Focused ultrasound excites action potentials in mammalian peripheral neurons in part through the mechanically gated ion channel PIEZO2.

Neurons of the peripheral nervous system (PNS) are tasked with diverse roles, from encoding touch, pain, and itch to interoceptive control of inflammation and organ physiology. Thus, technologies that allow precise control of peripheral nerve activity have the potential to regulate a wide range of biological processes. Noninvasive modulation of neuronal activity is an important translational application of focused ultrasound (FUS). Recent studies have identified effective strategies to modulate brain circuits; however, reliable parameters to control the activity of the PNS are lacking. To develop robust noninvasive technologies for peripheral nerve modulation, we employed targeted FUS stimulation and electrophysiology in mouse ex vivo skin-saphenous nerve preparations to record the activity of individual mechanosensory neurons. Parameter space exploration showed that stimulating neuronal receptive fields with high-intensity, millisecond FUS pulses reliably and repeatedly evoked one-to-one action potentials in all peripheral neurons recorded. Interestingly, when neurons were classified based on neurophysiological properties, we identified a discrete range of FUS parameters capable of exciting all neuronal classes, including myelinated A fibers and unmyelinated C fibers. Peripheral neurons were excited by FUS stimulation targeted to either cutaneous receptive fields or peripheral nerves, a key finding that increases the therapeutic range of FUS-based peripheral neuromodulation. FUS elicited action potentials with millisecond latencies compared with electrical stimulation, suggesting ion channel­mediated mechanisms. Indeed, FUS thresholds were elevated in neurons lacking the mechanically gated channel PIEZO2. Together, these results demonstrate that transcutaneous FUS drives peripheral nerve activity by engaging intrinsic mechanotransduction mechanisms in neurons [B. U. Hoffman, PhD thesis, (2019)].

Technical Note: Modulation of fMRI brainstem responses by transcutaneous vagus nerve stimulation.

Our increasing knowledge about gut-brain interaction is revolutionising the understanding of the links between digestion, mood, health, and even decision making in our everyday lives. In support of this interaction, the vagus nerve is a crucial pathway transmitting diverse gut-derived signals to the brain to monitor of metabolic status, digestive processes, or immune control to adapt behavioural and autonomic responses. Hence, neuromodulation methods targeting the vagus nerve are currently explored as a treatment option in a number of clinical disorders, including diabetes, chronic pain, and depression. The non-invasive variant of vagus nerve stimulation (VNS), transcutaneous auricular VNS (taVNS), has been implicated in both acute and long-lasting effects by modulating afferent vagus nerve target areas in the brain. The physiology of neither of those effects is, however, well understood, and evidence for neuronal response upon taVNS in vagal afferent projection regions in the brainstem and its downstream targets remain to be established. Therefore, to examine time-dependent effects of taVNS on brainstem neuronal responses in healthy human subjects, we applied taVNS during task-free fMRI in a single-blinded crossover design. During fMRI data acquisition, we either stimulated the left earlobe (sham), or the target zone of the auricular branch of the vagus nerve in the outer ear (cymba conchae, verum) for several minutes, both followed by a short 'stimulation OFF' period. Time-dependent effects were assessed by averaging the BOLD response for consecutive 1-minute periods in an ROI-based analysis of the brainstem. We found a significant response to acute taVNS stimulation, relative to the control condition, in downstream targets of vagal afferents, including the nucleus of the solitary tract, the substantia nigra, and the subthalamic nucleus. Most of these brainstem regions remarkably showed increased activity in response to taVNS, and these effect sustained during the post-stimulation period. These data demonstrate that taVNS activates key brainstem regions, and highlight the potential of this approach to modulate vagal afferent signalling. Furthermore, we show that carry-over effects need to be considered when interpreting fMRI data in the context of general vagal neurophysiology and its modulation by taVNS.

Anatomy of Trigeminal Neuromodulation Targets: From Periphery to the Brain.

The trigeminal nerve complex is a very important and somewhat unique component of the nervous system. It is responsible for the sensory signals that arise from the most part of the face, mouth, nose, meninges, and facial muscles, and also for the motor commands carried to the masticatory muscles. These signals travel through a very complex set of structures: dermal receptors, trigeminal branches, Gasserian ganglion, central nuclei, and thalamus, finally reaching the cerebral cortex. Other neural structures participate, directly or indirectly, in the transmission and modulation of the signals, especially the nociceptive ones; these include vagus nerve, sphenopalatine ganglion, occipital nerves, cervical spinal cord, periaqueductal gray matter, hypothalamus, and motor cortex. But not all stimuli transmitted through the trigeminal system are perceivable. There is a constant selection and modulation of the signals, with either suppression or potentiation of the impulses. As a result, either normal sensory perceptions are elicited or erratic painful sensations are created. Electrical neuromodulation refers to adjustable manipulation of the central or peripheral pain pathways using electrical current for the purpose of reversible modification of the function of the nociceptive system through the use of implantable devices. Here, we discuss not only the distal components, the nerve itself, but also the sensory receptors and the main central connections of the brain, paying attention to the possible neuromodulation targets.

Functional spectroscopic imaging reveals specificity of glutamate response in mouse brain to peripheral sensory stimulation.

Non-invasive investigation of physiological changes and metabolic events associated with brain activity in mice constitutes a major challenge. Conventionally, fMRI assesses neuronal activity by evaluating activity-evoked local changes in blood oxygenation levels (BOLD). In isoflurane-anaethetized mice, however, we found that BOLD signal changes during paw stimulation appear to be dominated by arousal responses even when using innocuous stimuli. Widespread responses involving both hemispheres have been observed in response to unilateral stimulation. MRS allows probing metabolic changes associated with neuronal activation and provides a complementary readout to BOLD fMRI for investigating brain activity. In this study we evaluated the sensitivity of a free induction decay (FID) based spectroscopic imaging (MRSI) protocol for the measurement of alterations in glutamate levels elicited by unilateral electrical paw stimulation at different current amplitudes. Coronal MRSI maps of glutamate distribution with 17 × 17 voxels of 1 µl volume have been recorded with a temporal resolution of 12 min. Significant region-specific increases in glutamate levels have been observed in the contralateral but not in the ispiateral S1 somatosensory cortex upon stimulation. The amplitude of glutamate changes increased in a dose-dependent manner with the stimulus amplitude. The study demonstrates feasibility of functional MRSI in mice for studying activity-evoked glutamate changes in a temporo-spatially resolved manner.

Neural responses to electrical stimulation in 2D and 3D in vitro environments.

Electrical stimulation (ES) to manipulate the central (CNS) and peripheral nervous system (PNS) has been explored for decades, recently gaining momentum as bioelectronic medicine advances. The application of ES in vitro to modulate a variety of cellular functions, including regenerative potential, migration, and stem cell fate, are being explored to aid neural degeneration, dysfunction, and injury. This review describes the materials and approaches for the application of ES to the PNS and CNS microenvironments, towards an improved understanding of how ES can be harnessed for beneficial clinical applications. Emphasized are some recent advances in ES, including conductive polymers, methods of charge transfer, impact on neural cells, and a brief overview of alternative methodologies for cellular targeting including magneto, ultrasonic, and optogenetic stimulation. This review will examine how heterogenous cell populations, including neurons, glia, and neural stem cells respond to a wide range of conductive 2D and 3D substrates, stimulation regimes, known mechanisms of response, and how cellular sources impact the response to ES.

The effects of electrical stimulation of the peripheral vestibular system on neurochemical release in the rat striatum.

For over a century, it has been speculated that the vestibular system transmits information about self-motion to the striatum. There have been inconsistent reports of such a connection, and interest in the subject has been increased by the experimental use of galvanic vestibular stimulation in the treatment of Parkinson's Disease patients. Nonetheless, there are few data available on the effects of vestibular stimulation on neurochemical changes in the striatum. We used in vivo microdialysis to analyse changes in the extracellular levels of amino acids and monoamines in the rat striatum, following electrical vestibular stimulation. Stimulation caused a significant decrease in serine and threonine, compared to the no-stimulation controls (P ≤ 0.005 and P ≤ 0.01, respectively). The ratio of DOPAC:dopamine, decreased on the ipsilateral side following stimulation (P ≤ 0.005). There was a significant treatment x side x intensity interaction for taurine levels (P ≤ 0.002), due to a decrease on the contralateral side in stimulated animals, which varied as a function of current. These results show that peripheral vestibular stimulation causes some neurochemical changes in the striatum and support the view that activaton of the vestibular system exerts effects on the function of the striatum.

Signalling from the periphery to the brain that regulates energy homeostasis.

The CNS regulates body weight; however, we still lack a clear understanding of what drives decisions about when, how much and what to eat. A vast array of peripheral signals provides information to the CNS regarding fluctuations in energy status. The CNS then integrates this information to influence acute feeding behaviour and long-term energy homeostasis. Previous paradigms have delegated the control of long-term energy homeostasis to the hypothalamus and short-term changes in feeding behaviour to the hindbrain. However, recent studies have identified target hindbrain neurocircuitry that integrates the orchestration of individual bouts of ingestion with the long-term regulation of energy balance.

Combined Brain and Peripheral Nerve Stimulation in Chronic Stroke Patients With Moderate to Severe Motor Impairment.

OBJECTIVES: To evaluate effects of somatosensory stimulation in the form of repetitive peripheral nerve sensory stimulation (RPSS) in combination with transcranial direct current stimulation (tDCS), tDCS alone, RPSS alone, or sham RPSS + tDCS as add-on interventions to training of wrist extension with functional electrical stimulation (FES), in chronic stroke patients with moderate to severe upper limb impairments in a crossover design. We hypothesized that the combination of RPSS and tDCS would enhance the effects of FES on active range of movement (ROM) of the paretic wrist to a greater extent than RPSS alone, tDCS alone or sham RPSS + tDCS. MATERIALS AND METHODS: The primary outcome was the active ROM of extension of the paretic wrist. Secondary outcomes were ROM of wrist flexion, grasp, and pinch strength of the paretic and nonparetic upper limbs, and ROM of wrist extension of the nonparetic wrist. Outcomes were blindly evaluated before and after each intervention. Analysis of variance with repeated measures with factors "session" and "time" was performed. RESULTS: After screening 2499 subjects, 22 were included. Data from 20 subjects were analyzed. There were significant effects of "time" for grasp force of the paretic limb and for ROM of wrist extension of the nonparetic limb, but no effects of "session" or interaction "session x time." There were no significant effects of "session," "time," or interaction "session x time" regarding other outcomes. CONCLUSIONS: Single sessions of PSS + tDCS, tDCS alone, or RPSS alone did not improve training effects in chronic stroke patients with moderate to severe impairment.

Unraveling the Mechanisms of Manual Therapy: Modeling an Approach.

Synopsis Manual therapy interventions are popular among individual health care providers and their patients; however, systematic reviews do not strongly support their effectiveness. Small treatment effect sizes of manual therapy interventions may result from a "one-size-fits-all" approach to treatment. Mechanistic-based treatment approaches to manual therapy offer an intriguing alternative for identifying patients likely to respond to manual therapy. However, the current lack of knowledge of the mechanisms through which manual therapy interventions inhibit pain limits such an approach. The nature of manual therapy interventions further confounds such an approach, as the related mechanisms are likely a complex interaction of factors related to the patient, the provider, and the environment in which the intervention occurs. Therefore, a model to guide both study design and the interpretation of findings is necessary. We have previously proposed a model suggesting that the mechanical force from a manual therapy intervention results in systemic neurophysiological responses leading to pain inhibition. In this clinical commentary, we provide a narrative appraisal of the model and recommendations to advance the study of manual therapy mechanisms. J Orthop Sports Phys Ther 2018;48(1):8-18. doi:10.2519/jospt.2018.7476.

Peripheral sensory stimulation is neuroprotective in a rat photothrombotic ischemic stroke model.

Ischemic stroke is one of the leading causes of death and disability in the world. Thrombolytic therapy using recombinant tissue plasminogen activator (rtPA), the only FDA-approved drug for acute ischemia, is limited by a narrow therapeutic time window and risk of hemorrhage. There is a serious need for a neuroprotective therapy which is clinically viable. We earlier demonstrated that peripheral sensory stimulation (PSS) is a potential therapeutic intervention for hyperacute ischemia resulting in recovery of neurovascular functions when administered immediately following ischemia onset in a rat model. Here, we investigated the potential neuroprotective effect of PSS during the hyperacute phase of stroke in a rat photothrombotic ischemia (PTI) model. We employed electrocorticography (ECoG) to image cortical neural activity responses pre-and post-ischemia. Results showed that the neural activity including somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were restored following administration of PSS. Further, immunohistochemistry and TTC staining also indicated the neuroprotective effect of PSS intervention, protecting more neurons and reduced infarct. Overall, the study demonstrated that PSS administered immediately following ischemia induction in a rat PTI model can significantly promote neuroprotection via inhibition of peri-infarct expansion and enhanced cortical neural activity functions, suggesting effective recovery. Future work utilizing multimodal imaging to probe changes in neurovascular functions, will explore application of PSS as an adjuvant intervention for improving rtPA thrombolysis therapy.

Cannabidiol and endogenous opioid peptide-mediated mechanisms modulate antinociception induced by transcutaneous electrostimulation of the peripheral nervous system.

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological therapy for the treatment of pain. The present work investigated the effect of cannabidiol, naloxone and diazepam in combination with 10 Hz and 150 Hz TENS. Male Wistar rats were submitted to the tail-flick test (baseline), and each rodent received an acute administration (intraperitoneal) of naloxone (3.0mg/kg), diazepam (1.5mg/kg) or cannabidiol (0.75 mg/kg, 1.5mg/kg, 3.0mg/kg, 4.5mg/kg, 6.0mg/kg and 12.0mg/kg); 10 min after the acute administration, 10 Hz or 150 Hz TENS or a sham procedure was performed for 30 min. Subsequently, tail-flick measures were recorded over a 90-min period, at 5-min intervals. 10 Hz TENS increased the nociceptive threshold during the 90-min period. This antinociceptive effect was reversed by naloxone pre-treatment, was not altered by diazepam pre-treatment and was abolished by cannabidiol pre-treatment (1.5mg/kg). Moreover, 150 Hz TENS increased tail-flick latencies by 35 min post-treatment, which was partially inhibited by naloxone pre-treatment and totally inhibited by cannabidiol (1.5mg/kg). These data suggest the involvement of the endogenous opioid system and the cannabinoid-mediated neuromodulation of the antinociception induced by transcutaneous electrostimulation at 10 Hz and 150 Hz TENS.

Spinal cord stimulation (SCS) in conjunction with peripheral nerve field stimulation (PNfS) for the treatment of complex pain in failed back surgery syndrome (FBSS).

BACKGROUND: Failed back surgery syndrome (FBSS) is a well-defined pathologic condition observed over many years. DESIGN: We have investigated the effect of spinal cord stimulation (SCS) with peripheral nerve field stimulation (PNfS) in eight patients with FBSS. OUTCOME MEASURE: The following parameters were collected and analyzed: The pain intensity score on a 0-10 numbering rating scale (NRS), the psychologic profile with Beck Depression Inventory (BDI), the pain quality with McGill Pain Questionnaire-short form (MGPQ-sf), the back pain with Oswestry scale score (OS), and the health general quality pattern with QualityMetric's SF-36v2(®) Health Survey. PATIENTS: Eight patients with low back and radicular pain in FBSS are reported. The mean duration of pain was 6.7 months, and the mean NRS score was 9.5, BDI 28.8, MGPQ-sf 16.8, OS 44.5, and SF-36 score was 72.8. The average drug intake of opioids was 250 mg/day. INTERVENTION: In six patients, two octopolar leads were placed in epidural space at D7-D8 and D8-D9, in conjunction with two octopolar leads placed in lumbar-sacral subcutaneous space (Precision System, Boston Scientific, Valencia, CA, USA), and in two patients, a two tetrapolar leads was placed in epidural space at D8-D9 with two tetrapolar leads (Pisces Quad, Plus, Medtronic Inc., Minneapolis, MN, USA) placed in lumbar-sacral subcutaneous space (Restore Ultra, Medtronic Inc., Minneapolis, MN, USA). RESULTS: After one year mean of follow-up, the mean NRS score was 4, BDI 8, MGPQ-sf 5, OS 21, and the SF-36 score was increased at 108.5. The mean drug intake of opioids was decreased at 20 mg/day. CONCLUSION: The combination of SCS and PNfS, using the latest rechargeable systems, may be a valid therapeutic strategy in FBSS.

In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration.

In the peripheral nervous system (PNS), damaged axons regenerate successfully, whereas axons in the CNS fail to regrow. In neurons of the dorsal root ganglia (DRG), which extend branches to both the PNS and CNS, only a PNS lesion but not a CNS lesion induces axonal growth. How this differential growth response is regulated in vivo is only incompletely understood. Here, we combine in vivo time-lapse fluorescence microscopy with genetic manipulations in mice to reveal how the transcription factor STAT3 regulates axonal regeneration. We show that selective deletion of STAT3 in DRG neurons of STAT3-floxed mice impairs regeneration of peripheral DRG branches after a nerve cut. Further, overexpression of STAT3 induced by viral gene transfer increases outgrowth and collateral sprouting of central DRG branches after a dorsal column lesion by more than 400%. Notably, repetitive in vivo imaging of individual fluorescently labeled PNS and CNS axons reveals that STAT3 selectively regulates initiation but not later perpetuation of axonal growth. With STAT3, we thus identify a phase-specific regulator of axonal outgrowth. Activating STAT3 might provide an opportunity to "jumpstart" regeneration, and thus prime axons in the injured spinal cord for application of complementary therapies that improve axonal elongation.

Stimulation of the peripheral nervous system for the painful extremity.

Peripheral nerve stimulation and, recently, peripheral nerve field stimulation are excellent options for the control of extremity pain in instances where conventional methods have failed and surgical treatment is ruled inappropriate. New techniques, ultrasound guidance, smaller generators, and task-specific neuromodulatory hardware and leads result in increasingly safe, stable and efficacious treatment of pain in the extremities. Peripheral nerve stimulation has shown to be an increasingly viable option for many painful conditions with neuropathic and possibly nociceptive origins. This chapter focuses on the historical use of neuromodulation in the extremities, technical tasks associated with implant, selection of candidates, and potential pitfalls of and solutions for implanting devices around the peripheral nervous system for extremity pain.

Peripheral responses to attended and unattended angry prosody: a dichotic listening paradigm.

We investigated the effects of angry prosody, varying focus of attention, and laterality of presentation of angry prosody on peripheral nervous system activity. Participants paid attention to either their left or their right ear while performing a sex discrimination task on dichotically presented pseudo-words. These pseudo-words were characterized by either angry or neutral prosody and presented stereophonically (anger/neutral, neutral/anger, or neutral/neutral, for the left/right ear, respectively). Reaction times and physiological responses (heart period, skin conductance, finger and forehead temperature) in this study were differentially sensitive to the effects of anger versus neutral prosody, varying focus of attention, and laterality of presentation of angry prosody.

Effects and mechanisms of electroacupuncture on glucagon-induced small intestinal hypomotility in dogs.

BACKGROUND: Little is known on the effect of electroacupuncture (EA) (Br Med J, 2, 1976, 1225) on intestinal motility. The aim of this study was to investigate effects and mechanisms of EA on small intestinal contractions, transit, and slow waves in dogs. METHODS: Six dogs were equipped with two intestinal cannulas for the measurement of small intestinal contractions and transit. Glucagon was used to induce postprandial intestinal hypomotility. Each dog was studied in five randomized sessions: Control, glucagon, glucagon + EA, glucagon + EA + naloxone, and glucagon + EA + atropine. KEY RESULTS: 1 In the fasting state, EA induced intestinal contractions during motor quiescence (contractile index or CI: 4.4 ± 0.8 VS 8.3 ± 0.7, P < 0.05). 2 In the fed state, EA improved glucagon-induced intestinal hypomotility (CI: 3.8 ± 0.4 VS 6.1 ± 0.6, P < 0.05). 3 Electroacupuncture accelerated intestinal transit delayed by glucagon (67.9 ± 4.3 VS 40.2 ± 5.0 min, P < 0.05). 4 There was a negative correlation between the CI and the total transit time (R(2) = 0.59, P < 0.05). 5 The excitatory effect of EA was blocked by naloxone and partially blocked by atropine. 6 The percentage of normal slow waves was reduced with glucagon (70 ± 2%VS 98 ± 1% at baseline, P = 0.0015). Electroacupuncture normalized impaired slow waves and the effect was blocked by naloxone. CONCLUSIONS & INFERENCES: Electroacupuncture enhances intestinal contractions during Phase I of the migrating motor complex and glucagon-induced hypomotility in the fed state, and accelerates intestinal transit via the opioid and cholinergic pathways in dogs. Electroacupuncture may have a therapeutic potential for intestinal hypomotility.

Transcuticular optical imaging of stimulus-evoked neural activities in the Drosophila peripheral nervous system.

The nervous system of Drosophila is widely used to study neuronal signal processing because the activities of neurons can be controlled and monitored by cell type-specific expression of genetically encoded actuator and sensor proteins. Measuring neural activities in adult flies, however, usually requires surgical approaches to penetrate the firm and pigmented cuticular exoskeleton. Interfering with this exoskeleton is critical in the case of the peripheral nervous system (PNS), as sensory neurons are often located directly beneath the cuticle and are associated with specialized stimulus-receiving and -conducting cuticular structures. In this article, we describe how the activities of these neurons can be probed nondestructively through the cuticle if a genetically encoded fluorescent protein sensor with strong baseline fluorescence is used. The method is exemplified for mechanosensory neurons in the adult antenna but can also be applied to many other PNS neurons, as is shown for the femoral chordotonal organ located in the fly's leg.

Chemotherapy-induced peripheral neuropathy: clinical features, diagnosis, prevention and treatment strategies.

Chemotherapy-induced peripheral neuropathy (CIN) is a common toxicity of anticancer treatment and its incidence is growing. It significantly affects quality of life and is a dose-limiting factor that interferes with treatment. Its diagnosis can be established in clinical terms but some complementary tests can help when the diagnosis is difficult. There is still no proven method to prevent it that has become a standard of care in spite of the huge amount of investigation carried out in recent years. There are promising strategies that could help reduce the burden of this complication. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.

Neuroactive steroids: an update of their roles in central and peripheral nervous system.

After five editions, the congress on "Steroids and Nervous System" held in Torino, Italy, represents an important international event for researchers involved in this field aimed to recapitulate mechanisms, physiological and pharmacological effects of neuroactive steroids. The present review introduces manuscripts collected in this supplement issue which are based on new interesting findings such as the influence of sex steroids on cannabinoid-regulated biology, the role of steroids in pain, the importance of co-regulators in steroidal mechanisms and the understanding of new non classical mechanism, the emerging role of vitamin D as a neuroactive steroid and the pathogenetic mechanisms mediated by glucocorticoid receptors. Finally, we have integrated these aspects with an update on some of the several and important observations recently published on this hot topic.