Stimulation Amplitude Research Articles

Comparing amplitudes of transcranial direct current stimulation (tDCS) to the sensorimotor cortex during swallowing.

Transcranial direct current stimulation (tDCS) can alter cortical excitability, making it a useful tool for promoting neuroplasticity in dysphagia rehabilitation. Clinical trials show functional improvements in swallowing following anodal tDCS despite varying dosing parameters and outcomes. The aim of the current study was to determine the most effective amplitude criterion (e.g., 0mA [sham/control], 1mA, 2mA) of anodal tDCS for upregulating the swallowing sensorimotor cortex. As a novel paradigm, tDCS, functional near-infrared spectroscopy (fNIRS), and surface electromyography (sEMG) were simultaneously administered while participants completed a swallowing task. This allowed for measurement of the cortical hemodynamic response and submental muscle contraction before, during, and after tDCS. At the conclusion of the study, participants were asked to rate their level of discomfort associated with tDCS using a visual analog scale. There was no significant difference in the hemodynamic response by time or amplitude. However, post-hoc analyses indicated that in the post-stimulation period, changes to the hemodynamic response in the left (stimulated) hemisphere were significantly different for the groups receiving 1mA and 2mA of tDCS compared to baseline. Participants receiving 1mA of tDCS demonstrated reduced hemodynamic response. There was no significant difference in submental muscle contraction during or after tDCS regardless of amplitude. Anodal tDCS was well tolerated in healthy adults with no difference among participant discomfort scores across tDCS amplitude. During a swallowing task, healthy volunteers receiving 1mA of anodal tDCS demonstrated a suppressed hemodynamic response during and after stimulation whereas those receiving 2mA of anodal tDCS had an increase in the hemodynamic response. tDCS remains a promising tool in dysphagia rehabilitation, but dosing parameters require further clarification.

Low Stimulation Amplitude is Associated with Improved Tremor Outcome in VIM DBS for ET (P14-11.007)

Low Stimulation Amplitude is Associated with Improved Tremor Outcome in VIM DBS for ET (P14-11.007)

Soft silicone‐based neural interface to modulate bladder function: chronic studies in awake behaving cats

Direct bladder wall stimulation has been attempted for decades to restore bladder function in people with spinal cord injury and other voiding dysfunctions. However, these efforts were limited by co‐activation of the urethra, legs and other pelvic organs at stimulus intensities that evoked bladder contractions. Neural interfaces for the detrusor muscle itself face several challenges due to its structure and the volume changes it undergoes in normal function. We designed a stretchable silicone net that can be placed around the bladder body to anchor a soft electrode array that interfaces directly with the base of bladder to generate bladder contractions.We created implantable versions of the electrode nets and tested them in chronic experiments. We implanted 5 healthy cats (4 females, 1 male) and tested them with and without anesthesia for 2‐3 months. A pressure catheter was implanted into the bladder to control volume and measure pressure.Bladder wall stimulation through various electrode configurations (monopolar, bipolar), temporal patterns (single electrode, sequential stimulation of multiple electrodes) and stimulus intensities were able to generate complete bladder emptying. In behaving cats, bladder wall stimulation at many different stimulus intensities elicited efficient voiding at physiological bladder pressures (med: 41, IQR: 27‐60 cmH2O). However, there was little relationship (r<0.28) between stimulation amplitude and bladder pressure itself. Rather, stimulation amplitude had an effect on the time between stimulation onset and bladder contraction onset. At low stimulation amplitudes, there was a longer time between stimulation onset and voiding (med: 35s, IQR: 13.5‐68.2s) than occurred at higher amplitudes, which evoked more rapid voiding (med: 23s, IQR: 10‐45s). This contrasts with anesthetized tests, where stimulation at 3 ± 2 mA evoked increases in bladder pressure up to 35 cmH2O. These results suggest that stimulation of the bladder wall recruits sensory pathways leading to an urge to void, but that can be suppressed by the animals. For most of the duration of the implants, stimulation evoked functional voiding with consistent electrical stimulation thresholds. However, after several months there was a failure of an implanted bond that limited the overall duration of the implants.Chronic experiments demonstrate that these electrode nets can be used as a neural interface to generate or initiate comfortable, complete bladder emptying in awake behaving cats. Future efforts include understanding the effects of evoked sensations on voiding and improving the integrity of the bonding between the flexible conductors and the lead wire.

Toward therapeutic electrophysiology: beta-band suppression as a biomarker in chronic local field potential recordings

Adaptive deep brain stimulation (aDBS) is a promising concept for feedback-based neurostimulation, with the potential of clinical implementation with the sensing-enabled Percept neurostimulator. We aim to characterize chronic electrophysiological activity during stimulation and to validate beta-band activity as a biomarker for bradykinesia. Subthalamic activity was recorded during stepwise stimulation amplitude increase OFF medication in 10 Parkinson’s patients during rest and finger tapping. Offline analysis of wavelet-transformed beta-band activity and assessment of inter-variable relationships in linear mixed effects models were implemented. There was a stepwise suppression of low-beta activity with increasing stimulation intensity (p = 0.002). Low-beta power was negatively correlated with movement speed and predictive for velocity improvements (p < 0.001), stimulation amplitude for beta suppression (p < 0.001). Here, we characterize beta-band modulation as a chronic biomarker for motor performance. Our investigations support the use of electrophysiology in therapy optimization, providing evidence for the use of biomarker analysis for clinical aDBS.

P 47 The Impact of directional deep brain stimulation on subthalamic beta power in Parkinson's disease

Introduction : Beta power in subthalamic local field potentials (LFPs) is a well established biomarker for bradykinesia-rigidity in idiopathic Parkinson's Disease (IPS) and is a promising feedback signal for adaptive deep brain stimulation (DBS). However, the effect of directional stimulation on this biomarker has not yet been elaborated. With new DBS-systems allowing to combine directional stimulation with relatively artifact-free recordings of local field potentials (LFPs), we want to assess the impact of directionality on beta power and motor performance. Patients & Methods : So far, 6 IPS patients implanted with Medtronic SenSight directional electrodes in the subthalamic nucleus (STN) have been included in the study. LFPs were recorded post-operatively and during a 3 months follow up visit (3MFU) with the patient at rest using the Medtronic Percept PC implantable pulse-generator. Additionally, at the 3MFU, a monopolar review of all segmented contacts (separately and combined as ring) was carried out in the medication “off” state. A rotameter task was used to assess motor performance. Following each block consisting of 2 minutes of rest and 30 seconds of rotation, stimulation amplitude was increased stepwise up to a maximum amplitude of 3 mA or the occurrence of side effects. LFPs were streamed throughout the review. The primary outcome is the reduction of mean beta power with directional stimulation compared with (1) no stimulation and (2) ring stimulation. The secondary outcomes are: (1) Beta burst length distribution, (2) motor performance and (3) rate of side effects with directional compared to ring stimulation. Results : Further patient inclusion to a minimum of 10 patients is planned before the summit. Directional and ring stimulation led to dose-dependent reduction of mean beta power in the STN. Stimulation had an effect on both movement amplitude and velocity. In 4 out of 6 patients, the side effect threshold was higher with directional stimulation compared to ring stimulation. At the summit, we will also report changes in beta burst length distribution with directional compared to ring stimulation and the predictive value of beta power in postoperative intersegmental rest recordings for the clinically most effective directional contact. Conclusion : Our study contributes to characterizing LFP beta power in the context of directional stimulation and its relation to motor performance. This is a prerequisite for combining directional stimulation with beta-driven adaptive DBS, which ultimately could further improve DBS therapy.

FV 9 Deep Brain Stimulation for targeting tremor and ataxia in SCA 27

Introduction: Spinocerebellar ataxia 27 (SCA 27) is a rare cerebellar ataxia caused by mutations in the FGF14 gene. It is characterised by tremor manifesting in early adulthood and slowly progressive ataxia in later decades. Here, we report the case of a 51 years old male patient who was initially diagnosed with medication-refractory essential tremor and therefore received thalamic deep brain stimulation (DBS). After the patient developed signs of cerebellar ataxia exome sequencing led to the diagnosis of SCA 27. In our clinical practice, we tested stimulation paradigms to target tremor and ataxia inspired by model findings (Anderson et al. 2019) suggesting differential effects of low- and high-frequency stimulation. Methods: The patient was implanted with quadripolar electrodes (model 3389, Medtronic) in the nucleus ventralis intermedius of the thalamus (VIM) with the lowest contact reaching the subthalamic fibre tracts. Initially, stimulation-induced manifestation of cerebellar ataxia was ruled out by a wash-out of DBS for 96 h. Next, we established a high-frequency (180 Hz) programme located at the thalamic contacts achieving best tremor control and a low-frequency (30 Hz) programme located at the lowest contacts to interfere with subthalamic fibre tracts. Electrode placement was verified using Lead-DBS. The Fahn-Tolosa-Marin Tremor Rating Scale (TRS) and the Scale of the Assessment and Rating of Ataxia (SARA) were performed for clinical assessment. At baseline, we evaluated the condition without stimulation (StimOFF) vs. 180 Hz vs. subthalamic 30 Hz stimulation. Further follow-up examinations were scheduled after 5 and 10 weeks. In the meantime, the patient activated the 180 Hz programme at daytime and either StimOff or 30 Hz stimulation at night. The investigator and patient were blinded to the night setting of the previous interval. Results: At baseline, tremor severity was attenuated by 180Hz DBS compared to StimOFF (TRS 13 vs. 21). Tremor was also attenuated by 30 Hz stimulation of the subthalamus at 1 mA (TRS: 14) but was gradually entrained with higher stimulation amplitudes up to 7 mA (TRS: 27). Changes of the SARA where mainly driven by the tremor component. During the first interval period, the patient adopted the 30 Hz night stimulation programme with 4 mA. In the follow-up examination tremor in the StimOFF condition (TRS: 12) improved to a TRS of 7 using the 180 Hz programme. Eventually, after the second period during which the patient adopted StimOFF at night, the baseline TRS was higher in the StimOFF condition (TRS: 23) and slightly improved to a TRS of 17 when using 180 Hz stimulation. Conclusions: Here, we report the first case of a patient with SCA 27 successfully treated with VIM-DBS in terms of tremor attenuation. We observed that low-frequency stimulation at night led to a more sustained tremor response by stimulation which may be due to antidromic stimulation of cerebellar-thalamic fibre tracts in the subthalamic area.

P 43 Optimizing beta-burst driven adaptive deep brain stimulation for Parkinson's disease

Introduction Adaptive deep brain stimulation (DBS) aims at improving DBS therapy by adjusting stimulation amplitude to patient specific biomarkers tracked in real-time. In Parkinson’s disease (PD), a promising closed-loop approach exploits fast fluctuations of beta power (beta bursts) in subthalamic local field potentials (LFP). With this method, stimulation is applied as soon as beta bursts of a given magnitude and duration are detected. However, closed-loop algorithms offer clinicians a wide range of possible settings. This will further increase the parameter space and thus the complexity of DBS programming, ultimately limiting ease of clinical usability. To increase the translational potential of adaptive DBS, this constraint must be overcome by narrowing down the parameter space towards a clinically optimal combination of stimulation settings. Objectives To explore the parameter space of a beta burst driven adaptive DBS algorithm and to characterize its neurophysiological and behavioral correlates in order to identify a clinically optimal parameter combination. Patients & methods A research platform for adaptive stimulation has been designed comprising a stimulation artifact suppressing amplifier, a custom-made software interface and an external neurostimulator. On this platform, a configurable LFP beta burst driven closed-loop algorithm has been implemented. This setup was used to conduct closed-loop stimulation in PD patients undergoing two-stage-surgery for DBS. Rest recordings were combined with a standardized motor task to quantify stimulation-induced behavioral effects. By systematically changing the minimum beta burst duration upon which stimulation is triggered and the amount of smoothing applied to real-time beta power, the parameter space of this algorithm was explored. Results Stimulation patterns were governed by parameter combination with higher minimum burst duration leading to less frequent stimulation. Beta dynamics varied depending on parameter choice. Clinically optimal settings are yet to be explored. Conclusion The choice of adaptive DBS parameter combination strongly influences stimulation patterns and stimulation-induced neurophysiological responses. Combined recordings of neurophysiological and behavioral adaptive DBS correlates for different parameter combinations may pave the way for guiding parameter choice based on electrophysiological evaluation. This may facilitate the clinical translation of adaptive DBS.

Maximum acceptable level for the determination of ECAP and ESRT in a paediatric population

Objectives Two of the most used objective measures are electrically evoked action potentials (ECAPs) and electrically evoked stapedius reflex thresholds (ESRTs). Although stimuli used for these measures differ considerably, both measures are influenced by subjective loudness percept. We focus on the subjective maximum acceptable loudness (MAL) to investigate if loudness sensitivity varied along the electrode array during ECAP recordings. In addition, we explored how the MAL reached during an ECAP recording related to the postoperative ESRT. Methods Uni- and bilaterally implanted young CI users (n = 15, average age = 9 y, age range 3–18 y) underwent ECAP and ESR recordings using the clinical software MAESTRO (MED-EL, Innsbruck, Austria) and a commercially available immittance instrument (PATH MEDICAL GmbH, Germering, Germany). Results Loudness tolerance during ECAP recordings was lowest at the two apical-most electrode contacts (number 1 and 2). There was a moderate correlation between the MAL achieved during ECAP recordings and ESR maximum stimulation amplitudes. (r: 0.44344). Conclusions ECAP recordings should commence at basal or medial contacts to increase the users’ comfort and loudness tolerance, especially in young CI users. A higher maximum stimulation appears to increase the chance of the automatic determination of ECAP thresholds for all electrode contacts.

An in-silico analysis of electrically evoked responses of midget and parasol retinal ganglion cells in different retinal regions

Objective. Visual outcomes provided by present retinal prostheses that primarily target retinal ganglion cells (RGCs) through epiretinal stimulation remain rudimentary, partly due to the limited knowledge of retinal responses under electrical stimulation. Better understanding of how different retinal regions can be quantitatively controlled with high spatial accuracy, will be beneficial to the design of micro-electrode arrays and stimulation strategies for next-generation wide-view, high-resolution epiretinal implants. Approach. A computational model was developed to assess neural activity at different eccentricities (2 mm and 5 mm) within the human retina. This model included midget and parasol RGCs with anatomically accurate cell distribution and cell-specific morphological information. We then performed in silico investigations of region-specific RGC responses to epiretinal electrical stimulation using varied electrode sizes (5–210 µm diameter), emulating both commercialized retinal implants and recently developed prototype devices. Main results. Our model of epiretinal stimulation predicted RGC population excitation analogous to the complex percepts reported in human subjects. Following this, our simulations suggest that midget and parasol RGCs have characteristic regional differences in excitation under preferred electrode sizes. Relatively central (2 mm) regions demonstrated higher number of excited RGCs but lower overall activated receptive field (RF) areas under the same stimulus amplitudes (two-way analysis of variance (ANOVA), p < 0.05). Furthermore, the activated RGC numbers per unit active RF area (number-RF ratio) were significantly higher in central than in peripheral regions, and higher in the midget than in the parasol population under all tested electrode sizes (two-way ANOVA, p < 0.05). Our simulations also suggested that smaller electrodes exhibit a higher range of controllable stimulation parameters to achieve pre-defined performance of RGC excitation. An empirical model: I = a · exp (b · D) + c of the stimulus amplitude (I)–electrode diameter (D) relationship was constructed to achieve the pre-defined objective function values in different retinal regions, indicating the ability of controlling retinal outputs by fine-tuning the stimulation amplitude with different electrode sizes. Finally, our multielectrode simulations predicted differential neural crosstalk between adjacent electrodes in central temporal and peripheral temporal regions, providing insights towards establishing a non-uniformly distributed multielectrode array geometry for wide-view retinal implants. Significance. Stimulus–response properties in central and peripheral retina can provide useful information to estimate electrode parameters for region-specific activation by retinal stimulation. Our findings support the possibility of improving the performance of epiretinal prostheses by exploring the influence of electrode array geometry on activation of different retinal regions.

Clinically-derived oscillatory biomarker predicts optimal subthalamic stimulation for Parkinson’s disease

Objective. Choosing the optimal electrode trajectory, stimulation location, and stimulation amplitude in subthalamic nucleus deep brain stimulation (STN DBS) for Parkinson’s disease remains a time-consuming empirical effort. In this retrospective study, we derive a data-driven electrophysiological biomarker that predicts clinical DBS location and parameters, and we consolidate this information into a quantitative score that may facilitate an objective approach to STN DBS surgery and programming. Approach. Random-forest feature selection was applied to a dataset of 1046 microelectrode recordings (MERs) sites across 20 DBS implant trajectories to identify features of oscillatory activity that predict clinically programmed volumes of tissue activation (VTAs). A cross-validated classifier was used to retrospectively predict VTA regions from these features. Spatial convolution of probabilistic classifier outputs along MER trajectories produced a biomarker score that reflects the probability of localization within a clinically optimized VTA. Main results. Biomarker scores peaked within the VTA region and were significantly correlated with percent improvement in postoperative motor symptoms (Part III of the Movement Disorders Society revision of the Unified Parkinson Disease Rating Scale, R = 0.61, p = 0.004). Notably, the length of STN, a common criterion for trajectory selection, did not show similar correlation (R = −0.31, p = 0.18). These findings suggest that biomarker-based trajectory selection and programming may improve motor outcomes by 9 ± 3 percentage points (p = 0.047) in this dataset. Significance. A clinically defined electrophysiological biomarker not only predicts VTA size and location but also correlates well with motor outcomes. Use of this biomarker for trajectory selection and initial stimulation may potentially simplify STN DBS surgery and programming.

Cluster analysis of upper airway stimulation adherence patterns and implications on clinical care

Upper airway stimulation (UAS) therapy is effective for a subset of obstructive sleep apnea (OSA) patients with continuous positive airway pressure (CPAP) intolerance. While overall adherence is high, some patients have suboptimal adherence, which limits efficacy. Our goal was to identify therapy usage patterns during the first 3 months of therapy to enable targeted strategies for improved adherence. Therapy data was retrieved from 2098 patients for three months after device activation. Data included mean and standard deviation (SD) of hours of use, therapy pauses, hours from midnight the therapy was turned ON and OFF, percentage of missing days, and stimulation amplitude. Cluster analysis was performed using Gaussian mixture models that categorized patients into six main groups. The six groups and their prevalence can be summarized as Cluster 1A: Excellent Use (34%); Cluster 1B: Excellent Use with variable timing (23%); Cluster 2A: Good Use with missing days and late therapy ON (16%), Cluster 2B: Good Use with missing days, late therapy ON, and early therapy OFF (12%); Cluster 3A: Variable Use with frequent missing days (8%); Cluster 3B: Variable Use with frequent pauses (7%). Most patients (85%) are excellent or good users with mean therapy use >6 hours per night. Cluster analysis of early UAS usage patterns identified six distinct groups that may enable personalized interventions for improved long-term management. Differentiation of the patient clusters may have clinical implications with regard to sleep hygiene education, therapy discomfort, comorbid insomnia, and other conditions that impact adherence.

Local and distant cortical responses to single pulse intracranial stimulation in the human brain are differentially modulated by specific stimulation parameters

BackgroundElectrical neuromodulation via direct electrical stimulation (DES) is an increasingly common therapy for a wide variety of neuropsychiatric diseases. Unfortunately, therapeutic efficacy is inconsistent, likely due to our limited understanding of the relationship between the massive stimulation parameter space and brain tissue responses. ObjectiveTo better understand how different parameters induce varied neural responses, we systematically examined single pulse-induced cortico-cortico evoked potentials (CCEP) as a function of stimulation amplitude, duration, brain region, and whether grey or white matter was stimulated. MethodsWe measured voltage peak amplitudes and area under the curve (AUC) of intracranially recorded stimulation responses as a function of distance from the stimulation site, pulse width, current injected, location relative to grey and white matter, and brain region stimulated (N = 52, n = 719 stimulation sites). ResultsIncreasing stimulation pulse width increased responses near the stimulation location. Increasing stimulation amplitude (current) increased both evoked amplitudes and AUC nonlinearly. Locally (<15 mm), stimulation at the boundary between grey and white matter induced larger responses. In contrast, for distant sites (>15 mm), white matter stimulation consistently produced larger responses than stimulation in or near grey matter. The stimulation location-response curves followed different trends for cingulate, lateral frontal, and lateral temporal cortical stimulation. ConclusionThese results demonstrate that a stronger local response may require stimulation in the grey-white boundary while stimulation in the white matter could be needed for network activation. Thus, stimulation parameters tailored for a specific anatomical-functional outcome may be key to advancing neuromodulatory therapy.

Characterization of bilateral, pudendal nerve-evoked, urethral rhabdosphincter contractions in anesthetized cats

Pudendal (PUD) efferent activity contracts urethral rhabdosphincters to resist urine leakage. This study evaluates the potential for PUD nerve stimulation to provide benefit for urinary incontinence. Acute responses of the urethral rhabdosphincter to modulation of current amplitude, pulse duration (PD), and frequency of stimulation were examined. Urethral pressure was measured using a microtip catheter in chloralose-anesthetized, male cats with or without acute spinalization at T10. Stimulation was applied from an external pulse generator coupled to cuff electrodes placed around left and right PUD nerves in the ischiorectal fossa, central to its branching. Bladder pressure clamp techniques were used for testing effects of stimulation on time and rate of leakage during PUD stimulation. Single pulses (0.1 ms) produced single transient increases in urethral pressure that peaked at 50 ms and diminished to 50% of peak at 90 ms. Threshold current was 88 ± 30μA with maximal responses occurring with 50% increases in current. Peak pressures increased with increasing PDs between 40–180μs. Summation, tetany, peak pressures, and fatigue of responses to increasing stimulation frequencies during 2 min periods of stimulation are described. Stimulation under pressures that are typical during bladder filling or during bladder contractions (30–40 cm H2O) prevented leakage up to an hour in some animals, increased the median time to leak from 0.3 min to 56.0 min, and decreased the median rate of leakage from 1.44 ml/min to 0.04 ml/min when leakage did occur in less than hour. During rapid elevations in bladder pressure to simulate a Valsalva-like bladder pressure (120 cm H2O), PUD stimulation increased the median time to leak from 9 s to 93 s and decreased the median rate of leakage from 5.5 ml/min to 3.4 ml/min. These results support future studies of bilateral PUD stimulation in a clinically-relevant, animal model of urinary incontinence.

Direct targeting of the ventral intermediate nucleus of the thalamus in deep brain stimulation for essential tremor: a prospective study with comparison to a historical cohort.

The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation (DBS) to control symptoms related to essential tremor. The VIM is typically targeted using indirect methods, although studies have reported visualization of the VIM on proton density-weighted MRI. This study compares the outcomes between patients who underwent VIM DBS with direct and indirect targeting. Between August 2013 and December 2019, 230 patients underwent VIM DBS at the senior author's institution. Of these patients, 92 had direct targeting (direct visualization on proton density 3-T MRI). The remaining 138 patients had indirect targeting (relative to the third ventricle and anterior commissure-posterior commissure line). Coordinates of electrodes placed with direct targeting were significantly more lateral (p < 0.001) and anterior (p < 0.001) than those placed with indirect targeting. The optimal stimulation amplitude for devices measured in voltage was lower for those who underwent direct targeting than for those who underwent indirect targeting (p < 0.001). Patients undergoing direct targeting had a greater improvement only in their Quality of Life in Essential Tremor Questionnaire hobby score versus those undergoing indirect targeting (p = 0.04). The direct targeting group had substantially more symptomatic hemorrhages than the indirect targeting group (p = 0.04). All patients who experienced a postoperative hemorrhage after DBS recovered without intervention. Patients who underwent direct VIM targeting for DBS treatment of essential tremor had similar clinical outcomes to those who underwent indirect targeting. Direct VIM targeting is safe and effective.

Antiparkinsonian Drug Reduction After Directional Versus Omnidirectional Bilateral Subthalamic Deep Brain Stimulation

BackgroundSeveral pilot trials and the Clinical Evaluation of the Infinity Deep Brain Stimulation System (PROGRESS) study have found that directional stimulation can provide a wider therapeutic window and lower therapeutic current strength than omnidirectional stimulation. ObjectiveWe conducted a single-center, open-label, registry-based, comparative trial to test the hypothesis that directional stimulation can be associated with a greater reduction in the total daily dose of antiparkinsonian medications (ApMeds) than omnidirectional stimulation. Materials and MethodsA total of 52 patients with directional and 57 subjects with omnidirectional bilateral subthalamic deep brain stimulation (STN-DBS) were enrolled. Preoperatively and 12 months postoperatively, the dose of different ApMeds, the number of tablets used daily, the severity of motor and nonmotor symptoms using the Movement Disorder Society–sponsored Unified Parkinson Disease Rating Scale, and the health-related quality of life (HRQoL) using the 39-item Parkinson’s Disease Questionnaire (PDQ-39) were assessed. ResultsAccording to the changes in the levodopa equivalent daily dose, directional STN-DBS led to a 13% greater reduction in the total daily dose of ApMed. The 10.3% greater reduction in the dose of levodopa was the main contributor to this difference. The number of different ApMed types also could be decreased in a greater manner with directional stimulation. The improvement in the severity of motor and nonmotor symptoms was comparable; however, we detected a 15.8% greater improvement in the global HRQoL among patients with directional stimulation according to the changes in the summary index of the PDQ-39. The total electrical energy delivered per second was comparable between the groups at 12-month postoperative visit, whereas the amplitude of stimulation was significantly lower and the impedance was significantly higher with directional leads. ConclusionsDirectional programming can further increase the reduction in the total daily dose of ApMed after STN-DBS. In addition, directional stimulation can have additional beneficial effects on the global HRQoL. The greater reduction of ApMed doses did not require more energy-consuming stimulation with directional stimulation.

Neuropathic pain in Charcot-Marie-Tooth disease: A clinical and laser-evoked potential study.

Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease. We investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study. We enrolled 50 patients: 19 with duplication of PMP22 (CMT1A), 11 with mutation of MPZ (CMT1B, CMT2I/J, or CMTDID), 12 with mutation of GJB1 (CMTX1), and 8 with mutation of MFN2 (CMT2A and CMT2A2B). Pain was rated with the 11-point Numerical Rating Scale and characterized through Neuropathic Pain Symptoms Inventory. Laser-evoked potentials (LEPs) were recorded after right foot and hand stimulation and N2-P2 complex amplitude and latency were compared with those of 41 controls. Overall pain prevalence was 36%. NP was present in 14.6% of patients, with a length-dependent distribution in 85.7% of cases, and it was significantly more frequent in CMT1A (p<0.001). Aδ fibers involvement greatly varies between CMT subtypes, reflecting differences in molecular pathology and pathophysiologic mechanisms. Prolonged N2 latency from foot stimulation was noted in 11 CMT1A patients, 5 of which report NP. MPZ-CMTs displayed different neurophysiological phenotypes and a very low prevalence of NP. LEPs were normal in all but one CMTX1 patients, although lower limbs N2-P2 amplitude was significantly reduced in males (p=0.043). MFN2-CMTs were NP free and LEPs recordings were all normal. NP strictly correlated with LEPs alterations (p=0.017). NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment. Neuropathic pain is a frequent finding in Charcot-Marie Tooth disease and is related to Aδ fibers impairment. Patients at higher risk are those belonging to certain genetic subtypes (i.e. CMT1A and CMT2J) or with laser-evoked potentials abnormalities. While managing this disease, clinicians should be aware of this symptom in order to offer best treatment options to their patients.

The Effects of Monophasic Anodal Transcranial Pulsed Current Stimulation on Corticospinal Excitability and Motor Performance in Healthy Young Adults: A Randomized Double-Blinded Sham-Controlled Study.

Introduction: Transcranial pulsed current stimulation (tPCS) could be used to deliver electrical pulses at different frequencies to entrain the cortical neurons of the brain. Frequency dependence of these pulses in the induction of changes in corticospinal excitability (CSE) has not been reported. Objective: We aimed to assess the effect of anodal tPCS (a-tPCS) at theta (4 Hz), and gamma (75 Hz) frequencies on CSE as assessed by the peak-to-peak amplitude of transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEPs) and motor performance. Method: In a randomized, double-blinded, sham-controlled, crossover design study, 17 healthy participants attended 3 experimental sessions and received either a-tPCS at 4 and 75 Hz, or sham a-tPCS with 1.5 mA for 15 min. The amplitude of TMS-induced resting MEPs and time for completion of the grooved pegboard test were recorded at baseline, immediately after, and 30 min after a-tPCS. Results: Both a-tPCS at 75 and 4 Hz showed significantly increased CSE compared with sham. The a-tPCS at 75 Hz induced significantly higher CSE changes compared with 4 Hz. There was a significant increase in intracortical facilitation and a significant reduction in short-interval intracortical inhibition with both 4 and 75 Hz stimulations. However, the inhibition and facilitation did not correlate with CSE. Motor performance was unaffected by the interventions. Conclusion: The high CSE changes in M1 in a-tPCS at 75 Hz provide an initial understanding of the frequency-specific effect of a-tPCS. More research is needed to establish this concept and to assess its behavioral relevance. Impact statement Transcranial pulsed current stimulation (tPCS) is a novel brain stimulation technique that can modulate neural oscillation via the pulsatile current induced by the stimulation. Using anodal tPCS, we demonstrate the neuromodulatory effect induced by the stimulation at theta and gamma frequencies. Our findings recommend anodal tPCS as a potential therapeutic tool for treating many neurological conditions with altered theta and gamma neural oscillatory activity.

Morphology and Dendrite-Specific Synaptic Properties of Midbrain Neurons Shape Multimodal Integration.

Multimodal integration facilitates object recognition and response to sensory cues. This depends on spatiotemporal coincidence of sensory information, recruitment of NMDA-type glutamate receptors and inhibitory feedback. Shepherd's crook neurons (SCNs) in the avian optic tectum (TeO) are an ideal model for studying cellular mechanism of multimodal integration. They receive different sensory modalities through spatially segregated dendrites, are important for stimulus selection and have an axon-carrying dendrite (AcD). We performed whole-cell patch-clamp experiments in chicken midbrain slices of both sexes. We emulated visual and auditory input in vitro by stimulating presynaptic afferents electrically. Simultaneous stimulation enhanced responses inversely depending on stimulation amplitude demonstrating the principle of inverse effectiveness. Contribution of NMDA-type glutamate receptors prolonged postsynaptic events for visual inputs only, causing a strong modality-specific difference in synaptic efficacy. We designed a multicompartment model to study the effect of morphological and physiological parameters on multimodal integration by varying the distance between soma and axonal origin and the amount of NMDA receptor (NMDAR) contribution. These parameters changed the preference of the model for one input channel and adjusted the range of input rates at which multimodal enhancement occurred on naturalistic stimulation. Thus, the unique morphology and synaptic features of SCNs shape the integration of input at different dendrites and generates an enhanced multimodal response.SIGNIFICANCE STATEMENT Multimodal integration improves perception and responses to objects. The underlying cellular mechanism depends on a balance between excitation and inhibition, and NMDA-type glutamate receptors that are involved in the multiplicative nature of enhancement following the principle of inverse effectiveness. Based on a detailed analysis of an identified multimodal cell type in the vertebrate midbrain, we studied the influence of cellular morphology and unimodal synaptic properties on multimodal integration. We can show that the combination of cellular morphology and modality-specific synaptic properties including NMDA receptor (NMDAR) contribution is optimal for nonlinear, multimodal enhancement and determines the dynamic response range of the integrating neuron. Our findings mechanistically explain how synaptic properties and cellular morphology of a midbrain neuron contribute to multimodal enhancement.

Transcorneal Electrical Stimulation Induces Long-Lasting Enhancement of Brain Functional and Directional Connectivity in Retinal Degeneration Mice.

To investigate neuromodulation of functional and directional connectivity features in both visual and non-visual brain cortices after short-term and long-term retinal electrical stimulation in retinal degeneration mice. We performed spontaneous electrocorticography (ECoG) in retinal degeneration (rd) mice following prolonged transcorneal electrical stimulation (pTES) at varying currents (400, 500 and 600 μA) and different time points (transient or day 1 post-stimulation, 1-week post-stimulation and 2-weeks post-stimulation). We also set up a sham control group of rd mice which did not receive any electrical stimulation. Subsequently we analyzed alterations in cross-frequency coupling (CFC), coherence and directional connectivity of the primary visual cortex and the prefrontal cortex. It was observed that the sham control group did not display any significant changes in brain connectivity across all stages of electrical stimulation. For the stimulated groups, we observed that transient electrical stimulation of the retina did not significantly alter brain coherence and connectivity. However, for 1-week post-stimulation, we identified enhanced increase in theta-gamma CFC. Meanwhile, enhanced coherence and directional connectivity appeared predominantly in theta, alpha and beta oscillations. These alterations occurred in both visual and non-visual brain regions and were dependent on the current amplitude of stimulation. Interestingly, 2-weeks post-stimulation demonstrated long-lasting enhancement in network coherence and connectivity patterns at the level of cross-oscillatory interaction, functional connectivity and directional inter-regional communication between the primary visual cortex and prefrontal cortex. Application of electrical stimulation to the retina evidently neuromodulates brain coherence and connectivity of visual and non-visual cortices in retinal degeneration mice and the observed alterations are largely maintained. pTES holds strong possibility of modulating higher cortical functions including pathways of cognition, awareness, emotion and memory.

Artifact Characterization and a Multipurpose Template-Based Offline Removal Solution for a Sensing-Enabled Deep Brain Stimulation Device

Background: The Medtronic “Percept” is the first FDA-approved deep brain stimulation (DBS) device with sensing capabilities during active stimulation. Its real-world signal-recording properties have yet to be fully described. Objective: This study details three sources of artifact (and potential mitigations) in local field potential (LFP) signals collected by the Percept and assesses the potential impact of artifact on the future development of adaptive DBS (aDBS) using this device. Methods: LFP signals were collected from 7 subjects in both experimental and clinical settings. The presence of artifacts and their effect on the spectral content of neural signals were evaluated in both the stimulation ON and OFF states using three distinct offline artifact removal techniques. Results: Template subtraction successfully removed multiple sources of artifact, including (1) electrocardiogram (ECG), (2) nonphysiologic polyphasic artifacts, and (3) ramping-related artifacts seen when changing stimulation amplitudes. ECG removal from stimulation ON (at 0 mA) signals resulted in spectral shapes similar to OFF stimulation spectra (averaged difference in normalized power in theta, alpha, and beta bands ≤3.5%). ECG removal using singular value decomposition was similarly successful, though required subjective researcher input. QRS interpolation produced similar recovery of beta-band signal but resulted in residual low-frequency artifact. Conclusions: Artifacts present when stimulation is enabled notably affected the spectral properties of sensed signals using the Percept. Multiple discrete artifacts could be successfully removed offline using an automated template subtraction method. The presence of unrejected artifact likely influences online power estimates, with the potential to affect aDBS algorithm performance.