Stimulus Amplitude Research Articles

Intracortical microstimulation of human somatosensory cortex induces natural perceptual biases

Time-order error, a psychophysical phenomenon in which the duration in between successive stimuli alters perception, has been studied for decades by neuroscientists and psychologists. To date, however, the locus of these effects is unknown. We use intracortical microstimulation of somatosensory cortex in three humans with spinal cord injury as a tool to bypass initial stages of processing and restrict the possible locations that signals could be modified. Using a 2-interval forced choice amplitude discrimination paradigm, we first assessed the extent to which order effects are observed. Comparing trials where the standard stimulus was in the first or second interval, we found that systematic biases are exhibited, typically causing the intensity of the second stimulus to be overestimated The degree of this overestimation for individual electrodes was dependent on the perceptual sensitivity to changes in stimulus amplitude. To investigate the role of memory on this phenomenon, we implemented a 2-interval magnitude estimation task in which participants were instructed to ignore the first stimulus and again found that the perceptual intensity of the second stimulus tended to be enhanced by the first in a manner that depended on the amplitude and duration of the first stimulus. Finally, we repeated both paradigms while varying the inter-stimulus interval to examine the timescale over which these effects occur and found that longer inter-stimulus intervals reduced the effect size. These results show that direct activation of primary somatosensory cortex is sufficient to induce time-order errors.

Neural correlates of trait anxiety in sensory processing and distractor filtering.

Evidence suggests that trait anxiety relates to cognitive processing and behavior. However, the relationships between trait anxiety and sensory processing, goal-directed performance and sensorimotor function are unclear, particularly in a multimodal context. This study used electroencephalography to evaluate whether trait anxiety influenced visual and tactile event-related potentials (ERPs), as well as behavioral distractor cost, in a bimodal sensorimotor task. Twenty-nine healthy young adults completed the State-Trait Anxiety Inventory. Participants were directed to focus on either tactile or visual stimuli while disregarding the other modality, responding to target stimulus amplitude with a proportional grip. Previous research suggests that somatosensory N70 and visual P2 ERPs serve as markers of attentional relevance, with attention also impacting the visual P3 ERP. It was hypothesized that trait anxiety would modulate the ERPs susceptible to attentional modulation (tactile N70, visual P2 and P3) and not affect behavioral performance. Trait anxiety showed a large, significant interaction with attention for visual P3 latency in response to unimodal visual stimuli, with a positive relationship between P3 latencies and trait anxiety when attending toward the stimulus and negative when attending away. A large, positive main effect of trait anxiety on visual N1 amplitude for bimodal stimuli was also detected. As predicted, trait anxiety related to ERPs but not behavioral distractor cost. These findings suggest that trait anxiety modulates visual but not somatosensory processing correlates based on attention. The absence of overt behavioral performance effects suggests compensatory mechanisms may offset underlying differences in sensory processing.

Detection of mild sensory hearing loss using a joint reflection-distortion otoacoustic emission profile.

Measuring and analyzing both nonlinear-distortion and linear-reflection otoacoustic emissions (OAEs) combined creates what we have termed a "joint-OAE profile." Here, we test whether these two classes of emissions have different sensitivities to hearing loss and whether our joint-OAE profile can detect mild-moderate hearing loss better than conventional OAE protocols have. 2f1-f2 distortion-product OAEs and stimulus-frequency OAEs were evoked with rapidly sweeping tones in 300 normal and impaired ears. Metrics included OAE amplitude for fixed-level stimuli as well as slope and compression features derived from OAE input/output functions. Results show that mild-moderate hearing loss impacts distortion and reflection emissions differently. Clinical decision theory was applied using OAE metrics to classify all ears as either normal-hearing or hearing-impaired. Our best OAE classifiers achieved 90% or better hit rates (with false positive rates of 5%-10%) for mild hearing loss, across a nearly five-octave range. In summary, results suggest that distortion and reflection emissions have distinct sensitivities to hearing loss, which supports the use of a joint-OAE approach for diagnosis. Results also indicate that analyzing both reflection and distortion OAEs together to detect mild hearing loss produces outstanding accuracy across the frequency range, exceeding that achieved by conventional OAE protocols.

Olfactory facilitation of visual categorization in the 4-month-old brain depends on visual demand.

To navigate their environment, infants rely on intersensory facilitation when unisensory perceptual demand is high, a principle known as inverse effectiveness. Given that this principle was mainly documented in the context of audiovisual stimulations, here we aim to determine whether it applies to olfactory-to-visual facilitation. We build on previous evidence that the mother's body odor facilitates face categorization in the 4-month-old brain, and investigate whether this effect depends on visual demand. Scalp electroencephalogram (EEG) was recorded in two groups of 4-month-old infants while they watched 6-Hz streams of visual stimuli with faces displayed every 6th stimulus to tag a face-selective response at 1Hz. We used variable natural stimuli in one group (Nat Group), while stimuli were simplified in the other group (Simp Group) to reduce perceptual categorization demand. During visual stimulation, infants were alternatively exposed to their mother's versus a baseline odor. For both groups, we found an occipito-temporal face-selective response, but with a larger amplitude for the simplified stimuli, reflecting less demanding visual categorization. Importantly, the mother's body odor enhances the response to natural, but not to simplified, face stimuli, indicating that maternal odor improves face categorization when it is most demanding for the 4-month-old brain. Overall, this study demonstrates that the inverse effectiveness of intersensory facilitation applies to the sense of smell during early perceptual development. RESEARCH HIGHLIGHTS: Intersensory facilitation is a function of unisensory perceptual demand in infants (inverse effectiveness). This inverse relation between multisensory and unisensory perception has been mainly documented using audiovisual stimulations. Here we show that olfactory-to-visual facilitation depends on visual demand in 4-month-old infants. The inverse effectiveness of intersensory facilitation during early perceptual development applies to the sense of smell.

Collective behaviors of neural network regulated by the spatially distributed stimuli

Most external stimuli, including sound, temperature, and illumination, exhibit spatially heterogeneous, and different amplitudes of the same signal are received by neurons at different positions in the neural network. To address this issue, we constructed a grid-like neural network using memristive FitzHugh-Nagumo neurons. The neuronal responses depend on the spatially distributed stimuli, with the stimulus amplitudes being determined by the distance from the central area. Consequently, complete synchronization occurs in the network comprising periodic neurons, chaotic neurons, and their hybrid forms. Periodic patterns maintain the highest Hamilton energy whereas the lowest Hamilton energy appears in chaotic neurons. In a network consisting of chaotic neurons, the synchronization threshold is larger compared to the other types. In particular, the periodic neurons with the highest energy oscillations can regulate the low-energy chaotic neurons into periodic patterns. Similar conclusions are drawn in a chain-like network. The results advance the understanding of the synchronization mechanisms in the presence of spatial heterogeneity.

Adapting and optimizing GCaMP8f for use in Caenorhabditis elegans.

Improved genetically encoded calcium indicators (GECIs) are essential for capturing intracellular dynamics of both muscle and neurons. A novel set of GECIs with ultrafast kinetics and high sensitivity was recently reported by Zhang et al. (2023). While these indicators, called jGCaMP8, were demonstrated to work in Drosophila and mice, data for Caenorhabditis elegans were not reported. Here, we present an optimized construct for C. elegans and use this to generate several strains expressing GCaMP8f (fast variant of the indicator). Utilizing the myo-2 promoter, we compare pharyngeal muscle activity measured with GCaMP7f and GCaMP8f and find that GCaMP8f is brighter upon binding to calcium, shows faster kinetics, and is not disruptive to the intrinsic contraction dynamics of the pharynx. Additionally, we validate its application for detecting neuronal activity in touch receptor neurons which reveals robust calcium transients even at small stimulus amplitudes. As such, we establish GCaMP8f as a potent tool for C. elegans research which is capable of extracting fast calcium dynamics at very low magnifications across multiple cell types.

Velocity dependence of sensory reweighting in human balance control.

The relative contributions of proprioceptive, vestibular, and visual sensory cues to balance control change depending on their availability and reliability. This sensory reweighting is classically supported by nonlinear sway responses to increasing visual surround and/or surface tilt amplitudes. However, recent evidence indicates that visual cues are reweighted based on visual tilt velocity rather than tilt amplitude. Therefore, we designed a study to specifically test the hypothesized velocity dependence of reweighting while expanding on earlier findings for visual reweighting by testing proprioceptive reweighting for standing balance on a tilting surface. Twenty healthy young adults stood with their eyes closed on a toes-up/-down tilting platform. We designed four pseudorandom tilt sequences with either a slow (S) or a fast (F) tilt velocity and different peak-to-peak amplitudes. We used model-based interpretations of measured sway characteristics to estimate the proprioceptive sensory weight (Wprop) within each trial. In addition, root-mean-square values of measured body center of mass sway amplitude (RMS) and velocity (RMSv) were calculated for each tilt sequence. Wprop, RMS, and RMSv values varied depending on the stimulus velocity, exhibiting large effects (all Cohen's d >1.10). In contrast, we observed no significant differences across stimulus amplitudes for Wprop (Cohen's d: 0.02-0.16) and, compared with the differences in velocity, there were much smaller changes in RMS and RMSv values (Cohen's d: 0.05-0.91). These results confirmed the hypothesized velocity, rather than amplitude, dependence of sensory reweighting.NEW & NOTEWORTHY This novel study examined the velocity dependence of sensory reweighting for human balance control using support surface tilt stimuli with independently varied amplitude and velocity. Estimates of the proprioceptive contribution to standing balance, derived from model-based interpretations of sway characteristics, showed greater sensitivity to changes in surface tilt velocity than surface tilt amplitude. These results support a velocity-based mechanism underlying sensory reweighting for human balance control.

Design and simulation of artificial retinal stimulation IC with switched capacitor using Si nanowire optical properties.

This study introduces an approach for converting the current from a sensor into controllable voltage. To this end, a switched-capacitor structure was integrated to provide efficient current-to-voltage conversion. The generated voltage was further regulated by an operational amplifier current source, enhancing stability and precision. An n-type metal oxide semiconductor field-effect transistor structure under an H-bridge was integrated into the system to achieve fine-tuned control over current stimulation. This component contributed to voltage regulation and enabled bi-directional control of current flow, offering versatility in adjusting current amplitudes using working and counter electrodes. This dynamic control mechanism was pivotal for effectively controlling the intensity of current stimulation. We applied Verilog-A modeling to simulate the optical characteristics of Si nanowires. The proposed system efficiently converted sensor-derived current into voltage using a switched-capacitor structure. Simultaneously, the precision was enhanced via operational amplifier regulation and n-type metal-oxide-semiconductor field-effect transistor-based H-bridge control. The simulation showed a current stimulus amplitude ranging from 2 to 13 μA for a variable photocurrent of Si nanowires (Rex: 10 kΩ, pulse: 100 Hz, 1 ms). The ability to finely control current stimulation intensity holds promise for diverse applications requiring accurate and adjustable current manipulation. This study contributes to the growing field of sensor technology by offering a unique perspective on the integration of nanostructures and electronic components for an enhanced control and functionality.

Frequency-tagging of spatial attention using periliminal flickers

Abstract Steady-State Visually Evoked Potentials (SSVEP) manifest as a sustained rhythmic activity that can be observed in surface electroencephalography (EEG) in response to periodic visual stimuli, commonly referred to as flickers. SSVEPs are widely used in fundamental cognitive neuroscience paradigms and Brain-Computer Interfaces (BCI) due to their robust and rapid onset. However, they have drawbacks related to the intrusive saliency of flickering visual stimuli, which may induce eye strain, cognitive fatigue, and biases in visual exploration. Previous findings highlighted the potential of altering features of flicker stimuli to improve user experience. In this study, we propose to reduce the amplitude modulation depth of flickering stimuli down to the individuals’ perceptual visibility threshold (periliminal) and below (subliminal). The stimulus amplitude modulation depth represents the contrast difference between the two alternating states of a flicker. A simple visual attention task where participants responded to the presentation of spatially-cued target stimuli (left and right) was used to assess the validity of such periliminal and subliminal frequency-tagging probes to capture spatial attention. The left and right sides of the screen, where target stimuli were presented, were covered by large flickers (13 and 15 Hz respectively). The amplitude modulation depth of these flickers was manipulated across three conditions: control, periliminal, and subliminal. The latter two levels of flickers amplitude modulation depth were defined through a perceptual visibility threshold protocol on a single- subject basis. Subjective feedback indicated that the use of periliminal and subliminal flickers substantially improved user experience. The present study demonstrates that periliminal and subliminal flickers evoked SSVEP responses that can be used to derive spatial attention in frequency-tagging paradigms. The single-trial classification of attended space (left versus right) based on SSVEP response reached an average accuracy of 81.1% for the periliminal and 58% for the subliminal conditions. These findings reveal the promises held by the application of inconspicuous flickers to both cognitive neuroscience research and BCI development.

Membrane depolarization mediates both the inhibition of neural activity and cell-type-differences in response to high-frequency stimulation

Neuromodulation using high frequency (>1 kHz) electric stimulation (HFS) enables preferential activation or inhibition of individual neural types, offering the possibility of more effective treatments across a broad spectrum of neurological diseases. To improve effectiveness, it is important to better understand the mechanisms governing activation and inhibition with HFS so that selectivity can be optimized. In this study, we measure the membrane potential (Vm) and spiking responses of ON and OFF α-sustained retinal ganglion cells (RGCs) to a wide range of stimulus frequencies (100–2500 Hz) and amplitudes (10–100 µA). Our findings indicate that HFS induces shifts in Vm, with both the strength and polarity of the shifts dependent on the stimulus conditions. Spiking responses in each cell directly correlate with the shifts in Vm, where strong depolarization leads to spiking suppression. Comparisons between the two cell types reveal that ON cells are more depolarized by a given amplitude of HFS than OFF cells—this sensitivity difference enables the selective targeting. Computational modeling indicates that ion-channel dynamics largely account for the shifts in Vm, suggesting that a better understanding of the differences in ion-channel properties across cell types may improve the selectivity and ultimately, enhance HFS-based neurostimulation strategies.

Native language advantage in electrical brain responses to speech sound changes in passive and active listening condition

It is not clear whether the brain can detect changes in native and non-native speech sounds in both unattended and attended conditions, but this information would be important to understand the nature of potential native language advantage in speech perception. We recorded event-related potentials (ERPs) for changes in duration and in Chinese lexical tone in a repeated vowel /a/ in native speakers of Finnish and Chinese in passive and active listening conditions. ERP amplitudes reflecting deviance detection (mismatch negativity; MMN and N2b) and attentional shifts towards changes in speech sounds (P3a and P3b) were investigated. In the passive listening condition, duration changes elicited increased amplitude in the MMN latency window for both standard and deviant sounds in the Finnish speakers compared to the Chinese speakers, but no group differences were observed for P3a. In passive listening to lexical tones, P3a was increased in amplitude for both standard and deviant stimuli in Chinese speakers compared to Finnish speakers, but the groups did not differ in MMN. In active listening, both tone and duration changes elicited N2b and P3b, but the groups differed only in pattern of results for the deviant type. The results thus suggest an overall increased sensitivity to native speech sounds, especially in passive listening, while the mechanisms of change detection and attentional shifting seem to work well for both native and non-native speech sounds in the attentive mode.

Coordinated reset stimulation of plastic neural networks with spatially dependent synaptic connections.

Abnormal neuronal synchrony is associated with several neurological disorders, including Parkinson's disease (PD), essential tremor, dystonia, and epilepsy. Coordinated reset (CR) stimulation was developed computationally to counteract abnormal neuronal synchrony. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites. Computational studies in plastic neural networks reported that CR stimulation drove the networks into an attractor of a stable desynchronized state by down-regulating synaptic connections, which led to long-lasting desynchronization effects that outlasted stimulation. Later, corresponding long-lasting desynchronization and therapeutic effects were found in animal models of PD and PD patients. To date, it is unclear how spatially dependent synaptic connections, as typically observed in the brain, shape CR-induced synaptic downregulation and long-lasting effects. We performed numerical simulations of networks of leaky integrate-and-fire neurons with spike-timing-dependent plasticity and spatially dependent synaptic connections to study and further improve acute and long-term responses to CR stimulation. The characteristic length scale of synaptic connections relative to the distance between stimulation sites plays a key role in CR parameter adjustment. In networks with short synaptic length scales, a substantial synaptic downregulation can be achieved by selecting appropriate stimulus-related parameters, such as the stimulus amplitude and shape, regardless of the employed spatiotemporal pattern of stimulus deliveries. Complex stimulus shapes can induce local connectivity patterns in the vicinity of the stimulation sites. In contrast, in networks with longer synaptic length scales, the spatiotemporal sequence of stimulus deliveries is of major importance for synaptic downregulation. In particular, rapid shuffling of the stimulus sequence is advantageous for synaptic downregulation. Our results suggest that CR stimulation parameters can be adjusted to synaptic connectivity to further improve the long-lasting effects. Furthermore, shuffling of CR sequences is advantageous for long-lasting desynchronization effects. Our work provides important hypotheses on CR parameter selection for future preclinical and clinical studies.

High precision 3 × 3 coupler demodulation algorithm with an additional phase shift judgment module

Ellipse fitting algorithms (EFAs) have been widely used in 3×3 coupler demodulation systems to reduce the requirement for symmetry of the 3×3 couplers. Based on the relative stability of the splitting ratio and phase difference after the establishment of the 3×3 coupler demodulation system, we solve the problem that EFA fails to work when the stimulating signal is small. Depending on the existence of a symmetry point about the origin, an additional phase shift judgment module is used to determine whether the Lissajous figure is larger than π rad. If the elliptical arc exceeds π rad, the EFA is executed. Otherwise, the previous parameters are used to correct the ellipse. Parameters are updated in real time to ensure high precision. The experimental results show that the total harmonic distortion (THD) of the ameliorated algorithm is improved by 1.28% compared to the EFA without the judgment module with a stimulus amplitude of 30 mV. The proposed scheme can effectively improve the dynamic range of the 3×3 coupler demodulation to reach 125.64 dB @ 1 kHz and 1% THD. The algorithm ensures the effective operation of the EFA under small phase shift conditions and improves the accuracy of phase demodulation.

Axonal stimulation affects the linear summation of single-point perception in three Argus II users.

Objective.Retinal implants use electrical stimulation to elicit perceived flashes of light ('phosphenes'). Single-electrode phosphene shape has been shown to vary systematically with stimulus parameters and the retinal location of the stimulating electrode, due to incidental activation of passing nerve fiber bundles. However, this knowledge has yet to be extended to paired-electrode stimulation.Approach.We retrospectively analyzed 3548 phosphene drawings made by three blind participants implanted with an Argus II Retinal Prosthesis. Phosphene shape (characterized by area, perimeter, major and minor axis length) and number of perceived phosphenes were averaged across trials and correlated with the corresponding single-electrode parameters. In addition, the number of phosphenes was correlated with stimulus amplitude and neuroanatomical parameters: electrode-retina and electrode-fovea distance as well as the electrode-electrode distance to ('between-axon') and along axon bundles ('along-axon'). Statistical analyses were conducted using linear regression and partial correlation analysis.Main results.Simple regression revealed that each paired-electrode shape descriptor could be predicted by the sum of the two corresponding single-electrode shape descriptors (p < .001). Multiple regression revealed that paired-electrode phosphene shape was primarily predicted by stimulus amplitude and electrode-fovea distance (p < .05). Interestingly, the number of elicited phosphenes tended to increase with between-axon distance (p < .05), but not with along-axon distance, in two out of three participants.Significance.The shape of phosphenes elicited by paired-electrode stimulation was well predicted by the shape of their corresponding single-electrode phosphenes, suggesting that two-point perception can be expressed as the linear summation of single-point perception. The impact of the between-axon distance on the perceived number of phosphenes provides further evidence in support of the axon map model for epiretinal stimulation. These findings contribute to the growing literature on phosphene perception and have important implications for the design of future retinal prostheses.

Accurate detection of lead malfunction from ECG-derived bipolar pacing stimulus amplitude

BackgroundOne common mode of lead failure is insulation breach, which may result in myopotential noise and device malfunction. “Pseudo-unipolarization” of bipolar pacing stimuli, as observed from a routine 12-lead electrocardiogram (ECG) due to stimulus current leak, has been observed with insulation breaches. ObjectiveWe sought to characterize this electrocardiographic finding to detect this type of lead malfunction. MethodsA total of 138 transvenous leads were analyzed, including 88 with known malfunction and 50 normal leads. The amplitude of a bipolar pacing stimulus on the ECG was recorded and compared with a control data set of newly implanted leads with bipolar stimuli normalized for output. ResultsThe malfunction group consisted of 61% right atrium and 39% right ventricle leads with mean pacing output of 2.74 V at 0.5 ms. There was a significant difference in ECG bipolar stimulus amplitudes at time of identification of failure (7.89 ± 7.56 mm/V; P < .001) compared with those of normal leads (0.86 ± 0.41 mm/V). Receiver operating characteristic curve for the prediction of lead malfunction based on absolute ECG amplitude displayed an area under the curve of 0.93 (95% CI, 0.891–0.969). When normalized for programmed stimulus output, a cutoff of 5 mm/V demonstrated a sensitivity of 91% and a specificity of 92% (area under the curve, 0.967; 95% CI, 0.938–0.996). ConclusionThe maximum amplitude of a bipolar pacing stimulus on the ECG is significantly lower in normal functioning leads compared with those with known malfunction. This simply derived variable demonstrated good accuracy at identifying lead failure due to insulation breach.

Click SP/AP Area Ratio Vesrus Tone Burst SP Amplitude to Diagnose Ménière's Disease Using Electrocochleography.

To evaluate the sensitivity and the specificity of summating potential (SP)/action potential (AP) area under the curve (AUC) ratio by a transtympanic electrode and a click stimulus (TT-CS), SP/AP AUC ratio by an extratympanic electrode and a click stimulus (ET-CS) and SP amplitude value by a transtympanic electrode and tone burst stimulus (TT-TBS) in regard of Ménière's disease (MD) diagnosis. This is the first study that compares SP amplitude value performed by a TT-TBS and the SP/AP AUC ratio performed by a TT-CS. Retrospective comparative study. Ninety-five patients met the inclusion criteria for electrocochleography (ECochG) testing in a tertiary care center. The sensitivity and specificity of our different ECochG protocols were calculated in regardof the diagnosis of MD. The patients' mean age was 54 years old (female predominance). The sensitivity and the specificity of SP/AP area ratio by a TT-CS were 88.5% and 70.0%, respectively. On the other hand, the sensitivity and specificity for the SP amplitude value by a TT-TBS were 60.0% and 55.6%, respectively. SP/AP area ratio by TT-CS was statistically better than SP amplitude value by TT-TBS to detect MD disease (P = .016). However, no difference was identified between SP/AP area ratio by ET-CS and SP amplitude value by a TT-TBS (P = .573). SP/AP area ratio by click stimulation has higher sensitivity and specificity to detect MD compared to SP amplitude value by tone burst stimulation. ECochG would be extremely useful in the diagnosis of MD if we use the SP/AP area ratio (sensitivity: 88.5%); therefore, it changes the bad reputation of ECochG sensitivity using SP/AP amplitude ratio (sensitivity: 51.7%) for the diagnosis of MD.

A numerical study of a single isolated human ventricular cell response to a periodic pulse stimulus current using the Rogers–McCulloch model

Among the primary causes of cardiac arrhythmias are abnormalities in the generation of action potentials (APs) by the cardiac cells, which may be induced by alterations in the electrophysiological properties of the cells as well as the stimuli delivered to them. Through numerical simulations using the phenomenological model of Rogers–McCulloch, this study examined how external stimuli modulate the electrical activity of a single isolated human ventricular cell functioning under normal conditions. First, we investigated how the initial conditions of the two model state variables affect how the cell responds to a single rectangular current pulse. This allows for the determination of a critical curve, which separates the initial conditions that allow for AP activation from those that inhibit it. This critical curve can be used to predict AP activation not only when the cell is stimulated by a single current pulse but also by a periodic stimulus. Then, we examined the cell response to a periodic train of rectangular current pulses, with a focus on the effects of the stimulus pacing length and amplitude. Our findings demonstrated that, despite not considering any alteration in the dynamics of ionic currents through the cell membrane, the Rogers–McCulloch model was capable of reproducing some of the most common activation patterns that have been widely identified in several clinical, experimental, and numerical studies. Depending on the stimulus properties, the following activation patterns were identified: (1) AP activation in synchrony with the stimulus, with one AP activation per pulse; (2) quasi-periodic and periodic Wenckebach-like patterns, in which successive AP activations are interrupted by a skipped beat; (3) completely irregular patterns; (4) abnormal potential oscillations that interrupt the repolarization of a previously activated AP, followed or not by a skipped beat; and (5) abnormal potential oscillations that completely inhibit cell repolarization.

Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or ventral intermediate nucleus (VIM) are established targets for the treatment of Parkinson's disease (PD) or essential tremor (ET), respectively. However, DBS of the zona incerta (ZI) can be effective for both disorders. VIM DBS is assumed to achieve its therapeutic effect via activation of the cerebellothalamic (CBT) pathway, whereas the activation of the hyperdirect (HD) pathway likely plays a role in the mechanisms of STN DBS. Interestingly, HD pathway axons also emit collaterals to the ZI and red nucleus (RN) and the CBT pathway courses nearby to the ZI. The aim was to examine the ability of ZI DBS to mutually activate the HD and CBT pathways in a detailed computational model of human DBS. We extended a previous model of the human HD pathway to incorporate axon collaterals to the ZI and RN. The anatomical framework of the model system also included representations of the CBT pathway and internal capsule (IC) fibers of passage. We then performed detailed biophysical simulations to quantify DBS activation of the HD, CBT, and IC pathways with electrodes located in either the STN or ZI. STN DBS and ZI DBS both robustly activated the HD pathway. However, STN DBS was limited by IC activation at higher stimulus amplitudes. Alternatively, ZI DBS avoided IC activation while simultaneously activating the HD and CBT pathways. From both neuroanatomical and biophysical perspectives, ZI DBS represents an advantageous target for coupled activation of the HD and CBT pathways. © 2024 International Parkinson and Movement Disorder Society.

Abstract TMP35: Short Interval Intracortical Inhibition is Associated With Leg Motor Function in Chronic Stroke

Objective: Stroke disrupts inhibitory and excitatory networks in the brain. To develop better therapies, we need to understand the role of inhibitory and excitatory systems. Paired-pulse transcranial magnetic stimulation (ppTMS) allows for evaluation of these inhibitory and excitatory systems. Our objective was to explore the relationship between Short Interval Intracortical Inhibition (SICI) and Intracortical Facilitation (ICF) ppTMS measures for tibialis anterior (TA) and measures of lower limb motor function in chronic stroke. Methods: Lower limb motor function was evaluated with Fugl-Meyer for Lower Limb (FM), gait speed (max and preferred), Timed-up-and-go (TUG), Functional Gait Assessment (FGA) and Gait Assessment and Intervention Tool (GAIT). SICI was collected with interstimulus interval of 2ms and ICF with 10ms. The conditioning stimulus was 90% and test stimulus was 120% of active motor threshold. Motor evoked potentials (MEPs) were collected for both paretic or non-paretic TAs while volitionally activated to 20% of maximum effort. SICI and ICF were calculated as percent of test stimulus (TS) amplitude. Analysis included descriptive statistics and linear models controlling for age, months post-stroke, and gender. TUG test time was log-transformed. Results: Study participants (n=34) were 66±8 years old, 4.9±4 years after stroke and 76% male. Mean±SD FM was 25.1±3.7 and preferred gait speed was 0.52±0.30 m/s. Relative to TS amplitude, SICI was 107±27% and ICF was 175±71% for paretic leg and, for non-paretic leg, SICI was 108±42% and ICF was 159±66%. For paretic leg after controlling for ICF, a 10% lower SICI was associated with the following: 0.89 point better FM (95% CI: 0.37-1.42), 14% better TUG (95% CI: 3-23%), 0.08 m/s faster max speed (95% CI: 0.02-0.14), and 0.05 m/s faster preferred walking speed (95% CI: 0.01-0.10). For non-paretic limb, a 10% lower SICI was associated with a 0.43 point better FGA (95% CI: 0.11-0.76) while a 10% lower ICF was associated with a 0.73 point better GAIT (95% CI: 0.37-1.10). Conclusion: Greater inhibition with paired pulse of both paretic and non-paretic limbs was predictive better motor abilities. These findings are related to previous work and warrant future investigations.

Postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents: A simulation study.

Postinhibitory excitation is a transient overshoot of a neuron's baseline firing rate following an inhibitory stimulus and can be observed in vivo in human motoneurons. However, the biophysical origin of this phenomenon is still unknown and both reflex pathways and intrinsic motoneuron properties have been proposed. We hypothesized that postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents (h-currents). Using an electrical circuit model, we investigated how h-currents can modulate the postinhibitory response of motoneurons. Further, we analyzed the spike trains of human motor units from the tibialis anterior muscle during reciprocal inhibition. The simulations revealed that the activation of h-currents by an inhibitory postsynaptic potential can cause a short-term increase in a motoneuron's firing probability. This result suggests that the neuron can be excited by an inhibitory stimulus. In detail, the modulation of the firing probability depends on the time delay between the inhibitory stimulus and the previous action potential. Further, the postinhibitory excitation's strength correlates with the inhibitory stimulus's amplitude and is negatively correlated with the baseline firing rate as well as the level of input noise. Hallmarks of h-current activity, as identified from the modeling study, were found in 50% of the human motor units that showed postinhibitory excitation. This study suggests that h-currents can facilitate postinhibitory excitation and act as a modulatory system to increase motoneuron excitability after a strong inhibition.