Luteinizing hormone-releasing hormone and oxytocin response to hyperosmotic stimulation: in vitro study

It was shown previously that luteinizing hormone-releasing hormone (LHRH) affects the neurohypophysial oxytocin release in water-deprived rats. However, the detailed mechanisms by which LHRH modifies the oxytocin response to hyperosmotic stimulation have not been explained so far. Using the isolated hypothalamo-neurohypophysial explants obtained from euhydrated rats, the effect of LHRH on the oxytocin secretion was studied under conditions of direct osmotic (i.e., Na(+)- evoked) as well as nonosmotic (i.e., K(+)-evoked) stimulation. Additionally, the oxytocin response to LHRH was investigated using the explants obtained from animals drinking 2% saline for eight days (systemic, i. e., both direct and indirect, osmotic stimulation). LHRH significantly enhanced Na(+)- and K(+)-evoked oxytocin release from explants taken from rats drinking tap water, indicating that LHRH could affect the Na(+)/K(+)-dependent depolarization of perikarya of oxytocin neurones. In contrast, LHRH significantly diminished the K(+)-stimulated hormone release when the neurohypophysial complex was obtained from previously salt-loaded rats, suggesting that peripheral osmotic stimulation somehow modifies the sensitivity of oxytocinergic neurones to LHRH (possible mechanisms are discussed). It is concluded that LHRH may participate in the regulation of oxytocin secretion via both direct and indirect impact on magnocellular oxytocinergic neurones depending on the current functional status of the hypothalamo-neurohypophysial complex.     

Brain stimulation: a therapeutic approach for the treatment of neurological disorders

Brain stimulation has become one of the most acceptable therapeutic approaches in recent years and a powerful tool in the remedy against neurological diseases. Brain stimulation is achieved through the application of electric currents using non-invasive as well as invasive techniques. Recent technological advancements have evolved into the development of precise devices with capacity to produce well-controlled and effective brain stimulation. Currently, most used non-invasive techniques are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), whereas the most common invasive technique is deep brain stimulation (DBS). In last decade, application of these brain stimulation techniques has not only exploded but also expanded to wide variety of neurological disorders. Therefore, in the current review, we will provide an overview of the potential of both non-invasive (rTMS and tDCS) and invasive (DBS) brain stimulation techniques in the treatment of such brain diseases.     

Existing and emerging applications for the neuromodulation of nerve activity through targeted delivery of electric stimuli

Abstract

The effective treatment of many diseases requires the use of multiple treatment strategies among which neuromodulation is playing an increasingly important role. Neuromodulation devices that act to normalize or modulate nerve activity through the targeted delivery of electrical stimuli will be the focus of this review. These devices encompass deep brain stimulators, vagus nerve stimulators, spinal cord simulators and sacral nerve stimulators. Already neuromodulation has proven successful in the treatment of a broad range of conditions from Parkinson’s disease to chronic pain and urinary incontinence. Many of these approaches seek to exploit the activities of the autonomic nervous system, which influences organ function through the release of neurotransmitters and associated signalling cascades. This review will outline existing and emerging applications for each of these neuromodulation devices, proposed mechanisms of action and clinical studies evaluating both their safety and therapeutic efficacy.     

Non pharmacological treatment for neuropathic pain: Invasive and non-invasive cortical stimulation

The use of medications in chronic neuropathic pain may be limited with regard to efficacy and tolerance. Therefore, non-pharmacological approaches, using electrical stimulation of the cortex has been proposed as an alternative. First, in the early nineties, surgically-implanted epidural motor cortex stimulation (EMCS) was proven to be effective to relieve refractory neuropathic pain. Later, non-invasive stimulation techniques were found to produce similar analgesic effects, at least by means of repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1). Following “high-frequency” rTMS (e.g., stimulation frequency ranging from 5 to 20 Hz) delivered to the precentral gyrus (e.g., M1 region), it is possible to obtain an analgesic effect via the modulation of several remote brain regions involved in nociceptive information processing or control. This pain reduction can last for weeks beyond the time of the stimulation, especially if repeated sessions are performed, probably related to processes of long-term synaptic plasticity. Transcranial direct current stimulation (tDCS), another form of transcranial stimulation, using low-intensity electrical currents, generally delivered by a pair of large electrodes, has also shown some efficacy to improve patients with chronic pain syndromes. The mechanism of action of tDCS differs from that of EMCS and rTMS, but the cortical target is the same, which is M1. Although the level of evidence of therapeutic efficacy in the context of neuropathic pain is lower for tDCS than for rTMS, interesting perspectives are opened by using at-home tDCS protocols for long-term management. Now, there is a scientific basis for recommending both EMCS and rTMS of M1 to treat refractory chronic neuropathic pain, but their application in clinical practice remains limited due to practical and regulatory issues.     

Evidence for peripheral, but not central modulation of trigeminal cold receptive cells in the rat

The effects of locus coeruleus (LC), periaqueductal grey (PAG) and segmental stimulation (all of which are known to inhibit convergent nociceptive cells), were tested on the activity of cold receptive cells in the trigeminal system of the rat. LC and PAG stimulation from sites which inhibited convergent nociceptive cells had no effect on cells with cold receptive input in the trigeminal nucleus caudalis. Electrical or mechanical segmental stimulation caused suppression of activity in cold receptive trigeminal nucleus neurons. Recording from the trigeminal ganglion showed this suppression to be a property of the primary afferent cold receptors themselves and therefore it is not analogous to the proposed mechanism for the segmental inhibition of convergent nociceptive neurons.     

Preferential activation of muscle fibers with peripheral magnetic stimulation of the limb

Magnetic and electric activation of limb nerve and muscle were compared in normal subjects of different age, gender, and habitus. Direct stimulation of nerve and muscle showed that activation of intramuscular nerve fibers in the arm and leg occurs at a lower threshold for magnetic stimulation than for electric stimulation. Sensory nerve fibers had a lower threshold with electric stimulation. Muscle activation and stimulus artifact with magnetic stimulation precluded reliable recording of distal sensory nerve action potential in all subjects.     

Therapeutic potential of brain stimulation techniques in the treatment of mental,psychiatric, and cognitive disorders

Treatment for brain diseases has been disappointing because available medications have failed to produce clinical response across all the patients. Many patients either do not respond or show partial and inconsistent effect, and even in patients who respond to the medications have high relapse rates. Brain stimulation has been seen as an alternative and effective remedy. As a result, brain stimulation has become one of the most valuable therapeutic tools for combating against brain diseases. In last decade, studies with the application of brain stimulation techniques not only have grown exponentially but also have expanded to wide range of brain disorders. Brain stimulation involves passing electric currents into the cortical and subcortical area brain cells with the use of noninvasive as well as invasive methods to amend brain functions. Over time, technological advancements have evolved into the development of precise devices; however, at present, most used noninvasive techniques are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), whereas the most common invasive technique is deep brain stimulation (DBS). In the current review, we will provide an overview of the potential of noninvasive (rTMS and tDCS) and invasive (DBS) brain stimulation techniques focusing on the treatment of mental, psychiatric, and cognitive disorders.     

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19.ObjectiveTo facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS).MethodsThe present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research – with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics.ResultsA model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described.ConclusionThere is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.     

Challenges of proper placebo control for non‐invasive brain stimulation in clinical and experimental applications

A range of techniques are now available for modulating the activity of the brain in healthy people and people with neurological conditions. These techniques, including transcranial magnetic stimulation (TMS) and transcranial current stimulation (tCS, which includes direct and alternating current), create magnetic or electrical fields that cross the intact skull and affect neural processing in brain areas near to the scalp location where the stimulation is delivered. TMS and tCS have proved to be valuable tools in behavioural neuroscience laboratories, where causal involvement of specific brain areas in specific tasks can be shown. In clinical neuroscience, the techniques offer the promise of correcting abnormal activity, such as when a stroke leaves a brain area underactive. As the use of brain stimulation becomes more commonplace in laboratories and clinics, we discuss the safety and ethical issues inherent in using the techniques with human participants, and we suggest how to balance scientific integrity with the safety of the participant.     

Analgesic Efficacy of “Burst” and Tonic (500 Hz) Spinal Cord Stimulation Patterns: A Randomized Placebo-Controlled Crossover Study

ObjectiveSThe aim of this study was to compare the efficacy in reducing pain intensity in adult subjects suffering from chronic back and leg pain of burst (BST) and tonic sub-threshold stimulation at 500 Hz (T500) vs. sham stimulation delivered by a spinal cord stimulation (SCS) device capable of automated postural adjustment of current intensity.Materials and MethodsA multicentre randomized double-blind, three-period, three-treatment, crossover study was undertaken at two centers in the United Kingdom. Patients who had achieved stable pain relief with a conventional SCS capable of automated postural adjustment of current intensity were randomized to sequences of BST, T500, and sham SCS with treatment order balanced across the six possible sequences. A current leakage was programmed into the implantable pulse generator (IPG) in the sham period. The primary outcome was patient reported pain intensity using a visual analog scale (VAS).ResultsNineteen patients were enrolled and randomized. The mean reduction in pain with T500 was statistically significantly greater than that observed with either sham (25%; 95% CI, 8%–38%; p = 0.008) or BST (28%; 95% CI, 13%–41%; p = 0.002). There were no statistically significant differences in pain VAS for BST versus Sham (5%; 95% CI, −13% to 27%; p = 0.59). Exploratory sub-group analyses by study site and sex were also conducted for the T500 vs. sham and BST versus sham comparisons.ConclusionsThe findings suggest a superior outcome versus sham from T500 stimulation over BST stimulation and a practical equivalence between BST and sham in a group of subjects with leg and back pain habituated to tonic SCS and having achieved a stable status with stimulation.     

Spinal associative stimulation: A non-invasive stimulation paradigm to modulate spinal excitability

Objective

Repetitive, paired peripheral and transcranial stimulation targeting the cerebral cortex can increase cortical excitability, outlasting the stimulation period. It is unknown whether paired stimulation specifically targeting the spinal cord can modulate spinal excitability. We tested whether the H-reflex facilitation from a sub-threshold conditioning TMS pulse could modulate spinal excitability if delivered repetitively.

Method

In 13 healthy subjects, we delivered single-pulse TMS (80% RMT) for the right soleus muscle, 20 ms prior to an electrical peripheral nerve stimulus delivered over the posterior tibial nerve on the same side at 0.1 Hz during 15 min.

Results

PNS alone evoked an H-reflex of 0.25 mV ± 0.06 SEM, while pairing of TMS and PNS facilitated the H-reflex to 0.7 ± 0.11 mV. TMS–PNS pairs delivered at 0.1 Hz for 15 min progressively increased in the evoked response to ∼130% (r² = 0.97) of the starting amplitude (normalized to 1st min). Post-intervention, H-reflex threshold decreased (pre = 12.9 ± 1.7 mA; post = 11.6 ± 1.6 mA; p = 0.04), as did the stimulus intensity at maximum H-reflex amplitude (pre = 23.5 ± 02.8 mA; post = 21.6 ± 2.6 mA; p = 0.03), and recruitment curve width (pre = 11.6 ± 1.5 mA; post = 10.93 ± 1.4 mA; p = 0.03). No such changes were observed with intervention of PNS or TMS alone.

Conclusion

Paired stimulation targeting spinal facilitatory interactions, when applied repetitively, can increase spinal excitability during and after the intervention.

Significance

Spinal associative stimulation may have potential for neuromodulation in spinal cord injury patients.     

Neuromodulation With Burst and Tonic Stimulation Decreases Opioid Consumption: A Post Hoc Analysis of the Success Using Neuromodulation With BURST (SUNBURST) Randomized Controlled Trial

ObjectivesThe SUNBURST study was a prospective, multicenter, randomized crossover trial of a single device delivering burst and tonic spinal cord stimulation (SCS) for chronic trunk and/or limb pain. We performed a post hoc analysis of opioid consumption at baseline and after device implantation.Materials and MethodsAfter implantation, 100 patients were randomized to one mode (tonic or burst) for 12 weeks, and the other mode for the subsequent 12 weeks. After the crossover period (24 weeks), patients chose their preferred mode and were assessed for one year. We analyzed 69 patients who took opioid medication at baseline. The primary endpoint was opioid consumption in morphine milligram equivalents (MMEs) at baseline and 12 months postimplantation. Subgroup analysis included opioid consumption based on Center for Disease Control markers (<50, 50–90, 90–120, >120 MME/day) and stimulation mode preference.ResultsOpioid consumption at 12 months was lower compared to baseline (53.94 vs. 79.19 MME, MD −25.25, 95% CI −43.77 to 6.73, p = 0.008). By 12 months, 11 of 69 patients (15.9%) discontinued all opioid (p = 0.001). Based on CDC dose markers, the proportion of patients taking >120 MME/day decreased by 61.7% at 12 months postintervention compared to baseline (p = 0.043). Forty-five of 69 patients (65.2%) preferred burst SCS while 15 of 69 patients (21.7%) preferred tonic SCS (p < 0.001).ConclusionA device delivering tonic and burst SCS was associated with decreased opioid consumption after 12 months in patients with chronic trunk and/or limb pain. The proportion of patients reporting the highest opioid intake (>120 MME/day) decreased to a lower CDC dose category by 61.7%, carrying important implications for those at highest risk for opioid-related substance use disorder, overdose, and death.     

Can transcranial electric stimulation with multiple electrodes reach deep targets?

To reach a deep target in the brain with transcranial electric stimulation (TES), currents have to pass also through the cortical surface. Thus, it is generally thought that TES cannot achieve focal deep brain stimulation. Recent efforts with interfering waveforms and pulsed stimulation have argued that one can achieve deeper or more intense stimulation in the brain. Here we argue that conventional transcranial stimulation with multiple current sources is just as effective as these new approaches. The conventional multi-electrode approach can be numerically optimized to maximize intensity or focality at a desired target location. Using such optimal electrode configurations we find in a detailed and realistic head model that deep targets may in fact be strongly stimulated, with cerebro-spinal fluid guiding currents deep into the brain.     

磁刺激运动诱发肌电位对运动机能评价的临床应用

目的：观察磁刺激运动诱发肌电位对运动机能的评价。方法：用磁刺激装置对正常人１２例，运动障碍患者３１例进行了经颅脑刺激，记录运动诱发肌电位。结果：受检测的４３例，无一例引起头痛和感觉异常，也无癫痫及意识障碍等副作用。正常人中，诱发肌电位的潜伏期相对恒定，振幅在个体间虽存有差异，但同一例左右侧几乎相同。对２０例单侧肢体功能障碍的肌力按体征分级，比较患侧和健侧的诱发肌电位，发现患侧振幅较健侧明显减低。对肌力０～２级的病例，不能诱发出肌电位。结论：磁刺激运动诱发肌电位，在临床上可在数量上正确评价肢体的运动机能，并且经颅磁刺激法是安全的。     

Four Year Follow‐up of Dual Electrode Spinal Cord Stimulation for Chronic Pain

This paper reports on 80 patients using dual electrode, spinal cord stimulation (SCS) over a four‐year period Implant status, stimulation mode, anode‐cathode configuration (array), cathode position, paresthesia overlap, explantation rates, complications, Visual Analog Scores (VAS), and overall satisfaction were examined in patients implanted with dual 8 contact, staggered, percutaneous electrodes. All patients had undergone implantation for chronic axial and extremity pain [e.g., Failed Back Surgery Syndrome (FBSS), Complex Regional Pain Syndrome (CRPS)]. Outcomes were evaluated in view of our previous reports in this same group at 24 and 30 months 1 , 2 . Data was collected by a disinterested third party. At 48 months, 18 of the original 80 patients were lost to follow‐up. Of the 62 patients contacted, 33 remained implanted and 29 (47%) had been explanted. After an average evaluation of 85 arrays (PainDoc, Advanced Neuromodulation Systems, Plano, Texas), 88% of patients reported using one or two “best” arrays (bipolar or guarded tripolar) to maintain favorable paresthesia overlap (89%), VAS reduction (8.1 to 4.9), and overall patient satisfaction (63%). These arrays were most commonly positioned about the physiologic midline of the COL3–4 vertebral segments for upper extremity pain, and the T9–10 vertebral segments for low back and lower extremity pain. In contrast to our initial reports where essentially all patients preferred more than two arrays to maintain “best” paresthesia overlap and outcome, only 12% of these same patients maintained this trend in this long‐term follow‐up study. The arrays most commonly selected long‐term as the “best” ones (88% of all electrodes) were narrow (adjacent contact) bipoles and guarded cathode tripoles (< 8 contacts). Thirty‐five percent of patients with thoracic implants achieved paresthesia in the low back at 48 months. Explantation rates and overall patient satisfaction were significantly affected by painful radio frequency (RF) antenna coupling. This data supports the efficacy of dual electrodes in optimizing long‐term SCS paresthesia overlap and complex pain outcomes.     

The use of tDCS and CVS as methods of non-invasive brain stimulation

Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson's disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).     

Changes of inhibitory interneurons during transcallosal stimulations

Summary The present study was performed in order to determine the influence of ipsilateral transcranial magnetic stimulations (TMS) on the silent period evoked by contralateral cortical stimulations. Ipsilateral TMS preceded the contralateral magnetic or electrical cortex stimulation by 0–50ms. In all subjects, the duration of the silent period was decreased in interstimulus intervals of 20–30ms when using magnetic ipsi- and contralateral stimuli. No change in the silent period was seen with ipsilateral magnetic and contralateral electrical stimulations. Decreases of motor evoked potential amplitudes were an inconsistant phenomenon.The results indicate that ipsilateral TMS in activate inhibitory cortical interneurons, probably via transcallosal pathways. Different time courses and different degrees of inhibition indicate that motor excitation and inhibition may be mediated by different neuronal circuits.