Stimulation Of Afferent Fibers Research Articles

Medication "underuse" headache.

Many risk factors have been associated with migraine progression, including insufficient and ineffective utilization of migraine medications; however, they have been inadequately explored. This has resulted in suboptimal usage of medications without effective altering of prescribing recommendations for patients, posing a risk for migraine chronification. Our aim is to conduct a comprehensive review of the available evidence regarding the underuse of migraine medications, both acute and preventive. The term "underuse" includes, but is not limited to: (1) ineffective use of appropriate and inappropriate medication; (2) underutilization; (3) inappropriate timing of usage; and (4) patient dissatisfaction with medication. The underuse of both acute and preventive medications has been shown to contribute to the progression of migraine. In terms of acute medication, chronification occurs as a result of insufficient drug use, including failure of the prescriber to select the appropriate type based on pain intensity and disability, patients taking medication too late (more than 60 minutes after the onset or after central sensitization has occurred as evidenced by allodynia), and discontinuation because of lack of effect or intolerable side effects. The underlying cause of inadequate effectiveness of acute medication lies in its inability to halt the propagation of peripheral activation to central sensitization in a timely manner. For oral and injectable preventive migraine medications, insufficient efficacy and intolerable side effects have led to poor adherence and discontinuation with subsequent progression of migraine. The underlying pathophysiology here is rooted in the repetitive stimulation of afferent sensory pain fibers, followed by ascending brainstem pain pathways plus dysfunction of the endogenous descending brainstem pain inhibitory pathway. Although anti-calcitonin gene-related peptide (CGRP) medications partially address pain caused by the above factors, including decreased efficacy and tolerability from conventional therapy, some patients do not respond well to this treatment. Research suggests that initiating preventive anti-CGRP treatment at an early stage (during low frequency episodic migraine attacks) is more beneficial than commencing it during high frequency episodic attacks or when chronic migraine has begun. The term "medication underuse" is underrecognized, but it holds significant importance. Optimal usage of acute care and preventive migraine medications could potentially prevent migraine chronification and improve the treatment of migraine attacks.

Metabolic response of auditory brainstem neurons to their broad physiological activity range.

Neurons exhibit a high energetic need, and the question arises as how they metabolically adapt to changing activity states. This is relevant for interpreting functional neuroimaging in different brain areas. Particularly, neurons with a broad firing range might exhibit metabolic adaptations. Therefore, we studied MNTB (medial nucleus of the trapezoid body) principal neurons, which generate action potentials (APs) at frequencies up to several hundred hertz. We performed the experiments in acute brainstem slices of the Mongolian gerbil (Meriones unguiculatus) at 22.5-24.5°C. Upon electrical stimulation of afferent MNTB fibres with 400 stimuli at varying frequencies, we monitored autofluorescence levels of NAD(P)H and FAD and determined the extremum amplitudes of their biphasic response. Additionally, we compared these data with alterations in O2 concentrations measured with an electrochemical sensor. These O2 changes are prominent since MNTB neurons rely on oxidative phosphorylation as shown by our pharmacological experiments. We calculated the O2 consumption rate as change in O2 concentration divided by stimulus durations, because these periods varied inversely with stimulus frequency as a result of the constant number of 400 stimuli applied. The O2 consumption rate increased with stimulation frequency up to a constant value at 600 Hz; that is, energy demand depends on temporal characteristics of activity despite the same number of stimuli. The rates showed no correlation with peak amplitudes of NAD(P)H or FAD, whilst the values of the two molecules were linearly correlated. This points at the complexity of analysing autofluorescence imaging for quantitative metabolic studies, because these values report only relative net changes of many superimposed oxidative and reductive processes. Monitoring O2 concentration rates is, thus, an important tool to improve the interpretation of NAD(P)H/FAD autofluorescence data, as they do not under all conditions and in all systems appropriately reflect the metabolic activity or energy demand.

Distinguishing reflex from non-reflex responses elicited by transcutaneous spinal stimulation targeting the lumbosacral cord in healthy individuals

Transcutaneous spinal stimulation (TSS) studies rely on the depolarization of afferent fibers to provide input to the spinal cord; however, this has not been routinely ascertained. Thus, we aimed to characterize the types of responses evoked by TSS and establish paired-pulse ratio cutoffs that distinguish posterior root reflexes, evoked by stimulation of afferent nerve fibers, from motor responses, evoked by stimulation of efferent nerve fibers. Twelve neurologically intact participants (six women) underwent unipolar TSS (cathode over T11-12 spinal processes, anode paraumbilically) while resting supine. In six participants, unipolar TSS was repeated 2–3 months later and also compared to a bipolar TSS configuration (cathode 2.5 cm below T11-12, anode 5 cm above cathode). EMG signals were recorded from 16 leg muscles. A paired-pulse paradigm was applied at interstimulus intervals (ISIs) of 25, 50, 100, 200, and 400 ms. Responses were categorized by three assessors into reflexes, motor responses, or their combination (mixed responses) based on the visual presence/absence of paired-pulse suppression across ISIs. The paired-pulse ratio that best discriminated between response types was derived for each ISI. These cutoffs were validated by repeating unipolar TSS 2–3 months later and with bipolar TSS. Unipolar TSS evoked only reflexes (90%) and mixed responses (10%), which were mainly recorded in the quadriceps muscles (25–42%). Paired-pulse ratios of 0.51 (25-ms ISI) and 0.47 (50-ms ISI) best distinguished reflexes from mixed responses (100% sensitivity, > 99.2% specificity). These cutoffs performed well in the repeated unipolar TSS session (100% sensitivity, > 89% specificity). Bipolar TSS exclusively elicited reflexes which were all correctly classified. These results can be utilized in future studies to ensure that the input to the spinal cord originates from the depolarization of large afferents. This knowledge can be applied to improve the design of future neurophysiological studies and increase the fidelity of neuromodulation interventions.

Effects of tail nerve electrical stimulation on the activation and plasticity of the lumbar locomotor circuits and the prevention of skeletal muscle atrophy after spinal cord transection in rats.

Severe spinal cord injury results in the loss of neurons in the relatively intact spinal cord below the injury area and skeletal muscle atrophy in the paralyzed limbs. These pathological processes are significant obstacles for motor function reconstruction. We performed tail nerve electrical stimulation (TNES) to activate the motor neural circuits below the injury site of the spinal cord to elucidate the regulatory mechanisms of the excitatory afferent neurons in promoting the reconstruction of locomotor function. Eight days after T10 spinal cord transection in rats, TNES was performed for 7 weeks. Behavioral scores were assessed weekly. Electrophysiological tests and double retrograde tracings were performed at week 8. After 7 weeks of TNES treatment, there was restoration in innervation, the number of stem cells, and mitochondrial metabolism in the rats' hindlimb muscles. Double retrograde tracings of the tail nerve and sciatic nerve further confirmed the presence of synaptic connections between the tail nerve and central pattern generator (CPG) neurons in the lumbar spinal cord, as well as motor neurons innervating the hindlimb muscles. The mechanisms of TNES induced by the stimulation of primary afferent nerve fibers involves efficient activation of the motor neural circuits in the lumbosacral segment, alterations of synaptic plasticity, and the improvement of muscle and nerve regeneration, which provides the structural and functional foundation for the future use of cutting-edge biological treatment strategies to restore voluntary movement of paralyzed hindlimbs.

Recovery kinetics of short-term depression of GABAergic and glutamatergic synapses at layer 2/3 pyramidal cells in the mouse barrel cortex.

Short-term synaptic plasticity (STP) is a widespread mechanism underlying activity-dependent modifications of cortical networks. To investigate how STP influences excitatory and inhibitory synapses in layer 2/3 of mouse barrel cortex, we combined whole-cell patch-clamp recordings from visually identified pyramidal neurons (PyrN) and parvalbumin-positive interneurons (PV-IN) of cortical layer 2/3 in acute slices with electrical stimulation of afferent fibers in layer 4 and optogenetic activation of PV-IN. These experiments revealed that electrical burst stimulation (10 pulses at 10 Hz) of layer 4 afferents to layer 2/3 neurons induced comparable short-term depression (STD) of glutamatergic postsynaptic currents (PSCs) in PyrN and in PV-IN, while disynaptic GABAergic PSCs in PyrN showed a stronger depression. Burst-induced depression of glutamatergic PSCs decayed within <4 s, while the decay of GABAergic PSCs required >11 s. Optogenetically-induced GABAergic PSCs in PyrN also demonstrated STD after burst stimulation, with a decay of >11 s. Excitatory postsynaptic potentials (EPSPs) in PyrN were unaffected after electrical burst stimulation, while a selective optogenetic STD of GABAergic synapses caused a transient increase of electrically evoked EPSPs in PyrN. In summary, these results demonstrate substantial short-term plasticity at all synapses investigated and suggest that the prominent STD observed in GABAergic synapses can moderate the functional efficacy of glutamatergic STD after repetitive synaptic stimulations. This mechanism may contribute to a reliable information flow toward the integrative layer 2/3 for complex time-varying sensory stimuli.

ID: 208947 Ultrashort Microscopic Magnetic Vagal Stimulation

Electrical stimulation of the cervical vagus nerve is an emerging treatment field for various central nervous system disorders. Invasive electrical Vagus nerve stimulation (VNS) is an FDA-approved add-on treatment to medication for refractory partial-onset seizures in patients 12 years of age and older. However, only approximately 40-50% of patients experience a marked seizure reduction of 50% or more than seizures before treatment [1]. The effects of VNS on neurotransmitter systems, including the noradrenergic system originating from the locus coeruleus and the serotonergic system from the dorsal raphe nucleus, have been reported in experimental settings. The therapeutic effect of VNS in the brain is linked to the stimulation of large diameter afferent fibers. These large myelinated afferent fibers, terminating in the nucleus tractus solitarius in the brainstem, are assumed to deliver the therapeutic effect through further projections into the other brain areas. Non-selective stimulation results in inadvertent activation of efferent fibers that innervate a wide range of peripheral organs resulting in adverse effects [2] with a rare but severe risk of bradyarrhythmia and asystole.

Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties.

CR4056 is an imidazoline-2 receptor ligand having potent analgesic activity and synergistic effect with opioids. Very recently it has been found that CR4056 can revert the cognitive impairment in animal models of Alzheimer's disease (AD). Since several lines of evidence highlight the importance of NMDAR modulators in nociceptive signaling and in AD progression, we considered as important to investigate the effects of CR4056 on NMDAR activity. In primary culture of cortical neurons, application of NMDA and glycine elicits a current that is decreased in a dose-dependent fashion by CR4056 (IC50 5.3 ± 0.1 µM). CR4056 antagonism is reversible, not competitive and voltage-independent and it is not blocked by pertussis toxin. CR4056 interacts with the co-agonist glycine site in a competitive way, indeed high glycine concentrations diminish its effect. Fibroblasts expressing different recombinant NMDA receptors are differently modulated by CR4056: the potency and the efficacy of the compound are higher in GluN1- GluN2B than in GluN1-GluN2A containing receptors. In lamina II neurons of spinal cord slices, single stimulation of afferent fibers evokes an NMDA-mediated current that is inhibited by 10 µM CR4056. Repetitive stimulation of the dorsal root at high frequency and high intensity produces a firing activity that is significatively depressed by CR4056. Taken together, our results broad the understanding of the molecular mechanisms of CR4056 analgesic activity, involving the modulation of NMDAR activity. Therefore, we propose that the analgesic action of CR4056 and the neuroprotective effects in AD models may be mediated also by NMDAR inhibition.

Low intensity stimulation of aortic baroreceptor afferent fibers as a potential therapeutic alternative for hypertension treatment

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20–30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s) versus intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that “low intensity intermittent” electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.

Rationale and Evidence for Peripheral Nerve Stimulation for Treating Essential Tremor.

Background:There is growing recognition of peripheral stimulation techniques for controlling arm symptoms in essential tremor (ET). Recently, the FDA gave clearance to the Cala system, a device worn around the wrist to treat arm tremors. The Cala system stimulates the sensory afferents of the peripheral nerves with high-frequency pulses. These pulses are delivered to the median and radial nerves alternately at the tremor frequency of the individual patient.Methods:The PubMed database was searched using the terms (“Essential Tremor”[Mesh] OR “essential tremor” [Title/] OR “tremor” [Title/]) AND (“peripheral arm stimulation” [Title/] OR “Cala device” [Title/] OR “sensory afferent stimulation” [Title/] OR “afferent stimulation” [Title/] OR “arm stimulation” [Title/] OR “peripheral nerve stimulation” [Title/]).Results:The search yielded 54 articles. Many studies discussed the rationale and various strategies for peripheral modulation of tremor. While the Cala system was found to be safe and well-tolerated in ET, data on efficacy revealed mixed findings. In a large randomized, blinded trial (n = 77), the primary outcome evaluated with spiral drawing task did not improve but the secondary outcomes reflected by the arm tremor severity and the activities of the daily living score revealed 20–25% improvements. A subsequent trial (n = 323) found that the in-home use of the Cala device led to improvements of similar magnitude lasting for at least three months but the clinical assessments were open-labeled.Discussion:Peripheral stimulation techniques are promising therapeutic modalities for treating ET symptoms. Stimulation of sensory afferent nerve fibers at the wrist can potentially modulate the peripheral and central components of the tremor network. Although the Cala system is user-friendly, safe, and well-tolerated, the current clinical evidence on the efficacy is inconsistent and insufficient. Thus, more data is warranted for implementing peripheral nerve stimulation as a standard of care for ET.HighlightsThe current review discusses the rationale, background, and potential mechanisms for using peripheral arm stimulation devices for treating ET. The Cala system is a wrist-worn peripheral nerve stimulation device that received FDA clearance to treat arm tremors. The current review evaluates the evidence for the safety and efficacy of using the Cala system and similar devices in clinical practice.

Regulation of Rostral Nucleus of the Solitary Tract Responses to Afferent Input by A-type K+ Current

Responses in the rostral (gustatory) nucleus of the solitary tract (rNST) are modified by synaptic interactions within the nucleus and the constitutive membrane properties of the neurons themselves. The potassium current IA is one potential source of modulation. In the caudal NST, projection neurons with IA show lower fidelity to afferent stimulation compared to cells without. We explored the role of an A-type K+ current (IA) in modulating the response to afferent stimulation and GABA-mediated inhibition in the rNST using whole cell patch clamp recording in transgenic mice that expressed channelrhodopsin (ChR2 H134R) in GABAergic neurons. The presence of IA was determined in current clamp and the response to electrical stimulation of afferent fibers in the solitary tract was assessed before and after treatment with the specific Kv4 channel blocker AmmTX3. Blocking IA significantly increased the response to afferent stimulation by 53%. Using dynamic clamp to create a synthetic IA conductance, we demonstrated a significant 14% decrease in responsiveness to afferent stimulation in cells lacking IA. Because IA reduced excitability and is hyperpolarization-sensitive, we examined whether IA contributed to the inhibition resulting from optogenetic release of GABA. Although blocking IA decreased the percent suppression induced by GABA, this effect was attributable to the increased responsiveness resulting from AmmTX3, not to a change in the absolute magnitude of suppression. We conclude that rNST responses to afferent input are regulated independently by IA and GABA.

Sympathectomy and Neuromodulation in the Treatment of Critical Lower Limb Ischemia

INTRODUCTION Critical lower limb ischemia is a widespread disease that occurs due to atherosclerotic lesions of the arteries with progressive narrowing of their lumen. Clinically critical ischemia is manifested by pain at rest, resistant to narcotic analgesics, and/or ulcerative necrotic process on the legs. In the absence of treatment, patients undergo amputation of the lower limb. Almost all patients die 10 years after amputation of the lower limb at the level of the thigh. Currently, there are following methods of treatment of critical ischemia: conservative therapy, direct revascularization, lumbar sympathectomy and neurostimulation.AIM OF STUDY To present the data of modern scientifi c literature on the use of lumbar sympathectomy and epidural spinal cord stimulation in the treatment of critical lower limb ischemia.MATERIAL AND METHODS This review presents the latest data obtained as a result of studying domestic and foreign literature on the treatment of critical lower limb ischemia with lumbar sympathectomy and epidural spinal cord stimulation. Currently, lumbar sympathectomy is performed by surgical (open, mini-access and endoscopic) and percutaneous (chemical or radiofrequency) methods. Percutaneous access is becoming widespread due to its minimally invasiveness, maximum accessibility, ease of performance and low cost. Epidural spinal cord stimulation is performed for resistant pain syndrome. The mechanism of action of spinal stimulation is to block the transmission of nerve impulses at the level of the gelatinous substance of the posterior horns of the spinal cord during stimulation of afferent fi bers of a larger diameter (type A-alpha and A-beta fi bers).CONCLUSION Spinal neurostimulation and lumbar sympathectomy are promising methods of treatment for critical lower limb ischemia in case of impossibility of direct revascularization. Lumbar sympathectomy can reduce the intensity of pain and improve the quality of life of patients. According to a number of studies, epidural spinal cord stimulation signifi cantly reduces the likelihood of amputation of the lower limb, and also reduces the intensity of pain in patients refractory to conservative therapy, as well as in those who are not indicated for direct revascularization of the arteries of the lower extremities. More large-scale studies are needed to determine the indications for the above methods.

The increased in vivo firing of pyramidal cells but not interneurons in the anterior cingulate cortex after neuropathic pain

Chronic pain damages the balance between excitation and inhibition in the sensory cortex. It has been confirmed that the activity of cortical glutamatergic pyramidal cells increases after chronic pain. However, whether the activity of inhibitory interneurons synchronized changed remains obscure, especially in in vivo conditions. In the present study, we checked the firing rate of pyramidal cells and interneurons in the anterior cingulate cortex, a main cortical area for the regulation of nociceptive information in mice with spared nerve injury by using in vivo multi-channel recording system. We found that the firing rate of pyramidal cells but not interneurons increased in the ACC, which was further confirmed by the increased FOS expression in pyramidal cells but not interneurons, in mice with neuropathic pain. Selectively high frequency stimulation of the ACC nociceptive afferent fibers only potentiated the activity of pyramidal cells either. Our results thus suggest that the increased activity of pyramidal cells contributes to the damaged E/I balance in the ACC and is important for the pain hypersensitivity in mice with neuropathic pain.

Synergistic interaction between sensory inputs and propriospinal signalling underlying quadrupedal locomotion.

Stimulation of hindlimb afferent fibres can both stabilize and increase the activity of fore- and hindlimb motoneurons during fictive locomotion. The increase in motoneuron activity is at least partially due to the production of doublets of action potentials in a subpopulation of motoneurons. These results were obtained using an in vitro brainstem/spinal cord preparation of neonatal rat. Quadrupedal locomotion relies on a dynamic coordination between central pattern generators (CPGs) located in the cervical and lumbar spinal cord, and controlling the fore- and hindlimbs, respectively. It is assumed that this CPG interaction is achieved through separate closed-loop processes involving propriospinal and sensory pathways. However, the functional consequences of a concomitant involvement of these different influences on the degree of coordination between the fore- and hindlimb CPGs is still largely unknown. Using an in vitro brainstem/spinal cord preparation of neonatal rat, we found that rhythmic, bilaterally alternating stimulation of hindlimb sensory input pathways elicited coordinated hindlimb and forelimb CPG activity. During pharmacologically induced fictive locomotion, lumbar dorsal root (DR) stimulation entrained and stabilized an ongoing cervico-lumbar locomotor-like rhythm and increased the amplitude of both lumbar and cervical ventral root bursting. The increase in cervical burst amplitudes was correlated with the occurrence of doublet action potential firing in a subpopulation of motoneurons, enabling the latter to transition between low and high frequency discharge according to the intensity of DR stimulation. Moreover, our data revealed that propriospinal and sensory pathways act synergistically to strengthen cervico-lumbar interactions. Indeed, split-bath experiments showed that fully coordinated cervico-lumbar fictive locomotion was induced by combining pharmacological stimulation of either the lumbar or cervical CPGs with lumbar DR stimulation. This study thus highlights the powerful interactions between sensory and propriospinal pathways which serve to ensure the coupling of the fore- and hindlimb CPGs for effective quadrupedal locomotion.

Apical intercalated cell cluster: A distinct sensory regulator in the amygdala.

GABAergic neurons regulate different aspects of information processing in the amygdala. Among these are clusters of intercalated cells (ITCs), which have been implicated in fear-related behaviors. Although a few of the ITC clusters have been studied, the functional role of apical ITCs (apITCs) is unknown. Here, we combine monosynaptic rabies tracing with optogenetics and demonstrate that apITCs receive synaptic input from medial geniculate nucleus (MGm), posterior intralaminar nucleus (PIN), and medial dorsal nucleus of the thalamus and from a diverse range of cortical areas including temporal association, entorhinal, insular, piriform, and somatosensory cortex. Upon fear learning, PIN/MGm inputs are strengthened, indicative of their involvement in fear behaviors. 3-D reconstruction of apITCs reveals local arborization and innervation of the dorsal striatum and lateral amygdala. We further show that apITCs provide sensory feedforward inhibition to LA principal cells, a putative mechanism for controlling plasticity during fear learning.

Divergence of neuroimmune circuits activated by afferent and efferent vagal nerve stimulation in the regulation of inflammation.

It has previously been shown that afferent and efferent vagal nerve stimulation potently inhibits lipopolysaccharide (LPS)-induced inflammation Our data show inhibition of inflammation by efferent but not afferent vagal nerve stimulation requires T-cell derived acetylcholine We show that afferent and efferent neuroimmune circuits require β2 -adrenergic receptor signalling ABSTRACT: Chronic inflammation due to inappropriate immune cell activation can have significant effects on a variety of organ systems, reducing lifespan and quality of life. As such, highly targeted control of immune cell activation is a major therapeutic goal. Vagus nerve stimulation (VNS) has emerged as a therapeutic modality that exploits neuroimmune communication to reduce immune cell activation and consequently inflammation. Although vagal efferent fibres were originally identified as the primary driver of anti-inflammatory actions, the vagus nerve in most species of animals predominantly comprises afferent fibres. Stimulation of vagal afferent fibres can also reduce inflammation; it is, however, uncertain how these two neuroimmune circuits diverge. Here we show that afferent VNS induces a mechanism distinct from efferent VNS, ameliorating lipopolysaccharide (LPS)-induced inflammation independently of T-cell derived acetylcholine (ACh) which is required by efferent VNS. Using a β2 -adrenergic receptor antagonist (β2 -AR), we find that immune regulation induced by intact, afferent, or efferent VNS occurs in a β2- AR-dependent manner. Together, our findings indicate that intact VNS activates at least two distinct neuroimmune circuits each with unique mechanisms of action. Selective targeting of either the vagal efferent or afferent fibres may provide more personalized, robust and effective control over inappropriate immune responses.

Discriminability of multiple cutaneous and proprioceptive hand percepts evoked by intraneural stimulation with Utah slanted electrode arrays in human amputees

BackgroundElectrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity.MethodsWe implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations.ResultsParticipants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p < 0.0001) and seven different proprioceptive location-intensity combinations (21/40 successes, p < 0.0001). Variations in the site of stimulation within the nerve, via electrode selection, enabled discrimination among up to five locations and qualities (35/35 successes, p < 0.0001). Variations in the stimulation frequency enabled discrimination among four different intensities at the same location (13/20 successes, p < 0.0005). One participant also discriminated among individual stimulation of two different USEA electrodes, simultaneous stimulation on both electrodes, and interleaved stimulation on both electrodes (20/24 successes, p < 0.0001).ConclusionElectrode location, stimulation frequency, and stimulation pattern can be modulated to evoke functionally discriminable sensations with a range of locations, qualities, and intensities. This rich source of artificial sensory feedback may enhance functional performance and embodiment of bionic arms endowed with a sense of touch.

Suppressing synchronous firing of epileptiform activity by high-frequency stimulation of afferent fibers in rat hippocampus.

AimsDeep brain stimulation (DBS) is a promising technology for treating epilepsy. However, the efficacy and underlying mechanisms of the high‐frequency stimulation (HFS) utilized by DBS to suppress epilepsy remain uncertain. Previous studies have shown that HFS can desynchronize the firing of neurons. In this study, we investigated whether the desynchronization effects of HFS can suppress epileptiform events.MethodsHFS trains with seconds of duration (short) and a minute of duration (long) were applied at the afferent fibers (ie, Schaffer collaterals) of the hippocampal CA1 region in anesthetized rats in vivo. The amplitude and the rate of population spikes (PS) appeared in the downstream of stimulation were calculated to evaluate the intensity of synchronized firing of neuronal populations between short and long HFS groups. A test of paired‐pulse depression (PPD) was used to assess the alteration of inhibitory neuronal circuits.ResultsThe sustained stimulation of a 60‐s long HFS suppressed the afterdischarges that were induced by a 5‐s short HFS to impair the local inhibitions. During the sustained HFS, the mean PS amplitude reduced significantly and the burst firing decreased, while the amount of neuronal firing did not change significantly. The paired‐pulse tests showed that with a similar baseline level of small PS2/PS1 ratio indicating a strong PPD, the 5‐s HFS increased the PS2/PS1 ratio to a value that was significantly greater than the corresponding ratio during sustained HFS, indicating that the PPD impaired by a short HFS may be restored by a sustained HFS.ConclusionsThe sustained HFS can desynchronize the population firing of epileptiform activity and accelerate a recovery of inhibitions to create a balance between the excitation and the inhibition of local neuronal circuits. The study provides new clues for further understanding the mechanism of DBS and for advancing the clinical application of DBS in treating epilepsy.

Chronic Electrical Stimulation of the Superior Laryngeal Nerve in the Rat: A Potential Therapeutic Approach for Postmenopausal Osteoporosis.

Electrical stimulation of myelinated afferent fibers of the superior laryngeal nerve (SLN) facilitates calcitonin secretion from the thyroid gland in anesthetized rats. In this study, we aimed to quantify the electrical SLN stimulation-induced systemic calcitonin release in conscious rats and to then clarify effects of chronic SLN stimulation on bone mineral density (BMD) in a rat ovariectomized disease model of osteoporosis. Cuff electrodes were implanted bilaterally on SLNs and after two weeks recovery were stimulated (0.5 ms, 90 microampere) repetitively at 40 Hz for 8 min. Immunoreactive calcitonin release was initially measured and quantified in systemic venous blood plasma samples from conscious healthy rats. For chronic SLN stimulation, stimuli were applied intermittently for 3–4 weeks, starting at five weeks after ovariectomy (OVX). After the end of the stimulation period, BMD of the femur and tibia was measured. SLN stimulation increased plasma immunoreactive calcitonin concentration by 13.3 ± 17.3 pg/mL (mean ± SD). BMD in proximal metaphysis of tibia (p = 0.0324) and in distal metaphysis of femur (p = 0.0510) in chronically SLN-stimulated rats was 4–5% higher than that in sham rats. Our findings demonstrate chronic electrical stimulation of the SLNs produced enhanced calcitonin release from the thyroid gland and partially improved bone loss in OVX rats.

Large-scale functional ultrasound imaging of the spinal cord reveals in-depth spatiotemporal responses of spinal nociceptive circuits in both normal and inflammatory states.

Despite a century of research on the physiology/pathophysiology of the spinal cord in chronic pain condition, the properties of the spinal cord were rarely studied at the large-scale level from a neurovascular point of view. This is mostly due to the limited spatial and/or temporal resolution of the available techniques. Functional ultrasound imaging (fUS) is an emerging neuroimaging approach that allows, through the measurement of cerebral blood volume, the study of brain functional connectivity or functional activations with excellent spatial (100 μm) and temporal (1 msec) resolutions and a high sensitivity. The aim of this study was to increase our understanding of the spinal cord physiology through the study of the properties of spinal hemodynamic response to the natural or electrical stimulation of afferent fibers. Using a combination of fUS and ultrasound localization microscopy, the first step of this study was the fine description of the vascular structures in the rat spinal cord. Then, using either natural or electrical stimulations of different categories of afferent fibers (Aβ, Aδ, and C fibers), we could define the characteristics of the typical hemodynamic response of the rat spinal cord experimentally. We showed that the responses are fiber-specific, located ipsilaterally in the dorsal horn, and that they follow the somatotopy of afferent fiber entries in the dorsal horn and that the C-fiber response is an N-methyl-D-aspartate receptor-dependent mechanism. Finally, fUS imaging of the mesoscopic hemodynamic response induced by natural tactile stimulations revealed a potentiated response in inflammatory condition, suggesting an enhanced response to allodynic stimulations.

Distinct Age-Dependent C Fiber-Driven Oscillatory Activity in the Rat Somatosensory Cortex.

When skin afferents are activated, the sensory signals are transmitted to the spinal cord and eventually reach the primary somatosensory cortex (S1), initiating the encoding of the sensory percept in the brain. While subsets of primary afferents mediate specific somatosensory information from an early age, the subcortical pathways that transmit this information undergo striking changes over the first weeks of life, reflected in the gradual emergence of specific sensory behaviors. We therefore hypothesized that this period is associated with differential changes in the encoding of incoming afferent volleys in S1. To test this, we compared S1 responses to A fiber skin afferent stimulation and A + C skin afferent fiber stimulation in lightly anaesthetized male rats at postnatal day (P)7, P14, P21, and P30. Differences in S1 activity following A and A + C fiber stimulation changed dramatically over this period. At P30, A + C fiber stimulation evoked significantly larger γ, β, and α energy increases compared with A fiber stimulation alone. At younger ages, the changes in S1 oscillatory activity evoked by the two afferent volleys were not significantly different. Silencing TRPV1+ C fibers with QX-314 significantly reduced the γ and β S1 oscillatory energy increases evoked by A + C fibers, at P30 and P21, but not at younger ages. Thus, C fibers differentially modulate S1 oscillatory activity only from the third postnatal week, well after the functional maturation of the somatosensory cortex. This age-related change in afferent evoked S1 oscillatory activity may underpin the maturation of sensory discrimination in the developing brain.