Electrical Stimulation publications

This study implements the use of Danish Landrace pigs as subjects for the long-term potentiation (LTP)-like pain model. This is accomplished by analyzing changes in the primary somatosensory cortex (S1) in response to electrical stimulation on the ulnar nerve after applying high-frequency electrical stimulation (HFS) on the ulnar nerve. In this study, eight Danish Landrace pigs were electrically stimulated, through the ulnar nerve, to record the cortically evoked response in S1 by a 16-channel microelectrode array (MEA). Six of these pigs were subjected to HFS (four consecutive, 15 mA, 100 Hz, 1000 µs pulse duration) 45 min after the start of the experiment. Two pigs were used as control subjects to compare the cortical response to peripheral electrical stimulation without applying HFS. Low-frequency components of the intracortical signals (0.3-300 Hz) were analyzed using event-related potential (ERP) analysis, where the minimum peak during the first 30-50 ms (N1 component) in each channel was detected. The change in N1 was compared over time across the intervention and control groups. Spectral analysis was used to demonstrate the effect of the intervention on the evoked cortical oscillations computed between 75 ms and 200 ms after stimulus. ERP analysis showed an immediate increase in N1 amplitude that became statistically significant 45 mins after HFS (p < 0.01) for the intervention group. The normalized change in power in frequency oscillations showed a similar trend. The results show that the LTP-like pain model can be effectively implemented in pigs using HFS since the cortical responses are comparable to those described in humans.

Treatment refractory Tourette syndrome has been shown to be improved with deep brain stimulation, but with multiple possible stimulation locations and variable and incomplete benefit. This study presents a single case of complete amelioration of motor and verbal tics in a patient with Tourette syndrome during placement of 12 stereo-EEG electrodes to identify optimal targets for permanent stimulating electrodes. Subsequently, substantial improvement in motor and verbal tic frequency occurred with placement and programming of permanent electrodes in bilateral globus pallidus internus and nucleus accumbens, but without the complete resolution seen during depth electrode placement. We suggest that simultaneous stimulation at multiple patient-specific targets could provide effective control of Tourette symptomatology, but further study will be needed.

Brain injuries cause hemodynamic changes in several distant, spared areas from the lesion. Our objective was to better understand the neuronal correlates of this reorganization in awake, behaving female monkeys. We used reversible inactivation techniques to “injure” the primary motor cortex, while continuously recording neuronal activity of the ventral premotor cortex in the two hemispheres, before and after the onset of behavioral impairments. Inactivation rapidly induced profound alterations of neuronal discharges that were heterogeneous within each and across the two hemispheres, occurred during movements of either the affected or nonaffected arm, and varied during different phases of grasping. Our results support that extensive, and much more complex than expected, neuronal reorganization takes place in spared areas of the bihemispheric cortical network involved in the control of hand movements. This broad pattern of reorganization offers potential targets that should be considered for the development of neuromodulation protocols applied early after brain injury. SIGNIFICANCE STATEMENT It is well known that brain injuries cause changes in several distant, spared areas of the network, often in the premotor cortex. This reorganization is greater early after the injury and the magnitude of early changes correlates with impairments. However, studies to date have used noninvasive brain imaging approaches or have been conducted in sedated animals. Therefore, we do not know how brain injuries specifically affect the activity of neurons during the generation of movements. Our study clearly shows how a lesion rapidly impacts neurons in the premotor cortex of both hemispheres. A better understanding of these complex changes can help formulate hypotheses for the development of new treatments that specifically target neuronal reorganization induced by lesions in the brain.

As a promising future treatment for stroke rehabilitation, researchers have developed direct brain stimulation to manipulate the neural excitability. However, there has been less interest in energy consumption and unexpected side effect caused by electrical stimulation to bring functional recovery for stroke rehabilitation. In this study, we propose an engineering approach with subthreshold electrical stimulation (STES) to bring functional recovery. Here, we show a low level of electrical stimulation boosted causal excitation in connected neurons and strengthened the synaptic weight in a simulation study. We found that STES with motor training enhanced functional recovery after stroke in vivo. STES was shown to induce neural reconstruction, indicated by higher neurite expression in the stimulated regions and correlated changes in behavioral performance and neural spike firing pattern during the rehabilitation process. This will reduce the energy consumption of implantable devices and the side effects caused by stimulating unwanted brain regions.

Background Cerebellar electrical stimulation has shown promise in improving motor recovery post-stroke in both rodent and human studies. Past studies have used motor evoked potentials (MEPs) to evaluate how cerebellar stimulation modulates ongoing activity in the cortex, but the underlying mechanisms are incompletely understood. Here we used invasive electrophysiological recordings from the intact and stroke-injured rodent primary motor cortex (M1) to assess how epidural cerebellar stimulation modulates neural dynamics at the level of single neurons as well as at the level of mesoscale dynamics. Methods We recorded single unit spiking and local field potentials (LFPs) in both the intact and acutely stroke-injured M1 contralateral to the stimulated cerebellum in adult Long-Evans rats under anesthesia. We analyzed changes in the firing rates of single units, the extent of synchronous spiking and power spectral density (PSD) changes in LFPs during and post-stimulation. Results Our results show that post-stimulation, the firing rates of a majority of M1 neurons changed significantly with respect to their baseline rates. These firing rate changes were diverse in character, as the firing rate of some neurons increased while others decreased. Additionally, these changes started to set in during stimulation. Furthermore, cross-correlation analysis showed a significant increase in coincident firing amongst neuronal pairs. Interestingly, this increase in synchrony was unrelated to the direction of firing rate change. We also found that neuronal ensembles derived through principal component analysis were more active post-stimulation. Lastly, these changes occurred without a significant change in the overall spectral power of LFPs post-stimulation. Conclusions Our results show that cerebellar stimulation caused significant, long-lasting changes in the activity patterns of M1 neurons by altering firing rates, boosting neural synchrony and increasing neuronal assemblies’ activation strength. Our study provides evidence that cerebellar stimulation can directly modulate cortical dynamics. Since these results are present in the perilesional cortex, our data might also help explain the facilitatory effects of cerebellar stimulation post-stroke.

High-frequency peripheral nerve stimulation has emerged as a noninvasive alternative to thalamic deep brain stimulation for some patients with essential tremor. It is not known whether such techniques might be effective for movement disorders in children, nor is the mechanism and transmission of the peripheral stimuli to central brain structures understood. This study was designed to investigate the fidelity of transmission from peripheral nerves to thalamic nuclei in children with dystonia undergoing deep brain stimulation surgery. The ventralis intermediate (VIM) thalamus nuclei showed a robust evoked response to peripheral high-frequency burst stimulation, with a greatest response magnitude to intra-burst frequencies between 50 and 100 Hz, and reliable but smaller responses up to 170 Hz. The earliest response occurred at 12–15 ms following stimulation onset, suggesting rapid high-fidelity transmission between peripheral nerve and thalamic nuclei. A high-bandwidth, low-latency transmission path from peripheral nerve to VIM thalamus is consistent with the importance of rapid and accurate sensory information for the control of coordination and movement via the cerebello-thalamo-cortical pathway. Our results suggest the possibility of non-invasive modulation of thalamic activity in children with dystonia, and therefore the possibility that a subset of children could have beneficial clinical response without the need for invasive deep brain stimulation.

Recovering arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control practically limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts, triggered by intracortical signals produced sustained arm movements enabling monkeys with arm paralysis to perform an unconstrained, three-dimensional reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that artificial recruitment of the sensory afferents was synergistically integrated with spared descending inputs and spinal reflexes to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.

Recent studies have shown that rats are a useful model for binaural cochlear implant (CI) research, with behavioral sensitivity to interaural time differences (ITDs) of CI stimuli which are better than those of human patients. Here, we characterize ITD tuning in the rat inferior colliculus (IC) and explore whether quality of tuning can predict behavioral performance. We recorded IC responses to stimuli of varying pulse rates and envelope types and quantified both mutual information (MI) and neural d ′ as measures of ITD sensitivity. Neural d ′ values paralleled behavioral ones, declining with increasing click rates or when envelopes changed from rectangular to Hanning windows. While MI values increased with experience, neural d ′ did not. However, neural d ′ values correlated much better with behavioral performance than MI. Thus, neural d ′ appears to be a particularly well suited to predicting how stimulus parameters will impact behavioral performance.

Spatial hearing in cochlear implant (CI) patients remains a major challenge, with many early deaf users reported to have no measurable sensitivity to interaural time differences (ITDs). Deprivation of binaural experience during an early critical period is often hypothesized to be the cause of this shortcoming. However, we show that neonatally deafened (ND) rats provided with precisely synchronized CI stimulation in adulthood can be trained to lateralize ITDs with essentially normal behavioral thresholds near 50 μs. Furthermore, comparable ND rats show high physiological sensitivity to ITDs immediately after binaural implantation in adulthood. Our result that ND-CI rats achieved very good behavioral ITD thresholds, while prelingually deaf human CI patients often fail to develop a useful sensitivity to ITD raises urgent questions concerning the possibility that shortcomings in technology or treatment, rather than missing input during early development, may be behind the usually poor binaural outcomes for current CI patients.

There is considerable interest in understanding cortical processing and the function of top-down and bottom-up human neural circuits that control speech production. Research efforts to investigate these circuits are aided by analysis of spectro-temporal response characteristics of neural activity recorded by electrocorticography (ECoG). Further, cortical processing may be altered in the case of hearing-impaired cochlear implant (CI) users, as electric excitation of the auditory nerve creates a markedly different neural code for speech compared with that of the functionally intact hearing system. Studies of cortical activity in CI users typically record scalp potentials and are hampered by stimulus artifact contamination and by spatiotemporal filtering imposed by the skull. We present a unique case of a CI user who required direct recordings from the cortical surface using subdural electrodes implanted for epilepsy assessment. Using experimental conditions where the subject vocalized in the presence (CIs ON) or absence (CIs OFF) of auditory feedback, or listened to playback of self-vocalizations without production, we observed ECoG activity primarily in γ (32-70 Hz) and high γ (70-150 Hz) bands at focal regions on the lateral surface of the superior temporal gyrus (STG). High γ band responses differed in their amplitudes across conditions and cortical sites, possibly reflecting different rates of stimulus presentation and differing levels of neural adaptation. STG γ responses to playback and vocalization with auditory feedback were not different from responses to vocalization without feedback, indicating this activity reflects not only auditory, but also attentional, efference-copy, and sensorimotor processing during speech production.

Mammalian cortex has both local and cross-area connections, suggesting vital roles for both local and cross-area neural population dynamics in cortically-dependent tasks, like movement learning. Prior studies of movement learning have focused on how single-area population dynamics change during short-term adaptation. It is unclear how cross-area dynamics contribute to movement learning, particularly long-term learning and skill acquisition. Using simultaneous recordings of rodent motor (M1) and premotor (M2) cortex and computational methods, we show how cross-area activity patterns evolve during reach-to-grasp learning in rats. The emergence of reach-related modulation in cross-area activity correlates with skill acquisition, and single-trial modulation in cross-area activity predicts reaction time and reach duration. Local M2 neural activity precedes local M1 activity, supporting top–down hierarchy between the regions. M2 inactivation preferentially affects cross-area dynamics and behavior, with minimal disruption of local M1 dynamics. Together, these results indicate that cross-area population dynamics are necessary for learned motor skills.

The basal ganglia play a crucial role in the control of voluntary movements. Neurons in both the external and internal segments of the globus pallidus, the connecting and output nuclei of the basal ganglia, respectively, change their firing rates in relation to movements. Firing rate changes of movement‐related neurons seem to convey signals for motor control. On the other hand, coincident spikes among neurons, that is, correlated activity, may also contribute to motor control. To address this issue, we first identified multiple pallidal neurons receiving inputs from the forelimb regions of the primary motor cortex and supplementary motor area, recorded neuronal activity of these neurons simultaneously, and analyzed their spike correlations while monkeys performed a hand‐reaching task. Most (79%) pallidal neurons exhibited task‐related firing rate changes, whereas only a small fraction (20%) showed significant but small and short correlated activity during the task performance. These results suggest that motor control signals are conveyed primarily by firing rate changes in the external and internal segments of the globus pallidus and that the contribution of correlated activity may play only a minor role in the healthy state.

Neural implants that deliver multi-site electrical stimulation to the nervous systems are no longer the last resort but routine treatment options for various neurological disorders. Multi-site electrical stimulation is also widely used to study nervous system function and neural circuit transformations. These technologies increasingly demand dynamic electrical stimulation and closed-loop feedback control for real-time assessment of neural function, which is technically challenging since stimulus-evoked artifacts overwhelm the small neural signals of interest. We report a novel and versatile artifact removal method that can be applied in a variety of settings, from single- to multi-site stimulation and recording and for current waveforms of arbitrary shape and size. The method capitalizes on linear electrical coupling between stimulating currents and recording artifacts, which allows us to estimate a multi-channel linear Wiener filter to predict and subsequently remove artifacts via subtraction. We confirm and verify the linearity assumption and demonstrate feasibility in a variety of recording modalities, including in vitro sciatic nerve stimulation, bilateral cochlear implant stimulation, and multi-channel stimulation and recording between the auditory midbrain and cortex. We demonstrate a vast enhancement in the recording quality with a typical artifact reduction of 25-40 dB. The method is efficient and can be scaled to arbitrary number of stimulus and recording sites, making it ideal for applications in large-scale arrays, closed-loop implants, and high-resolution multi-channel brain-machine interfaces.

Animal behavioral paradigms, such as classical conditioning and operant conditioning, are an important tool to study the neural basis of cognition and behavior. These paradigms involve manipulating sensory stimuli in a way that learning processes are induced under controlled experimental conditions. However, the majority of the commercially available equipment did not offer flexibility to manipulate stimuli. Therefore, the development of most versatile devices would allow the study of more complex cognitive functions. The purpose of this work is to present a low-cost, customized and wireless-operated chamber for animal behavior conditioning, based on the joint operation of two microcontroller modules: Arduino Due and ESP8266-12E. Our results showed that the auditory stimulation system allows setting the carrier frequency in the range of 1 Hz up to more than 100 kHz and the sound stimulus can be modulated in amplitude, also over a wide range of frequencies. Likewise, foot-shock could be precisely manipulated regarding its amplitude (from ∼200 μA to ∼1500 μA) and frequency (up to 20 pulses per second). Finally, adult rats exposed to a protocol of cued fear conditioning in our device showed consistent behavioral response and electrophysiological evoked responses in the midbrain auditory pathway. Furthermore, the device developed in the current study represents an open source alternative to develop customized protocols to study fear memory under conditions of varied sensory stimuli.

The studies described in this paper for the first time characterize the acute and chronic performance of optically transparent thin-film micro-electrocorticography (μECoG) grids implanted on a thinned skull as both an electrophysiological complement to existing thinned skull preparation for optical recordings/manipulations, and a less invasive alternative to epidural or subdurally placed μECoG arrays. In a longitudinal chronic study, μECoG grids placed on top of a thinned skull maintain impedances comparable to epidurally placed μECoG grids that are stable for periods of at least 1 month. Optogenetic activation of cortex is also reliably demonstrated through the optically transparent μECoG grids acutely placed on the thinned skull. Finally, spatially distinct electrophysiological recordings were evident on μECoG electrodes placed on a thinned skull separated by 500-750 μm, as assessed by stimulation evoked responses using optogenetic activation of cortex as well as invasive and epidermal stimulation of the sciatic and median nerve at chronic time points. Neural signals were collected through a thinned skull in mice and rats, demonstrating potential utility in neuroscience research applications such as in vivo imaging and optogenetics.

Vagal nerve stimulation (VNS) is an FDA approved treatment method for intractable epilepsy, treatment resistant depression, cluster headaches and migraine with over 100,000 patients having received vagal nerve implants to date. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood and an area of active research. In parallel, the glymphatic and meningeal lymphatic systems have recently been proposed and experimentally validated to explain how the brain maintains a healthy homeostasis without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins from the interstitium. Of note, clearance is sensitive to adrenergic signaling, and a primary driver of CSF influx into the parenchyma appears to be cerebral arterial pulsations and respiration. As VNS has well-documented effects on cardiovascular and respiratory physiology as well as brain adrenergic signaling, we hypothesized that VNS delivered at clinically derived parameters would increase CSF influx in the brain. To test this hypothesis, we injected a low molecular weight (3 kD) lysine-fixable fluorescent tracer (TxRed) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following VNS. We found that the clinical VNS group showed a significant increase in CSF dye penetrance as compared to the naïve control and sham groups. This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies. One Sentence Summary Cervical vagus nerve stimulation using clinically derived parameters enhances movement of cerebrospinal fluid into the brain parenchyma presenting a previously unreported effect of vagus nerve stimulation with potential clinical utility.

Objective: Reanimation of muscles paralyzed by disease states such as spinal cord injury remains a highly sought therapeutic goal of neuroprosthetic research. Optogenetic stimulation of peripheral motor nerves expressing light-sensitive opsins is a promising approach to muscle reanimation that may overcome several drawbacks of traditional methods such as functional electrical stimulation (FES). However, the utility of these methods has only been demonstrated in rodents to date, while translation to clinical practice will likely first require demonstration and refinement of these gene therapy techniques in non-human primates. Approach: Three rhesus macaques were injected intramuscularly with either one or both of two optogenetic constructs (AAV6-hSyn-ChR2-eYFP and/or AAV6-hSyn-Chronos-eYFP) to transduce opsin expression in the corresponding nerves. Neuromuscular junctions were targeted for virus delivery using an electrical stimulating injection technique. Functional opsin expression was periodically evaluated up to 13 weeks post-injection by optically stimulating targeted nerves with a 472 nm fiber-coupled laser while recording electromyographic (EMG) responses. Main Results: One monkey demonstrated functional expression of ChR2 at 8 weeks post-injection in each of two injected muscles, while the second monkey briefly exhibited contractions coupled to optical stimulation in a muscle injected with the Chronos construct at 10 weeks. A third monkey injected only in one muscle with the ChR2 construct showed strong optically coupled contractions at 5 ½ weeks which then disappeared by 9 weeks. EMG responses to optical stimulation of ChR2-transduced nerves demonstrated graded recruitment relative to both stimulus pulse-width and light intensity, and followed stimulus trains up to 16 Hz. In addition, the EMG response to prolonged stimulation showed delayed fatigue over several minutes. Significance: These results demonstrate the feasibility of viral transduction of peripheral motor nerves for functional optical stimulation of motor activity in non-human primates, a variable timeline of opsin expression in a animal model closer to humans, and fundamental EMG response characteristics to optical nerve stimulation. Together, they represent an important step in translating these optogenetic techniques as a clinically viable gene therapy.

Glassy carbon (GC) has high potential to serve as a biomaterial in neural applications because it is biocompatible, electrochemically inert and can be incorporated in polyimide-based implantable devices. Miniaturization and applicability of GC is, however, thought to be partially limited by its electrical conductivity. For this study, ultra-conformable polyimide-based electrocorticography (ECoG) devices with different-diameter GC electrodes were fabricated and tested in vitro and in rat models. For achieving conformability to the rat brain, polyimide was patterned in a finger-like shape and its thickness was set to 8 µm. To investigate different electrode sizes, each ECoG device was assigned electrodes with diameters of 50, 100, 200 and 300 µm. They were electrochemically characterized and subjected to 10 million biphasic pulses—for achieving a steady-state—and to X-ray photoelectron spectroscopy, for examining their elemental composition. The electrodes were then implanted epidurally to evaluate the ability of each diameter to detect neural activity. Results show that their performance at low frequencies (up to 300 Hz) depends on the distance from the signal source rather than on the electrode diameter, while at high frequencies (above 200 Hz) small electrodes have higher background noises than large ones, unless they are coated with poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS).

Electrical nerve recording and stimulation technologies are critically needed to monitor and modulate nerve activity to treat a variety of neurological diseases. However, current neuromodulation technologies presented in the literature or commercially available products cannot support simultaneous recording and stimulation on the same nerve. To solve this problem, a new bidirectional neuromodulation system-on-chip (SoC) is proposed in this paper, which includes a frequency-shaping neural recorder and a fully integrated neural stimulator with charge balancing capability. In addition, auxiliary circuits consisting of power management and data transmission circuits are designed to provide the necessary power supply for the SoC and the bidirectional data communication between the SoC and an external computer via a universal serial bus (USB) interface, respectively. To achieve sufficient low input noise for sensing nerve activity at a sub-10 μ V range, several noise reduction techniques are developed in the neural recorder. The designed SoC was fabricated in a 0.18 μ m high-voltage Bipolar CMOS DMOS (BCD) process technology that was described in a previous publication and it has been recently tested in animal experiments that demonstrate the proposed SoC is capable of achieving reliable and simultaneous electrical stimulation and recording on the same nerve.

Patients with chronic spinal cord injury (SCI) cannot urinate at will and must empty the bladder by self-catheterization. We tested the hypothesis that non-invasive, transcutaneous magnetic spinal cord stimulation (TMSCS) would improve bladder function in individuals with SCI. Five individuals with American Spinal Injury Association Impairment Scale A/B, chronic SCI and detrusor sphincter dyssynergia enrolled in this prospective, interventional study. After a two-week assessment to determine effective stimulation characteristics, each patient received sixteen weekly TMSCS treatments and then received “sham” weekly stimulation for six weeks while bladder function was monitored. Bladder function improved in all five subjects, but only during and after repeated weekly sessions of 1 Hz TMSCS. All subjects achieved volitional urination. The volume of urine produced voluntarily increased from 0 cc/day to 1120 cc/day (p = 0.03); self-catheterization frequency decreased from 6.6/day to 2.4/day (p = 0.04); the capacity of the bladder increased from 244 ml to 404 ml (p = 0.02); and the average quality of life ranking increased significantly (p = 0.007). Volitional bladder function was re-enabled in five individuals with SCI following intermittent, non-invasive TMSCS. We conclude that neuromodulation of spinal micturition circuitry by TMSCS may be used to ameliorate bladder function.