Pathways and parameters of sacral neuromodulation in rats.

The stimulation paradigm for sacral neuromodulation has remained largely unchanged since its inception. We sought to determine, in rats, whether stimulation-induced increases in bladder capacity correlated with the proportion of sensory pudendal (PudS) neurons at each stimulated location (L6, S1). If supported, this finding could guide the choice of stimulation side (left/right) and level (S2, S3, S4) in humans. Unexpectedly, we observed that acute stimulation at clinically relevant (low) amplitudes [1-1.5 × motor threshold (Tm)], did not increase bladder capacity, regardless of stimulus location (L6 or S1). More importantly for the ability to test our hypothesis, there was little anatomic variation, and S1 infrequently contributed nerve fibers to the PudS nerve. During mapping studies we noticed that large increases in PudS nerve activation occurred at amplitudes exceeding 2Tm. Thus, additional cystometric studies were conducted, this time with stimulation of the L6-S1 trunk, to examine further the relationship between stimulation amplitude and cystometric parameters. Stimulation at 1Tm to 6Tm evoked increases in bladder capacity and decreases in voiding efficiency that mirrored those produced by PudS nerve stimulation. Many animal studies involving electrical stimulation of nerves of the lower urinary tract use stimulation amplitudes that exceed those used clinically (∼1Tm). Our results confirm that high amplitudes generate immediate changes in cystometric parameters; however, the relationship to low-amplitude chronic stimulation in humans remains unclear. Additional studies are needed to understand changes that occur with chronic stimulation, how these changes relate to therapeutic outcomes, and the contribution of specific nerve fibers to these changes.NEW & NOTEWORTHY Acute low-amplitude electrical stimulation of sacral nerve (sacral neuromodulation) did not increase bladder capacity in anesthetized CD, obese-prone, or obese-resistant rats. Increasing stimulation amplitude correlated with increases in bladder capacity and pudendal sensory nerve recruitment. It is unclear how the high-amplitude acute stimulation that is commonly used in animal experiments to generate immediate effects compares mechanistically to the chronic low-amplitude stimulation used clinically.

Asynchronous axonal firing patterns evoked via continuous subthreshold kilohertz stimulation.

Objective.Transcutaneous electrical stimulation of peripheral nerves is a common technique to assist or rehabilitate impaired muscle activation. However, conventional stimulation paradigms activate nerve fibers synchronously with action potentials time-locked with stimulation pulses. Such synchronous activation limits fine control of muscle force due to synchronized force twitches. Accordingly, we developed a subthreshold high-frequency stimulation waveform with the goal of activating axons asynchronously.Approach.We evaluated our waveform experimentally and through model simulations. During the experiment, we delivered continuous subthreshold pulses at frequencies of 16.67, 12.5, or 10 kHz transcutaneously to the median and ulnar nerves. We obtained high-density electromyographic (EMG) signals and fingertip forces to quantify the axonal activation patterns. We used a conventional 30 Hz stimulation waveform and the associated voluntary muscle activation for comparison. We modeled stimulation of biophysically realistic myelinated mammalian axons using a simplified volume conductor model to solve for extracellular electric potentials. We compared the firing properties under kHz and conventional 30 Hz stimulation.Main results.EMG activity evoked by kHz stimulation showed high entropy values similar to voluntary EMG activity, indicating asynchronous axon firing activity. In contrast, we observed low entropy values in EMG evoked by conventional 30 Hz stimulation. The muscle forces evoked by kHz stimulation also showed more stable force profiles across repeated trials compared with 30 Hz stimulation. Our simulation results provide direct evidence of asynchronous firing patterns across a population of axons in response to kHz frequency stimulation, while 30 Hz stimulation elicited synchronized time-locked responses across the population.Significance.We demonstrate that the continuous subthreshold high-frequency stimulation waveform can elicit asynchronous axon firing patterns, which can lead to finer control of muscle forces.

Control of colonic motility using electrical stimulation to modulate enteric neural activity.

Electrical stimulation of the enteric nervous system (ENS) is an attractive approach to modify gastrointestinal transit. Colonic motor complexes (CMCs) occur with a periodic rhythm, but the ability to elicit a premature CMC depends, at least in part, upon the intrinsic refractory properties of the ENS, which are presently unknown. The objectives of this study were to record myoelectric complexes (MCs, the electrical correlates of CMCs) in the smooth muscle and 1) determine the refractory periods of MCs, 2) inform and evaluate closed-loop stimulation to repetitively evoke MCs, and 3) identify stimulation methods to suppress MC propagation. We dissected the colon from male and female C57BL/6 mice, preserving the integrity of intrinsic circuitry while removing the extrinsic nerves, and measured properties of spontaneous and evoked MCs in vitro. Hexamethonium abolished spontaneous and evoked MCs, confirming the necessary involvement of the ENS for electrically evoked MCs. Electrical stimulation reduced the mean interval between evoked and spontaneous CMCs (24.6 ± 3.5 vs. 70.6 ± 15.7 s, P = 0.0002, n = 7). The absolute refractory period was 4.3 s (95% confidence interval (CI) = 2.8-5.7 s, R2 = 0.7315, n = 8). Electrical stimulation applied during fluid distention-evoked MCs led to an arrest of MC propagation, and following stimulation, MC propagation resumed at an increased velocity (n = 9). The timing parameters of electrical stimulation increased the rate of evoked MCs and the duration of entrainment of MCs, and the refractory period provides insight into timing considerations for designing neuromodulation strategies to treat colonic dysmotility.NEW & NOTEWORTHY Maintained physiological distension of the isolated mouse colon induces rhythmic cyclic myoelectric complexes (MCs). MCs evoked repeatedly by closed-loop electrical stimulation entrain MCs more frequently than spontaneously occurring MCs. Electrical stimulation delivered at the onset of a contraction temporarily suppresses the propagation of MC contractions. Controlled electrical stimulation can either evoke MCs or temporarily delay MCs in the isolated mouse colon, depending on timing relative to ongoing activity.

Stimulation of the pelvic nerve increases bladder capacity in the PGE2 cat model of overactive bladder.

Selective electrical stimulation of the pudendal nerve exhibits promise as a potential therapy for treating overactive bladder (OAB) across species (rats, cats, and humans). More recently, pelvic nerve (PelN) stimulation was demonstrated to improve cystometric bladder capacity in a PGE2 rat model of OAB. However, PelN stimulation in humans or in an animal model that is more closely related to humans has not been explored. Therefore, our objective was to quantify the effects of PGE2 and PelN stimulation in the cat. Acute cystometry experiments were conducted in 14 α-chloralose-anesthetized adult, neurologically intact female cats. Intravesical PGE2 decreased bladder capacity, residual volume, threshold contraction pressure, and mean contraction pressure. PelN stimulation reversed the PGE2-induced decrease in bladder capacity and increased evoked external urethral sphincter electromyographic activity without influencing voiding efficiency. The increases in bladder capacity generated by PelN stimulation were similar in the rat and cat, but the stimulation parameters to achieve this effect differed (threshold amplitude at 10 Hz in the rat vs. twice threshold amplitude at 1 Hz in the cat). These results highlight the potential of PGE2 as a model of OAB and provide further evidence that PelN stimulation is a promising approach for the treatment of OAB symptoms.

Effects of ramped-frequency thalamic deep brain stimulation on tremor and activity of modeled neurons.

OBJECTIVE: We conducted intraoperative measurements of tremor to quantify the effects of temporally patterned ramped-frequency DBS trains on tremor. METHODS: Seven patterns of stimulation were tested in nine subjects with thalamic DBS for essential tremor: stimulation 'off', three ramped-frequency stimulation (RFS) trains from 130 â†’ 50 Hz, 130 â†’ 60 Hz, and 235 â†’ 90 Hz, and three constant frequency stimulation (CFS) trains at 72, 82, and 130 Hz. The same patterns were applied to a computational model of the thalamic neural network. RESULTS: Temporally patterned 130 â†’ 60 Hz ramped-frequency trains suppressed tremor relative to stimulation 'off,' but 130 â†’ 50 Hz, 130 â†’ 60 Hz, and 235 â†’ 90 Hz ramped-frequency trains were no more effective than constant frequency stimulation with the same mean interpulse interval (IPI). Computational modeling revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but long IPIs, concurrent with pauses in afferent cerebellar and cortical firing, allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions. CONCLUSION: Frequency-ramped DBS produced equivalent tremor suppression as constant frequency thalamic DBS. Tremor-related thalamic burst activity may result from burst-driver input, rather than by an intrinsic rebound mechanism. SIGNIFICANCE: Ramping stimulation frequency may exacerbate thalamic burst firing by introducing consecutive pauses of increasing duration to the stimulation pattern.

Average firing rate rather than temporal pattern determines metabolic cost of activity in thalamocortical relay neurons.

Thalamocortical (TC) relay cells exhibit different temporal patterns of activity, including tonic mode and burst mode, to transmit sensory information to the cortex. Our aim was to quantify the metabolic cost of different temporal patterns of neural activity across a range of average firing rates. We used a biophysically-realistic model of a TC relay neuron to simulate tonic and burst patterns of firing. We calculated the metabolic cost by converting the calculated ion fluxes into the demand for ATP to maintain homeostasis of intracellular ion concentrations. Most energy was expended on reversing Na+ entry during action potentials and pumping Ca2+ out of the cell. Average firing rate determined the ATP cost across firing patterns by controlling the overall number of spikes. Varying intraburst frequency or spike number in each burst influenced the metabolic cost by altering the interactions of inward and outward currents on multiple timescales, but temporal pattern contributed substantially less to the metabolic demand of neural activity as compared to average firing rate. These predictions should be considered when interpreting findings of functional imaging studies that rely of estimates of neuronal metabolic demand, e.g., functional magnetic resonance imaging.

Frequency-dependent antidromic activation in thalamocortical relay neurons: effects of synaptic inputs.

OBJECTIVE: Deep brain stimulation (DBS) generates action potentials (APs) in presynaptic axons and fibers of passage. The APs may be antidromically propagated to invade the cell body and/or orthodromically transmitted to downstream structures, thereby affecting widespread targets distant from the electrode. Activation of presynaptic terminals also causes trans-synaptic effects, which in turn alter the excitability of the post-synaptic neurons. Our aim was to determine how synaptic inputs affect the antidromic invasion of the cell body. APPROACH: We used a biophysically-based multi-compartment model to simulate antidromic APs in thalamocortical relay (TC) neurons. We applied distributed synaptic inputs to the model and quantified how excitatory and inhibitory inputs contributed to the fidelity of antidromic activation over a range of antidromic frequencies. MAIN RESULTS: Antidromic activation exhibited strong frequency dependence, which arose from the hyperpolarizing afterpotentials in the cell body and its respective recovery cycle. Low-frequency axonal spikes faithfully invaded the soma, whereas frequent failures of antidromic activation occurred at high frequencies. The frequency-dependent pattern of the antidromic activation masked burst-driver inputs to TC neurons from the cerebellum in a frequency-dependent manner. Antidromic activation also depended on the excitability of the cell body. Excitatory synaptic inputs improved the fidelity of antidromic activation by increasing the excitability, and inhibitory inputs suppressed antidromic activation by reducing soma excitability. Stimulus-induced depolarization of neuronal segments also facilitated antidromic propagation and activation. SIGNIFICANCE: The results reveal that synaptic inputs, stimulus frequency, and electrode position regulate antidromic activation of the cell body during extracellular stimulation. These findings provide a biophysical basis for interpreting the widespread inhibition/activation of target nuclei during DBS.

Model-based deconstruction of cortical evoked potentials generated by subthalamic nucleus deep brain stimulation.

Parkinson's disease is associated with altered neural activity in the motor cortex. Chronic high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS-mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal of this study was to determine the neural origin of STN DBS-generated cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA-lesioned parkinsonian rats. Second, we used a detailed, biophysically based model of the thalamocortical network to deconstruct the neural origin of the recorded cEP. The in vivo cEP included short (R1)-, intermediate (R2)-, and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. The short-latency response was generated by antidromic activation of layer 5 pyramidal neurons, whereas recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced the intermediate-latency response. The long-latency response was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico-thalamo-cortical synaptic interactions were sufficient to generate cortical potential evoked by STN DBS, and orthodromic activation through basal ganglia-thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms. NEW & NOTEWORTHY Subthalamic nucleus (STN) deep brain stimulation (DBS) is increasingly used to treat Parkinson's disease (PD). Cortical potentials evoked by STN DBS in patients with PD exhibit consistent short-latency (1-3 ms), intermediate-latency (5-15 ms), and long-latency (18-25 ms) responses. The short-latency response occurs as a result of antidromic activation of the hyperdirect pathway comprising corticosubthalamic axons. However, the neural origins of intermediate- and long-latency responses remain elusive, and the dominant view is that these are produced through the orthodromic pathway (basal ganglia-thalamus-cortex). By combining in vivo electrophysiology with computational modeling, we demonstrate that antidromic activation of the cortico-thalamic-cortical pathway is sufficient to generate the intermediate- and long-latency cortical responses to STN DBS.

Sensory percepts induced by microwire array and DBS microstimulation in human sensory thalamus.

BACKGROUND: Microstimulation in human sensory thalamus (ventrocaudal, VC) results in focal sensory percepts in the hand and arm which may provide an alternative target site (to somatosensory cortex) for the input of prosthetic sensory information. Sensory feedback to facilitate motor function may require simultaneous or timed responses across separate digits to recreate perceptions of slip as well as encoding of intensity variations in pressure or touch. OBJECTIVES: To determine the feasibility of evoking sensory percepts on separate digits with variable intensity through either a microwire array or deep brain stimulation (DBS) electrode, recreating "natural" and scalable percepts relating to the arm and hand. METHODS: We compared microstimulation within ventrocaudal sensory thalamus through either a 16-channel microwire array (∼400 kΩ per channel) or a 4-channel DBS electrode (∼1.2 kΩ per contact) for percept location, size, intensity, and quality sensation, during thalamic DBS electrode placement in patients with essential tremor. RESULTS: Percepts in small hand or finger regions were evoked by microstimulation through individual microwires and in 5/6 patients sensation on different digits could be perceived from stimulation through separate microwires. Microstimulation through DBS electrode contacts evoked sensations over larger areas in 5/5 patients, and the apparent intensity of the perceived response could be modulated with stimulation amplitude. The perceived naturalness of the sensation depended both on the pattern of stimulation as well as intensity of the stimulation. CONCLUSIONS: Producing consistent evoked perceptions across separate digits within sensory thalamus is a feasible concept and a compact alternative to somatosensory cortex microstimulation for prosthetic sensory feedback. This approach will require a multi-element low impedance electrode with a sufficient stimulation range to evoke variable intensities of perception and a predictable spread of contacts to engage separate digits.

Stimulation of the sensory pudendal nerve increases bladder capacity in the rat.

Pudendal nerve stimulation is a promising treatment approach for lower urinary tract dysfunction, including symptoms of overactive bladder. Despite some promising clinical studies, there remain many unknowns as to how best to stimulate the pudendal nerve to maximize therapeutic efficacy. We quantified changes in bladder capacity and voiding efficiency during single-fill cystometry in response to electrical stimulation of the sensory branch of the pudendal nerve in urethane-anesthetized female Wistar rats. Increases in bladder capacity were dependent on both stimulation amplitude and rate. Stimulation that produced increases in bladder capacity also led to reductions in voiding efficiency. Also, there was a stimulation carryover effect, and increases in bladder capacity persisted during several nonstimulated trials following stimulated trials. Intravesically administered PGE2 reduced bladder capacity, producing a model of overactive bladder (OAB), and sensory pudendal nerve stimulation again increased bladder capacity but also reduced voiding efficiency. This study serves as a basis for future studies that seek to maximize the therapeutic efficacy of sensory pudendal nerve stimulation for the symptoms of OAB.

Multiple Reflex Pathways Contribute to Bladder Activation by Intraurethral Stimulation in Persons With Spinal Cord Injury.

OBJECTIVE: To measure the urodynamic effects of electrical co-stimulation of 2 individual sites in the proximal and distal urethra in persons with spinal cord injury (SCI). This work was motivated by preclinical findings that selective co-stimulation of the cranial urethral sensory nerve and the dorsal genital nerve, which innervate the proximal and distal portions of the urethra, respectively, increased reflex bladder activation and voiding efficiency. MATERIALS AND METHODS: Electrical co-stimulation of urethral afferents was conducted in persons with chronic SCI during urodynamics. The effects of different frequencies of intraurethral stimulation at multiple urethral locations on bladder pressure and pelvic floor electromyographic activity were measured. RESULTS: Electromyographic activity indicated that multiple reflex pathways were recruited through stimulation that contributed to bladder activation. The size of reflex bladder contractions evoked by stimulation was dependent on stimulation location or reflex activated and stimulation frequency. CONCLUSION: Pudendal nerve afferents are a promising target to restore lost bladder control, as stimulation with different frequencies may be used to treat urinary incontinence and increase continent volumes or to generate stimulation-evoked bladder contractions for on-demand voiding. This work identified that co-stimulation of multiple afferent reflex pathways can enhance activation of spinal circuits and may enable improved bladder emptying in SCI when stimulation of a single pathway is not sufficient.

Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E2 rat model of overactive bladder.

Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E2 (PGE2) rat model of OAB. Cystometry experiments were conducted in 17 urethane-anesthetized female Sprague-Dawley rats. The effects of intravesical PGE2 vs. vehicle and PelN stimulation after intravesical PGE2 on cystometric parameters were quantified. Intravesical infusion of PGE2 resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE2 PelN stimulation reversed the PGE2-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB.

The effects of neuromodulation in a novel obese-prone rat model of detrusor underactivity.

Obesity is a global epidemic associated with an increased risk for lower urinary tract dysfunction. Inefficient voiding and urinary retention may arise in late-stage obesity when the expulsive force of the detrusor smooth muscle cannot overcome outlet resistance. Detrusor underactivity (DUA) and impaired contractility may contribute to the pathogenesis of nonobstructive urinary retention. We used cystometry and electrical stimulation of peripheral nerves (pudendal and pelvic nerves) to characterize and improve bladder function in urethane-anesthetized obese-prone (OP) and obese-resistant (OR) rats following diet-induced obesity (DIO). OP rats exhibited urinary retention and impaired detrusor contractility following DIO, reflected as increased volume threshold, decreased peak micturition pressure, and decreased voiding efficiency (VE) compared with OR rats. Electrical stimulation of the sensory branch of the pudendal nerve did not increase VE, whereas patterned bursting stimulation of the motor branch of the pudendal nerve increased VE twofold in OP rats. OP rats required increased amplitude of electrical stimulation of the pelvic nerve to elicit bladder contractions, and maximum evoked bladder contraction amplitudes were decreased relative to OR rats. Collectively, these studies characterize a novel animal model of DUA that can be used to determine pathophysiology and suggest that neuromodulation is a potential management option for DUA.

Nerve excitation using an amplitude-modulated signal with kilohertz-frequency carrier and non-zero offset.

BACKGROUND: Incorporating kilohertz-frequency signals in transcutaneous electrical stimulation has been proposed as a means to overcome the impedance of the skin, thereby reaching deeper nerves. In particular, a transdermal amplitude modulated signal (TAMS), composed of a 210 kHz non-zero offset carrier modulated by rectangular pulses, was introduced recently for the treatment of overactive bladder. However, the contribution of the components of TAMS to nerve fiber activation has not been quantified. METHODS: We conducted in vivo experiments and applied direct stimulation to the sciatic nerve of cats and rats. We measured electromyogram and compound action potential activity evoked by pulses, TAMS and modified versions of TAMS in which we varied the size of the carrier. RESULTS: Nerve fiber activation using TAMS showed no difference with respect to activation with conventional pulse for carrier frequencies of 20 kHz and higher, regardless the relative amplitude of the carrier. For frequencies lower than 20 kHz, the offset needed to generate half of the maximal evoked response decreased significantly with respect to the pulse. Results of simulations in a computational model of nerve fiber stimulation using the same stimulation waveforms closely matched our experimental measurements. CONCLUSION: Taken together, these results suggest that a TAMS with carrier frequencies >20 kHz does not offer any advantage over conventional pulses, even with larger amplitudes of the carrier, and this has implications for design of waveforms for efficient and effective transcutaneous stimulation.

Effects of Electrical Stimulation in the Inferior Colliculus on Frequency Discrimination by Rhesus Monkeys and Implications for the Auditory Midbrain Implant.

UNLABELLED: Understanding the relationship between the auditory selectivity of neurons and their contribution to perception is critical to the design of effective auditory brain prosthetics. These prosthetics seek to mimic natural activity patterns to achieve desired perceptual outcomes. We measured the contribution of inferior colliculus (IC) sites to perception using combined recording and electrical stimulation. Monkeys performed a frequency-based discrimination task, reporting whether a probe sound was higher or lower in frequency than a reference sound. Stimulation pulses were paired with the probe sound on 50% of trials (0.5-80 µA, 100-300 Hz, n = 172 IC locations in 3 rhesus monkeys). Electrical stimulation tended to bias the animals' judgments in a fashion that was coarsely but significantly correlated with the best frequency of the stimulation site compared with the reference frequency used in the task. Although there was considerable variability in the effects of stimulation (including impairments in performance and shifts in performance away from the direction predicted based on the site's response properties), the results indicate that stimulation of the IC can evoke percepts correlated with the frequency-tuning properties of the IC. Consistent with the implications of recent human studies, the main avenue for improvement for the auditory midbrain implant suggested by our findings is to increase the number and spatial extent of electrodes, to increase the size of the region that can be electrically activated, and to provide a greater range of evoked percepts. SIGNIFICANCE STATEMENT: Patients with hearing loss stemming from causes that interrupt the auditory pathway after the cochlea need a brain prosthetic to restore hearing. Recently, prosthetic stimulation in the human inferior colliculus (IC) was evaluated in a clinical trial. Thus far, speech understanding was limited for the subjects and this limitation is thought to be partly due to challenges in harnessing the sound frequency representation in the IC. Here, we tested the effects of IC stimulation in monkeys trained to report the sound frequencies they heard. Our results indicate that the IC can be used to introduce a range of frequency percepts and suggest that placement of a greater number of electrode contacts may improve the effectiveness of such implants.

A biophysical model of the cortex-basal ganglia-thalamus network in the 6-OHDA lesioned rat model of Parkinson's disease.

Electrical stimulation of sub-cortical brain regions (the basal ganglia), known as deep brain stimulation (DBS), is an effective treatment for Parkinson's disease (PD). Chronic high frequency (HF) DBS in the subthalamic nucleus (STN) or globus pallidus interna (GPi) reduces motor symptoms including bradykinesia and tremor in patients with PD, but the therapeutic mechanisms of DBS are not fully understood. We developed a biophysical network model comprising of the closed loop cortical-basal ganglia-thalamus circuit representing the healthy and parkinsonian rat brain. The network properties of the model were validated by comparing responses evoked in basal ganglia (BG) nuclei by cortical (CTX) stimulation to published experimental results. A key emergent property of the model was generation of low-frequency network oscillations. Consistent with their putative pathological role, low-frequency oscillations in model BG neurons were exaggerated in the parkinsonian state compared to the healthy condition. We used the model to quantify the effectiveness of STN DBS at different frequencies in suppressing low-frequency oscillatory activity in GPi. Frequencies less than 40 Hz were ineffective, low-frequency oscillatory power decreased gradually for frequencies between 50 Hz and 130 Hz, and saturated at frequencies higher than 150 Hz. HF STN DBS suppressed pathological oscillations in GPe/GPi both by exciting and inhibiting the firing in GPe/GPi neurons, and the number of GPe/GPi neurons influenced was greater for HF stimulation than low-frequency stimulation. Similar to the frequency dependent suppression of pathological oscillations, STN DBS also normalized the abnormal GPi spiking activity evoked by CTX stimulation in a frequency dependent fashion with HF being the most effective. Therefore, therapeutic HF STN DBS effectively suppresses pathological activity by influencing the activity of a greater proportion of neurons in the output nucleus of the BG.

Short pauses in thalamic deep brain stimulation promote tremor and neuronal bursting.

OBJECTIVE: We conducted intraoperative measurements of tremor during DBS containing short pauses (⩽50 ms) to determine if there is a minimum pause duration that preserves tremor suppression. METHODS: Nine subjects with ET and thalamic DBS participated during IPG replacement surgery. Patterns of DBS included regular 130 Hz stimulation interrupted by 0, 15, 25 or 50 ms pauses. The same patterns were applied to a model of the thalamic network to quantify effects of pauses on activity of model neurons. RESULTS: All patterns of DBS decreased tremor relative to 'off'. Patterns with pauses generated less tremor reduction than regular high frequency DBS. The model revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but pauses in stimulation allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions. CONCLUSIONS: The temporal pattern of stimulation influences the efficacy of thalamic DBS. Pauses in stimulation resulted in decreased tremor suppression indicating that masking of pathological bursting is a mechanism of thalamic DBS for tremor. SIGNIFICANCE: Pauses in stimulation decreased the efficacy of open-loop DBS for suppression of tremor.

Electrical stimulation for the treatment of lower urinary tract dysfunction after spinal cord injury.

Electrical stimulation for bladder control is an alternative to traditional methods of treating neurogenic lower urinary tract dysfunction (NLUTD) resulting from spinal cord injury (SCI). In this review, we systematically discuss the neurophysiology of bladder dysfunction following SCI and the applications of electrical stimulation for bladder control following SCI, spanning from historic clinical approaches to recent pre-clinical studies that offer promising new strategies that may improve the feasibility and success of electrical stimulation therapy in patients with SCI. Electrical stimulation provides a unique opportunity to control bladder function by exploiting neural control mechanisms. Our understanding of the applications and limitations of electrical stimulation for bladder control has improved due to many pre-clinical studies performed in animals and translational clinical studies. Techniques that have emerged as possible opportunities to control bladder function include pudendal nerve stimulation and novel methods of stimulation, such as high frequency nerve block. Further development of novel applications of electrical stimulation will drive progress towards effective therapy for SCI. The optimal solution for restoration of bladder control may encompass a combination of efficient, targeted electrical stimulation, possibly at multiple locations, and pharmacological treatment to enhance symptom control.

Measurement of evoked potentials during thalamic deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) treats the symptoms of several movement disorders, but optimal selection of stimulation parameters remains a challenge. The evoked compound action potential (ECAP) reflects synchronized neural activation near the DBS lead, and may be useful for feedback control and automatic adjustment of stimulation parameters in closed-loop DBS systems. OBJECTIVES: Determine the feasibility of recording ECAPs in the clinical setting, understand the neural origin of the ECAP and sources of any stimulus artifact, and correlate ECAP characteristics with motor symptoms. METHODS: The ECAP and tremor response were measured simultaneously during intraoperative studies of thalamic DBS, conducted in patients who were either undergoing surgery for initial lead implantation or replacement of their internal pulse generator. RESULTS: There was large subject-to-subject variation in stimulus artifact amplitude, which model-based analysis suggested may have been caused by glial encapsulation of the lead, resulting in imbalances in the tissue impedance between the contacts. ECAP recordings obtained from both acute and chronically implanted electrodes revealed that specific phase characteristics of the signal varied systematically with stimulation parameters. Further, a trend was observed in some patients between the energy of the initial negative and positive ECAP phases, as well as secondary phases, and changes in tremor from baseline. A computational model of thalamic DBS indicated that direct cerebellothalamic fiber activation dominated the clinically measured ECAP, suggesting that excitation of these fibers is critical in DBS therapy. CONCLUSIONS: This work demonstrated that ECAPs can be recorded in the clinical setting and may provide a surrogate feedback control signal for automatic adjustment of stimulation parameters to reduce tremor amplitude.

Volume conductor model of transcutaneous electrical stimulation with kilohertz signals.

OBJECTIVE: Incorporating high-frequency components in transcutaneous electrical stimulation (TES) waveforms may make it possible to stimulate deeper nerve fibers since the impedance of tissue declines with increasing frequency. However, the mechanisms of high-frequency TES remain largely unexplored. We investigated the properties of TES with frequencies beyond those typically used in neural stimulation. APPROACH: We implemented a multilayer volume conductor model including dispersion and capacitive effects, coupled to a cable model of a nerve fiber. We simulated voltage- and current-controlled transcutaneous stimulation, and quantified the effects of frequency on the distribution of potentials and fiber excitation. We also quantified the effects of a novel transdermal amplitude modulated signal (TAMS) consisting of a non-zero offset sinusoidal carrier modulated by a square-pulse train. MAIN RESULTS: The model revealed that high-frequency signals generated larger potentials at depth than did low frequencies, but this did not translate into lower stimulation thresholds. Both TAMS and conventional rectangular pulses activated more superficial fibers in addition to the deeper, target fibers, and at no frequency did we observe an inversion of the strength-distance relationship. Current regulated stimulation was more strongly influenced by fiber depth, whereas voltage regulated stimulation was more strongly influenced by skin thickness. Finally, our model reproduced the threshold-frequency relationship of experimentally measured motor thresholds. SIGNIFICANCE: The model may be used for prediction of motor thresholds in TES, and contributes to the understanding of high-frequency TES.