-ms peak (P3) relating to clinical benefit, and a 10-ms peak (P10) suggesting nigral side effects. Here, we aimed to investigate the neuroanatomical origins of DBS EPs using probabilistic mapping. METHODS: EPs were recorded using EEG whilst low-frequency stimulation was delivered at all DBS-contacts individually. Next, EPs were mapped onto the patients' individual space and then transformed to MNI standard space. Using voxel-wise and fiber-wise probabilistic mapping, we determined hotspots/hottracts and coldspots/coldtracts for P3 and P10. Topography analysis was also performed to determine the spatial distribution of the DBS EPs. RESULTS: In all 13 patients (18 hemispheres), voxel- and fiber-wise probabilistic mapping resulted in a P3-hotspot/hottract centered on the posterodorsomedial STN border indicative of HDP stimulation, while the P10-hotspot/hottract covered large parts of the substantia nigra. CONCLUSION: This study investigated EP-based probabilistic mapping in PD patients during STN-DBS, revealing a P3-hotspot/hottract in line with HDP stimulation and P10-hotspot/hottract related to nigral stimulation. Results from this study provide key evidence for an electrophysiological measure of HDP and nigral stimulation.

Exploring the Use of Interleaved Stimuli to Measure Cochlear-Implant Excitation Patterns.

PURPOSE: Attempts to use current-focussing strategies with cochlear implants (CI) to reduce neural spread-of-excitation have met with only mixed success in human studies, in contrast to promising results in animal studies. Although this discrepancy could stem from between-species anatomical and aetiological differences, the masking experiments used in human studies may be insufficiently sensitive to differences in excitation-pattern width. METHODS: We used an interleaved-masking method to measure psychophysical excitation patterns in seven participants with four masker stimulation configurations: monopolar (MP), partial tripolar (pTP), a wider partial tripolar (pTP + 2), and, importantly, a condition (RP + 2) designed to produce a broader excitation pattern than MP. The probe was always in partial-tripolar configuration. RESULTS: We found a significant effect of stimulation configuration on both the amount of on-site masking (mask and probe on same electrode; an indirect indicator of sharpness) and the difference between off-site and on-site masking. Differences were driven solely by RP + 2 producing a broader excitation pattern than the other configurations, whereas monopolar and the two current-focussing configurations did not statistically differ from each other. CONCLUSION: A method that is sensitive enough to reveal a modest broadening in RP + 2 showed no evidence for sharpening with focussed stimulation. We also showed that although voltage recordings from the implant accurately predicted a broadening of the psychophysical excitation patterns with RP + 2, they wrongly predicted a strong sharpening with pTP + 2. We additionally argue, based on our recent research, that the interleaved-masking method can usefully be applied to non-human species and objective measures of CI excitation patterns.

Artifact removal by template subtraction enables recordings of the frequency following response in cochlear-implant users.

Electrically evoked frequency-following responses (eFFRs) provide insight in the phase-locking ability of brainstem of cochlear-implant (CI) users. eFFRs can potentially be used to gain insight in the individual differences in the biological limitation on temporal encoding of the electrically stimulated auditory pathway, which can be inherent to the electrical stimulation itself and/or the degenerative processes associated with hearing loss. One of the major challenge of measuring eFFRs in CI users is the process of isolating the stimulation artifact from the neural response, as both the response and the artifact overlap in time and have similar frequency characteristics. Here we introduce a new artifact removal method based on template subtraction that successfully removes the stimulation artifacts from the recordings when CI users are stimulated with pulse trains from 128 to 300 pulses per second in a monopolar configuration. Our results show that, although artifact removal was successful in all CI users, the phase-locking ability of the brainstem to the different pulse rates, as assessed with the eFFR differed substantially across participants. These results show that the eFFR can be measured, free from artifacts, in CI users and that they can be used to gain insight in individual differences in temporal processing of the electrically stimulated auditory pathway.

Similar susceptibility to temporary hearing threshold shifts despite different audiograms in harbor porpoises and harbor seals.

When they are exposed to loud fatiguing sounds in the oceans, marine mammals are susceptible to hearing damage in the form of temporary hearing threshold shifts (TTSs) or permanent hearing threshold shifts. We compared the level-dependent and frequency-dependent susceptibility to TTSs in harbor seals and harbor porpoises, species with different hearing sensitivities in the low- and high-frequency regions. Both species were exposed to 100% duty cycle one-sixth-octave noise bands at frequencies that covered their entire hearing range. In the case of the 6.5 kHz exposure for the harbor seals, a pure tone (continuous wave) was used. TTS was quantified as a function of sound pressure level (SPL) half an octave above the center frequency of the fatiguing sound. The species have different audiograms, but their frequency-specific susceptibility to TTS was more similar. The hearing frequency range in which both species were most susceptible to TTS was 22.5-50 kHz. Furthermore, the frequency ranges were characterized by having similar critical levels (defined as the SPL of the fatiguing sound above which the magnitude of TTS induced as a function of SPL increases more strongly). This standardized between-species comparison indicates that the audiogram is not a good predictor of frequency-dependent susceptibility to TTS.

Detection of Electrically Evoked Auditory Steady-State Responses in Cochlear-Implant Recipients With a System Identification Based Method.

OBJECTIVE: Electrically evoked auditory steady-state responses (EASSRs) can potentially be used as an objective measure to realize the automatic fitting of cochlear implants (CIs). They can be recorded using electroencephalography (EEG) and objectively detected at the modulation frequency of the stimulus. The main roadblock in using EASSRs is the presence of CI stimulation artifacts in the EEG recording. In this article, we present an improvement of a recently introduced system identification (SI) based artifact removal method. We evaluate its applicability for objective CI fitting on a larger dataset. METHODS: The parameter estimation problem of the SI is solved using ordinary least squares (OLS), where an additional regularization term is added to the cost function. We compare EASSR latencies as determined by the commonly used linear interpolation artifact removal method and SI, to evaluate the artifact removal and EASSR detection quality on a dataset of 16 CI recipients and four different stimulation levels. RESULTS: SI can fully remove stimulation artifacts and detect EASSRs, even for recordings from ipsilateral EEG channels, where all other artifact removal methods fail so far. Using OLS with regularization prevents false positive response detection. CONCLUSION: Using SI, EASSRs can reliably be detected in EEG recordings, even for ipsilateral recording channels and recordings with lower stimulation levels. As the recordings are obtained with clinically relevant settings of the CI, they reveal the potential impact of SI on the objective fitting of CIs. SIGNIFICANCE: We argue, that SI enables therefore a big step towards automated CI fitting with EASSRs.

EEG-based biomarkers for optimizing deep brain stimulation contact configuration in Parkinson's disease.

Objective: Subthalamic deep brain stimulation (STN-DBS) is a neurosurgical therapy to treat Parkinson's disease (PD). Optimal therapeutic outcomes are not achieved in all patients due to increased DBS technological complexity; programming time constraints; and delayed clinical response of some symptoms. To streamline the programming process, biomarkers could be used to accurately predict the most effective stimulation configuration. Therefore, we investigated if DBS-evoked potentials (EPs) combined with imaging to perform prediction analyses could predict the best contact configuration. Methods: In 10 patients, EPs were recorded in response to stimulation at 10 Hz for 50 s on each DBS-contact. In two patients, we recorded from both hemispheres, resulting in recordings from a total of 12 hemispheres. A monopolar review was performed by stimulating on each contact and measuring the therapeutic window. CT and MRI data were collected. Prediction models were created to assess how well the EPs and imaging could predict the best contact configuration. Results: EPs at 3 ms and at 10 ms were recorded. The prediction models showed that EPs can be combined with imaging data to predict the best contact configuration and hence, significantly outperformed random contact selection during a monopolar review. Conclusion: EPs can predict the best contact configuration. Ultimately, these prediction tools could be implemented into daily practice to ease the DBS programming of PD patients.

Effects of analysis window on 40-Hz auditory steady-state responses in cochlear implant users.

Auditory steady-state responses (ASSRs) are phase-locked responses of the auditory system to the envelope of a stimulus. These responses can be used as an objective proxy to assess temporal envelope processing and its related functional outcomes such as hearing thresholds and speech perception, in normal-hearing listeners, in persons with hearing impairment, as well as in cochlear-implant (CI) users. While ASSRs are traditionally measured using a continuous stimulation paradigm, an alternative is the intermittent stimulation paradigm, whereby stimuli are presented with silence intervals in between. This paradigm could be more useful in a clinical setting as it allows for other neural responses to be analysed concurrently. One clinical use case of the intermittent paradigm is to objectively program CIs during an automatic fitting session whereby electrically evoked ASSRs (eASSRs) as well as other evoked potentials are used to predict behavioural thresholds. However, there is no consensus yet about the optimal analysis parameters for an intermittent paradigm in order to detect and measure eASSRs reliably. In this study, we used the intermittent paradigm to evoke eASSRs in adult CI users and investigated whether the early response buildup affects the response measurement outcomes. To this end, we varied the starting timepoint and length of the analysis window within which the responses were analysed. We used the amplitude, signal-to-noise ratio (SNR), phase, and pairwise phase consistency (PPC) to characterize the responses. Moreover, we set out to find the optimal stimulus duration for efficient and reliable eASSR measurements. These analyses were performed at two stimulation levels, i.e., 100% and 50% of the dynamic range of each participant. Results revealed that inclusion of the first 300 ms in the analysis window leads to overestimation of response amplitude and underestimation of response phase. Additionally, the response SNR and PPC were not affected by the inclusion of the first 300 ms in the analysis window. However, the latter two metrics were highly dependent on the stimulus duration which complicates comparisons across studies. Finally, the optimal stimulus duration for quick and reliable characterization of eASSRs was found to be around 800 ms for the stimulation level of 100% DR. These findings suggest that inclusion of the early onset period of eASSR recordings negatively influences the response measurement outcomes and that efficient and reliable eASSR measurements are possible using stimuli of around 800 ms long. This will pave the path for the development of a clinically feasible eASSR measurement in CI users.

Using Interleaved Stimulation and EEG to Measure Temporal Smoothing and Growth of the Sustained Neural Response to Cochlear-Implant Stimulation.

Two EEG experiments measured the sustained neural response to amplitude-modulated (AM) high-rate pulse trains presented to a single cochlear-implant (CI) electrode. Stimuli consisted of two interleaved pulse trains with AM rates F1 and F2 close to 80 and 120 Hz respectively, and where F2 = 1.5F1. Following Carlyon et al. (J Assoc Res Otolaryngol, 2021), we assume that such stimuli can produce a neural distortion response (NDR) at F0 = F2-F1 Hz if temporal dependencies ("smoothing") in the auditory system are followed by one or more neural nonlinearities. In experiment 1, the rate of each pulse train was 480 pps and the gap between pulses in the F1 and F2 pulse trains ranged from 0 to 984 µs. The NDR had a roughly constant amplitude for gaps between 0 and about 200-400 µs, and decreased for longer gaps. We argue that this result is consistent with a temporal dependency, such as facilitation, operating at the level of the auditory nerve and/or with co-incidence detection by cochlear-nucleus neurons. Experiment 2 first measured the NDR for stimuli at each listener's most comfortable level ("MCL") and for F0 = 37, 40, and 43 Hz. This revealed a group delay of about 42 ms, consistent with a thalamic/cortical source. We then showed that the NDR grew steeply with stimulus amplitude and, for most listeners, decreased by more than 12 dB between MCL and 75% of the listener's dynamic range. We argue that the NDR is a potentially useful objective estimate of MCL.

The importance of temporal-fine structure to perceive time-compressed speech with and without the restoration of the syllabic rhythm.

Intelligibility of time-compressed (TC) speech decreases with increasing speech rate. However, intelligibility can be restored by 'repackaging' the TC speech by inserting silences between the syllables so that the original 'rhythm' is restored. Although restoration of the speech rhythm affects solely the temporal envelope, it is unclear to which extent repackaging also affects the perception of the temporal-fine structure (TFS). Here we investigate to which extent TFS contributes to the perception of TC and repackaged TC speech in quiet. Intelligibility of TC sentences with a speech rate of 15.6 syllables per second (sps) and the repackaged sentences, by adding 100 ms of silence between the syllables of the TC speech (i.e., a speech rate of 6.1 sps), was assessed for three TFS conditions: the original TFS and the TFS conveyed by an 8- and 16-channel noise vocoder. An overall positive effect on intelligibility of both the repackaging process and of the amount of TFS available to the listener was observed. Furthermore, the benefit associated with the repackaging TC speech depended on the amount of TFS available. The results show TFS contributes significantly to the perception of fast speech even when the overall rhythm/envelope of TC speech is restored.

Electrophysiological and Psychophysical Measures of Temporal Pitch Sensitivity in Normal-hearing Listeners.

To obtain combined behavioural and electrophysiological measures of pitch perception, we presented harmonic complexes, bandpass filtered to contain only high-numbered harmonics, to normal-hearing listeners. These stimuli resemble bandlimited pulse trains and convey pitch using a purely temporal code. A core set of conditions consisted of six stimuli with baseline pulse rates of 94, 188 and 280 pps, filtered into a HIGH (3365-4755 Hz) or VHIGH (7800-10,800 Hz) region, alternating with a 36% higher pulse rate. Brainstem and cortical processing were measured using the frequency following response (FFR) and auditory change complex (ACC), respectively. Behavioural rate change difference limens (DLs) were measured by requiring participants to discriminate between a stimulus that changed rate twice (up-down or down-up) during its 750-ms presentation from a constant-rate pulse train. FFRs revealed robust brainstem phase locking whose amplitude decreased with increasing rate. Moderate-sized but reliable ACCs were obtained in response to changes in purely temporal pitch and, like the psychophysical DLs, did not depend consistently on the direction of rate change or on the pulse rate for baseline rates between 94 and 280 pps. ACCs were larger and DLs lower for stimuli in the HIGH than in the VHGH region. We argue that the ACC may be a useful surrogate for behavioural measures of rate discrimination, both for normal-hearing listeners and for cochlear-implant users. We also showed that rate DLs increased markedly when the baseline rate was reduced to 48 pps, and compared the behavioural and electrophysiological findings to recent cat data obtained with similar stimuli and methods.

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease.

OBJECTIVES: Deep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway-a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks. MATERIALS AND METHODS: We measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD. RESULTS: A short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001). CONCLUSIONS: Our results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming. CLINICAL TRIAL REGISTRATION: The ClinicalTrials.gov registration number for the study is NCT04658641.

Evaluation of phase-locking to parameterized speech envelopes.

Humans rely on the temporal processing ability of the auditory system to perceive speech during everyday communication. The temporal envelope of speech is essential for speech perception, particularly envelope modulations below 20 Hz. In the literature, the neural representation of this speech envelope is usually investigated by recording neural phase-locked responses to speech stimuli. However, these phase-locked responses are not only associated with envelope modulation processing, but also with processing of linguistic information at a higher-order level when speech is comprehended. It is thus difficult to disentangle the responses into components from the acoustic envelope itself and the linguistic structures in speech (such as words, phrases and sentences). Another way to investigate neural modulation processing is to use sinusoidal amplitude-modulated stimuli at different modulation frequencies to obtain the temporal modulation transfer function. However, these transfer functions are considerably variable across modulation frequencies and individual listeners. To tackle the issues of both speech and sinusoidal amplitude-modulated stimuli, the recently introduced Temporal Speech Envelope Tracking (TEMPEST) framework proposed the use of stimuli with a distribution of envelope modulations. The framework aims to assess the brain's capability to process temporal envelopes in different frequency bands using stimuli with speech-like envelope modulations. In this study, we provide a proof-of-concept of the framework using stimuli with modulation frequency bands around the syllable and phoneme rate in natural speech. We evaluated whether the evoked phase-locked neural activity correlates with the speech-weighted modulation transfer function measured using sinusoidal amplitude-modulated stimuli in normal-hearing listeners. Since many studies on modulation processing employ different metrics and comparing their results is difficult, we included different power- and phase-based metrics and investigate how these metrics relate to each other. Results reveal a strong correspondence across listeners between the neural activity evoked by the speech-like stimuli and the activity evoked by the sinusoidal amplitude-modulated stimuli. Furthermore, strong correspondence was also apparent between each metric, facilitating comparisons between studies using different metrics. These findings indicate the potential of the TEMPEST framework to efficiently assess the neural capability to process temporal envelope modulations within a frequency band that is important for speech perception.

Current Steering Using Multiple Independent Current Control Deep Brain Stimulation Technology Results in Distinct Neurophysiological Responses in Parkinson's Disease Patients.

Background: Deep brain stimulation (DBS) is an effective neuromodulation therapy to treat people with medication-refractory Parkinson's disease (PD). However, the neural networks affected by DBS are not yet fully understood. Recent studies show that stimulating on different DBS-contacts using a single current source results in distinct EEG-based evoked potentials (EPs), with a peak at 3 ms (P3) associated with dorsolateral subthalamic nucleus stimulation and a peak at 10 ms associated with substantia nigra stimulation. Multiple independent current control (MICC) technology allows the center of the electric field to be moved in between two adjacent DBS-contacts, offering a potential advantage in spatial precision. Objective: Determine if MICC precision targeting results in distinct neurophysiological responses recorded via EEG. Materials and Methods: We recorded cortical EPs in five hemispheres (four PD patients) using EEG whilst employing MICC to move the electric field from the most dorsal DBS-contact to the most ventral in 15 incremental steps. Results: The center of the electric field location had a significant effect on both the P3 and P10 amplitude in all hemispheres where a peak was detected (P3, detected in 4 of 5 hemispheres, p < 0.0001; P10, detected in 5 of 5 hemispheres, p < 0.0001). Post hoc analysis indicated furthermore that MICC technology can significantly refine the resolution of steering. Conclusion: Using MICC to incrementally move the center of the electric field to locations between adjacent DBS-contacts resulted in significantly different neurophysiological responses that may allow further precision of the programming of individual patients.

Temporal Pitch Sensitivity in an Animal Model: Psychophysics and Scalp Recordings : Temporal Pitch Sensitivity in Cat.

Cochlear implant (CI) users show limited sensitivity to the temporal pitch conveyed by electric stimulation, contributing to impaired perception of music and of speech in noise. Neurophysiological studies in cats suggest that this limitation is due, in part, to poor transmission of the temporal fine structure (TFS) by the brainstem pathways that are activated by electrical cochlear stimulation. It remains unknown, however, how that neural limit might influence perception in the same animal model. For that reason, we developed non-invasive psychophysical and electrophysiological measures of temporal (i.e., non-spectral) pitch processing in the cat. Normal-hearing (NH) cats were presented with acoustic pulse trains consisting of band-limited harmonic complexes that simulated CI stimulation of the basal cochlea while removing cochlear place-of-excitation cues. In the psychophysical procedure, trained cats detected changes from a base pulse rate to a higher pulse rate. In the scalp-recording procedure, the cortical-evoked acoustic change complex (ACC) and brainstem-generated frequency following response (FFR) were recorded simultaneously in sedated cats for pulse trains that alternated between the base and higher rates. The range of perceptual sensitivity to temporal pitch broadly resembled that of humans but was shifted to somewhat higher rates. The ACC largely paralleled these perceptual patterns, validating its use as an objective measure of temporal pitch sensitivity. The phase-locked FFR, in contrast, showed strong brainstem encoding for all tested pulse rates. These measures demonstrate the cat's perceptual sensitivity to pitch in the absence of cochlear-place cues and may be valuable for evaluating neural mechanisms of temporal pitch perception in the feline animal model of stimulation by a CI or novel auditory prostheses.

Tonotopic Selectivity in Cats and Humans: Electrophysiology and Psychophysics.

We describe a scalp-recorded measure of tonotopic selectivity, the "cortical onset response" (COR) and compare the results between humans and cats. The COR results, in turn, were compared with psychophysical masked-detection thresholds obtained using similar stimuli and obtained from both species. The COR consisted of averaged responses elicited by 50-ms tone-burst probes presented at 1-s intervals against a continuous noise masker. The noise masker had a bandwidth of 1 or 1/8th octave, geometrically centred on 4000 Hz for humans and on 8000 Hz for cats. The probe frequency was either - 0.5, - 0.25, 0, 0.25 or 0.5 octaves re the masker centre frequency. The COR was larger for probe frequencies more distant from the centre frequency of the masker, and this effect was greater for the 1/8th-octave than for the 1-octave masker. This pattern broadly reflected the masked excitation patterns obtained psychophysically with similar stimuli in both species. However, the positive signal-to-noise ratio used to obtain reliable COR measures meant that some aspects of the data differed from those obtained psychophysically, in a way that could be partly explained by the upward spread of the probe's excitation pattern. Our psychophysical measurements also showed that the auditory filter width obtained at 8000 Hz using notched-noise maskers was slightly wider in cat than previous measures from humans. We argue that although conclusions from COR measures differ in some ways from conclusions based on psychophysics, the COR measures provide an objective, noninvasive, valid measure of tonotopic selectivity that does not require training and that may be applied to acoustic and cochlear-implant experiments in humans and laboratory animals.

The Intelligibility of Time-Compressed Speech Is Correlated with the Ability to Listen in Modulated Noise.

Speech perception in difficult listening conditions depends highly on the temporal processing ability of the auditory pathway. In the present study, we investigate the inter-subject variability of young normal-hearing listeners in the identification of time-compressed speech and how the ability to identify time-compressed speech, as assessed by the speech reception threshold (SRTrate: the speech rate at which 50% of the speech is perceived correctly) is associated with the ability to identify speech in unmodulated (SRTunmod) and modulated noise (SRTmod). These tasks are highly dependent on the temporal processing abilities of the auditory pathway. We observed a large inter-subject variability in the SRTrate and found that it is significantly correlated with the SRT when listening to unmodulated and modulated noise. Furthermore, we found that listeners who are better at perceiving speech at high rates are better in listening to speech in modulated noise. This effect persisted even when controlling for their ability to perceive speech in unmodulated noise. In addition, we also found that an increase in speech rate from 2.7 to 6.6 syllables per second resulted in a reduction in glimpsing of 5.3 dB when listening to speech in a 4-Hz amplitude-modulated masker, even though speech in quiet was 100% intelligible at both rates. These results indicate that the ability of young normal-hearing individuals to efficiently process temporal features of speech is an imperative factor when listening to speech in difficult listening situations.

Towards biomarker-based optimization of deep brain stimulation in Parkinson's disease patients.

Background: Subthalamic deep brain stimulation (DBS) is an established therapy to treat Parkinson's disease (PD). To maximize therapeutic outcome, optimal DBS settings must be carefully selected for each patient. Unfortunately, this is not always achieved because of: (1) increased technological complexity of DBS devices, (2) time restraints, or lack of expertise, and (3) delayed therapeutic response of some symptoms. Biomarkers to accurately predict the most effective stimulation settings for each patient could streamline this process and improve DBS outcomes. Objective: To investigate the use of evoked potentials (EPs) to predict clinical outcomes in PD patients with DBS. Methods: In ten patients (12 hemispheres), a monopolar review was performed by systematically stimulating on each DBS contact and measuring the therapeutic window. Standard imaging data were collected. EEG-based EPs were then recorded in response to stimulation at 10 Hz for 50 s on each DBS-contact. Linear mixed models were used to assess how well both EPs and image-derived information predicted the clinical data. Results: Evoked potential peaks at 3 ms (P3) and at 10 ms (P10) were observed in nine and eleven hemispheres, respectively. Clinical data were well predicted using either P3 or P10. A separate model showed that the image-derived information also predicted clinical data with similar accuracy. Combining both EPs and image-derived information in one model yielded the highest predictive value. Conclusion: Evoked potentials can accurately predict clinical DBS responses. Combining EPs with imaging data further improves this prediction. Future refinement of this approach may streamline DBS programming, thereby improving therapeutic outcomes. Clinical trial registration: ClinicalTrials.gov, identifier NCT04658641.

Neural auditory processing of parameterized speech envelopes.

Speech perception depends highly on the neural processing of the speech envelope. Several auditory processing deficits are hypothesized to result in a reduction in fidelity of the neural representation of the speech envelope across the auditory pathway. Furthermore, this reduction in fidelity is associated with supra-threshold speech processing deficits. Investigating the mechanisms that affect the neural encoding of the speech envelope can be of great value to gain insight in the different mechanisms that account for this reduced neural representation, and to develop stimulation strategies for hearing prosthesis that aim to restore it. In this perspective, we discuss the importance of neural assessment of phase-locking to the speech envelope from an audiological view and introduce the Temporal Envelope Speech Tracking (TEMPEST) stimulus framework which enables the electrophysiological assessment of envelope processing across the auditory pathway in a systematic and standardized way. We postulate that this framework can be used to gain insight in the salience of speech-like temporal envelopes in the neural code and to evaluate the effectiveness of stimulation strategies that aim to restore temporal processing across the auditory pathway with auditory prostheses.

Frequency following responses and rate change complexes in cochlear implant users.

The upper limit of rate-based pitch perception and rate discrimination can differ substantially across cochlear implant (CI) users. One potential reason for this difference is the presence of a biological limitation on temporal encoding in the electrically-stimulated auditory pathway, which can be inherent to the electrical stimulation itself and/or to the degenerative processes associated with hearing loss. Electrophysiological measures, like the electrically-evoked frequency following response (eFFR) and auditory change complex (eACC), could potentially provide valuable insights in the temporal processing limitations at the level of the brainstem and cortex in the electrically-stimulated auditory pathway. Obtaining these neural responses, free from stimulation artifacts, is challenging, especially when the neural response is phase-locked to the stimulation rate, as is the case for the eFFR. In this study we investigated the feasibility of measuring eFFRs, free from stimulation artifacts, to stimulation rates ranging from 94 to 196 pulses per second (pps) and eACCs to pulse rate changes ranging from 36 to 108%, when stimulating in a monopolar configuration. A high-sampling rate EEG system was used to measure the electrophysiological responses in five CI users, and linear interpolation was applied to remove the stimulation artifacts from the EEG. With this approach, we were able to measure eFFRs for pulse rates up to 162 pps and eACCs to the different rate changes. Our results show that it is feasible to measure electrophysiological responses, free from stimulation artifacts, that could potentially be used as neural correlates for rate and pitch processing in CI users.

Using Interleaved Stimulation to Measure the Size and Selectivity of the Sustained Phase-Locked Neural Response to Cochlear Implant Stimulation.

We measured the sustained neural response to electrical stimulation by a cochlear implant (CI). To do so, we interleaved two stimuli with frequencies F1 and F2 Hz and recorded a neural distortion response (NDR) at F2-F1 Hz. We show that, because any one time point contains only the F1 or F2 stimulus, the instantaneous nonlinearities typical of electrical artefact should not produce distortion at this frequency. However, if the stimulus is smoothed, such as by charge integration at the nerve membrane, subsequent (neural) nonlinearities can produce a component at F2-F1 Hz. We stimulated a single CI electrode with interleaved sinusoids or interleaved amplitude-modulated pulse trains such that F2 = 1.5F1, and found no evidence for an NDR when F2-F1 was between 90 and 120 Hz. However, interleaved amplitude-modulated pulse trains with F2-F1~40 Hz revealed a substantial NDR with a group delay of about 45 ms, consistent with a thalamic and/or cortical response. The NDR could be measured even from recording electrodes adjacent to the implant and at the highest pulse rates (> 4000 pps) used clinically. We then measured the selectivity of this sustained response by presenting F1 and F2 to different electrodes and at different between-electrode distances. This revealed a broad tuning that, we argue, reflects the overlap between the excitation elicited by the two electrodes. Our results also provide a glimpse of the neural nonlinearity in the auditory system, unaffected by the biomechanical cochlear nonlinearities that accompany acoustic stimulation. Several potential clinical applications of our findings are discussed.