Can Neuromodulation Improve Sleep and Psychiatric Symptoms?

PURPOSE OF REVIEW: In this review, we evaluate recent studies that employ neuromodulation, in the form of non-invasive brain stimulation, to improve sleep in both healthy participants, and patients with psychiatric disorders. We review studies using transcranial electrical stimulation, transcranial magnetic stimulation, and closed-loop auditory stimulation, and consider both subjective and objective measures of sleep improvement. RECENT FINDINGS: Neuromodulation can alter neuronal activity underlying sleep. However, few studies utilizing neuromodulation report improvements in objective measures of sleep. Enhancements in subjective measures of sleep quality are replicable, however, many studies conducted in this field suffer from methodological limitations, and the placebo effect is robust. Currently, evidence that neuromodulation can effectively enhance sleep is lacking. For the field to advance, methodological issues must be resolved, and the full range of objective measures of sleep architecture, alongside subjective measures of sleep quality, must be reported. Additionally, validation of effective modulation of neuronal activity should be done with neuroimaging.

Two-Centre Retrospective Analysis on Selective Sensory Denervation of Shoulder Joint by Means of Cooled Radiofrequency in Chronic Shoulder Pain.

Purpose: Radiofrequency ablation has been used to treat chronic shoulder pain with mixed results. Thanks to recent anatomical studies, the precise location of articular branches of the suprascapular, lateropectoral and axillary nerves has been determined. Cooled radiofrequency is a neuroablative modality of treatment which has been demonstrated as efficient in different anatomical locations, and targeting the aforementioned nerves could result in a complete and efficient denervation of the shoulder. The aim of this study is to assess the efficacy of a fluoroscopic guided cooled radiofrequency technique for chronic shoulder pain. Patients and Methods: This is a retrospective observational study performed in two hospital in Wales and Italy (Wrexham NHS trust and Iseo Hospital). Forty-four patients were treated between December 2019 and January 2023. Follow-up was provided at 1-, 6- and 12-months post-procedure. Pain intensity was measured with a 0-10-point Numerical Rating Scale (NRS), and was assessed at rest and during movement. Disability was assessed with the Oxford Shoulder Score (OSS). All patients were treated with cooled radiofrequency under fluoroscopic guidance targeting the articular branches of the suprascapular, axillary and lateropectoral nerves. Results: In the 44 patients treated, the mean NRS significantly decreased at all follow ups, pain relief of >50% was obtained in 70.4%, 61% and 51% of the patients at 1.6 and 12 month follow-ups, respectively. Disability improved significantly, with a mean OSS at 12 months follow up of 30 ±17.5, compared to 15 ± 3 at baseline. Medication intake (non-steroidal anti-inflammatory drugs (NSAIDS) and/or opioids) significantly decreased at all follow ups. Conclusion: Cooled radiofrequency denervation can be an effective procedure to manage chronic shoulder pain, providing sustained pain relief and functional improvement in more than 50% of the patients.

Single Institutional Cross-Sectional Phone Survey Study: Evaluation of Causes for Loss to Follow-up After Spinal Cord Stimulator Implantation.

BACKGROUND: Spinal cord stimulation (SCS) is often an option of last resort for patients with post-laminectomy syndrome or an alternative option for patients with complex regional pain syndrome, chronic nonsurgical low back pain, or painful diabetic peripheral neuropathy when conservative management has failed. Although SCS is a helpful option, it is not without complications that can frequently lead to explantation of the SCS device and dissatisfaction with the treatment. Furthermore, as with any technology, SCS has potential issues that may lead to patient frustration and ultimately result in patient noncompliance and lack of follow-up visits. OBJECTIVES: The goals of this study are to explore the magnitude of and reasons for patient loss to follow-up after SCS device implantation. STUDY DESIGN: A cross-sectional phone survey. SETTING: A tertiary-care academic hospital. METHODS: A cross-sectional phone survey was performed on 49 patients who were deemed lost to follow-up when they did not return to the clinic one month after being implanted with permanent SCS devices at Beth Israel Deaconess Medical Center. Patients were administered an institutional review board-approved questionnaire exploring their reasons for not returning to the clinic. RESULTS: Over a 5-year period, 257 patients underwent full implantation of an SCS device. Of the 49 patients lost to follow-up, 24 were able to be contacted, and they completed the questionnaire. Twenty of the patients continued to use the SCS device but were lost to follow-up for the following reasons: 58% (14/24) due to improvement of pain, 13% (3/24) due to minimal improvement in pain control, 4% (1/24) due to other urgent health conditions, and 8% (2/24) due to patient noncompliance and missing follow-up appointments (4/24). Four patients discontinued using the SCS device after an average of 1.5 years +/- one year, 12% (3/24) due to inadequate pain control and 4% (1/24) due to inability to recharge the device (1/24). Of these patients, 2 of the 4 contacted their SCS representatives for help with troubleshooting prior to discontinuation. None of the patients was explanted. LIMITATIONS: The main limitation of this study was the incompletion rate, which was 51.0% (25 out of 49 patients). CONCLUSIONS: This paper, the first cross-sectional study of loss to follow-up among patients who are implanted with SCS devices, identifies that up to 19% of patients are quickly lost to follow-up after implantation. Only half of the patients in this study could be reached, with most successfully using their device for meaningful pain control, but a substantial number of patients likely required additional device optimization for pain relief.

Intraspinal microstimulation of the ventral horn has therapeutically relevant cross-modal effects on nociception.

Electrical stimulation of spinal networks below a spinal cord injury is a promising approach to restore functions compromised by inadequate and/or inappropriate neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared descending motor pathways and spinal motoneurons rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by spinal cord injury. Debilitating spasms, spasticity and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. Whereas spasms and spasticity can often be managed pharmacologically, spinal cord injury-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from aetiologies other than spinal cord injury, and the limited evidence available to date suggests that it holds considerable promise for reducing spinal cord injury-related neuropathic pain, as well. Spinal stimulation for pain amelioration has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for rehabilitation of movement impairments. Thus, we hypothesize that spinal stimulation intended to increase the ability to move voluntarily may simultaneously reduce transmission in spinal pain pathways. To test this hypothesis, we coupled a rat model of incomplete thoracic spinal cord injury, which results in moderate to severe bilateral movement impairments and spinal cord injury-related neuropathic pain, with in vivo electrophysiological measures of neural transmission in networks of spinal neurons integral to the development and persistence of the neuropathic pain state. We find that when intraspinal microstimulation is delivered to the ventral horn with the intent of enhancing voluntary movement, transmission through nociceptive specific and wide dynamic range neurons is significantly depressed in response to pain-related sensory feedback. By comparison, spinal responsiveness to non-pain-related sensory feedback is largely preserved. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with spinal cord injury.

Multistability of bursting rhythms in a half-center oscillator and the protective effects of synaptic inhibition.

For animals to meet environmental challenges, the activity patterns of specialized oscillatory neural circuits, central pattern generators (CPGs), controlling rhythmic movements like breathing and locomotion, are adjusted by neuromodulation. As a representative example, the leech heartbeat is controlled by a CPG driven by two pairs of mutually inhibitory interneurons, heart interneuron (HN) half-center oscillators (HCO). Experiments and modeling indicate that neuromodulation of HCO navigates this CPG between dysfunctional regimes by employing a co-regulating inverted relation; reducing Na+/K+ pump current and increasing hyperpolarization-activated (h-) current. Simply reducing pump activity or increasing h-current leads to either seizure-like bursting or an asymmetric bursting dysfunctional regime, respectively. Here, we demonstrate through modeling that, alongside this coregulation path, a new bursting regime emerges. Both regimes fulfill the criteria for functional bursting activity. Although the cycle periods and burst durations of these patterns are roughly the same, the new one exhibits an intra-burst spike frequency that is twice as high as the other. This finding suggests that neuromodulation could introduce additional functional regimes with higher spike frequency, and thus more effective synaptic transmission to motor neurons. We found that this new regime co-exists with the original bursting. The HCO can be switched between them by a short pulse of excitatory or inhibitory conductance. In this domain of coexisting functional patterns, an isolated cell model exhibits only one regime, a severely dysfunctional plateau-containing, seizure-like activity. This aligns with widely reported notion that deficiency of inhibition can cause seizures and other dysfunctional neural activities. We show that along the coregulation path of neuromodulation, the high excitability of the single HNs induced by myomodulin is harnessed by mutually inhibitory synaptic interactions of the HCO into the functional bursting pattern.

Ubiquitin ligase signalling networks shape presynaptic development, function and disease.

Ubiquitin ligases are important regulators of nervous system development, function and disease. To date, numerous ubiquitin ligases have been discovered that regulate presynaptic biology. Here, we discuss recent findings on presynaptic ubiquitin ligases that include members from the three major ubiquitin ligase classes: RING, RBR and HECT. Several themes emerge based on findings across a range of model systems. A cadre of ubiquitin ligases is required presynaptically to orchestrate development and transmission at synapses. Multiple ubiquitin ligases deploy both enzymatic and non-enzymatic mechanisms, and act as hubs for signalling networks at the synapse. Both excitatory and inhibitory presynaptic terminals are influenced by ligase activity. Finally, there are several neurodevelopmental disorders and neurodegenerative diseases associated with presynaptic ubiquitin ligases. These findings highlight the growing prominence and biomedical relevance of the presynaptic ubiquitin ligase network.

Research hotspots and trends of non-invasive vagus nerve stimulation: a bibliometric analysis from 2004 to 2023.

Objectives: Non-invasive vagus nerve stimulation (nVNS) is an emerging neuromodulation technique in recent years, which plays a role in nervous system diseases, psychiatric diseases, and autoimmune diseases. However, there is currently no comprehensive analysis of all the literature published in this field. Therefore, in this article, a bibliometric analysis will be conducted on all the literature published in the field of nVNS in the past 20 years. Methods: All articles and reviews published in this field from 2004 to 2023 were extracted from the WOS core database. VOSviewer 1.6.18.0, Scimago Graphica, CiteSpace 6.2.R2, and Excel 2021 were used to analyze the number of publications, participating countries, institutions, authors, references, and research hotspots in this field. Results: A total of 843 articles were included in the bibliometric analysis of nVNS. Over the past 20 years, the number of publications in this field has gradually increased, reaching a peak in 2023. The United States and China ranked top two in terms of publication volume, and institutions from these two countries also ranked high in terms of publication volume, citation count, and collaboration intensity. Rong Peijing is the author with the most publications, while Bashar W Badran is the most cited author. Articles in the field of nVNS were most frequently published in Frontiers in Neuroscience, while Brain Stimulation had the most citations. Currently, research hotspots in nVNS mainly focus on its application in diseases and related mechanisms. Conclusion: We conducted a comprehensive analysis of the field of nVNS, clarifying the previous research directions, which is helpful to expand its indications and promote clinical application.

tDCS and local scalp cooling do not change corticomotor and intracortical excitability in healthy humans.

OBJECTIVE: Scalp cooling might increase the long-term potentiation (LTP)-like effect of transcranial direct current stimulation (tDCS) by reducing the threshold for after-effects according to metaplasticity and increasing electrical current density reaching the cortical neurons. We aimed to investigate whether priming scalp cooling potentiates the tDCS after-effect on motor cortex excitability. METHODS: This study had a randomized, parallel-arms, sham-controlled, double-blinded design with an adequately powered sample of 105 healthy subjects. Corticomotor and intracortical excitability were assessed with motor evoked potentials (MEP) from transcranial magnetic stimulation (TMS) in short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) paradigms. Subjects were randomly allocated into six intervention groups, including anodal and cathodal tDCS (1-mA/20-min), scalp cooling, and sham. MEPs were recorded before, immediately, and 15 min after the interventions. RESULTS: We did not observe changes in MEP amplitude from single-pulse TMS, SICI, and ICF with any intervention protocol. CONCLUSION: Anodal and cathodal tDCS did not have an LTP-like neuromodulatory effect on corticospinal and did not provide detectable GABAergic and glutamatergic neurotransmission changes, which were not influenced by priming scalp cooling. SIGNIFICANCE: We provide strong evidence that tDCS (1-mA/20-min) does not alter corticomotor and intracortical excitability with or without priming scalp cooling.

Is Our Limited Understanding of the Effects of Nerve Stimulation Resulting in Poor Outcomes and the Need for Better "Rescue Programming" in SNM and PTNS, and Lost Opportunities for New Sites of Stimulation? ICI-RS 2024.

AIMS: Sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS) are strongly recommended by international guidelines bodies for complex lower urinary tract dysfunctions. However, treatment failure and the need for rescue programming still represent a significant need for long-term follow-up. This review aimed to describe current strategies and future directions in patients undergoing such therapies. MATERIALS AND METHODS: This is a consensus report of a Think Tank discussed at the Annual Meeting of the International Consultation on Incontinence - Research Society (ICI-RS), June 6-8, 2024 (Bristol, UK): "Is our limited understanding of the effects of nerve stimulation resulting in poor outcomes and the need for better 'rescue programming' in SNM and PTNS, and lost opportunities for new sites of stimulation?" RESULTS: Rescue programming is important from two different perspectives: to improve patient outcomes and to enhance device longevity (for implantable devices). Standard SNM parameters have remained unchanged since its inception for the treatment of OAB, nonobstructive urinary retention, and voiding dysfunction. SNM rescue programming includes intermittent stimulation (cycling on), increased frequency and changes in pulse width (PW). The effect of PW setting on SNM outcomes remains unclear. Monopolar configurations stimulate more motor nerve fibers at lower stimulation voltage; hence, this could be an option in patients who failed bipolar stimulation in the long term. Unfortunately, there is little evidence for rescue programming for PTNS. However, the development of implantable devices for intermittent stimulation of the tibial nerve may increase long-term adherence to therapy and increase interest in alternative programming. There has been recent promising neurostimulation targeting the pudendal nerve (PNS), especially in BPS/IC. More recently, preliminary data addressed the benefits of high-frequency bilateral pudendal nerve block for DESD and adaptive PNS on both urgency and stress UI in women. CONCLUSION: The exploration of rescue programming and new stimulation sites remains underutilized, and there are opportunities that could potentially expand the therapeutic applications of nerve stimulation. By broadening the range of target sites, clinicians may be able to tailor treatments according to individual patient needs and underlying conditions, thereby improving overall outcomes. However, further studies are still needed to increase the level of evidence, potentially allowing for an individualized treatment both in patients who are candidates for electrostimulation and in those who have already received surgical implants but seek a better outcome.

Dimensionality reduction of neuronal degeneracy reveals two interfering physiological mechanisms.

Neuronal systems maintain stable functions despite large variability in their physiological components. Ion channel expression, in particular, is highly variable in neurons exhibiting similar electrophysiological phenotypes, which raises questions regarding how specific ion channel subsets reliably shape intrinsic properties of neurons. Here, we use detailed conductance-based modeling to explore how stable neuronal function is achieved despite variability in channel composition among neurons. Using dimensionality reduction, we uncover two principal dimensions in the channel conductance space that capture most of the variance of the observed variability. These two dimensions correspond to two sources of variability that originate from distinct physiologically relevant mechanisms underlying the regulation of neuronal activity, providing quantitative insights into how channel composition is linked to the electrophysiological activity of neurons. These insights allow us to understand and design a model-independent, reliable neuromodulation rule for variable neuronal populations.

Vagus nerve stimulation (VNS): recent advances and future directions.

PURPOSE: Vagus nerve stimulation (VNS) is emerging as a unique and potent intervention, particularly within neurology and psychiatry. The clinical value of VNS continues to grow, while the development of noninvasive options promises to change a landscape that is already quickly evolving. In this review, we highlight recent progress in the field and offer readers a glimpse of the future for this bright and promising modality. METHODS: We compiled a narrative review of VNS literature using PubMed and organized the discussion by disease states with approved indications (epilepsy, depression, obesity, post-stroke motor rehabilitation, headache), followed by a section highlighting novel, exploratory areas of VNS research. In each section, we summarized the current role, recent advancements, and future directions of VNS in the treatment of each disease. RESULTS: The field continues to gain appreciation for the clinical potential of this modality. VNS was initially developed for treatment-resistant epilepsy, with the first depression studies following shortly thereafter. Overall, VNS has gained approval or clearance in the treatment of medication-refractory epilepsy, treatment-resistant depression, obesity, migraine/cluster headache, and post-stroke motor rehabilitation. CONCLUSION: Noninvasive VNS represents an opportunity to bridge the translational gap between preclinical and clinical paradigms and may offer the same therapeutic potential as invasive VNS. Further investigation into how VNS parameters modulate behavior and biology, as well as how to translate noninvasive options into the clinical arena, are crucial next steps for researchers and clinicians studying VNS.

Entorhinal cortex-hippocampal circuit connectivity in health and disease.

The entorhinal cortex (EC) and hippocampal (HC) connectivity is the main source of episodic memory formation and consolidation. The entorhinal-hippocampal (EC-HC) connection is classified as canonically glutamatergic and, more recently, has been characterized as a non-canonical GABAergic connection. Recent evidence shows that both EC and HC receive inputs from dopaminergic, cholinergic, and noradrenergic projections that modulate the mnemonic processes linked to the encoding and consolidation of memories. In the present review, we address the latest findings on the EC-HC connectivity and the role of neuromodulations during the mnemonic mechanisms of encoding and consolidation of memories and highlight the value of the cross-species approach to unravel the underlying cellular mechanisms known. Furthermore, we discuss how EC-HC connectivity early neurodegeneration may contribute to the dysfunction of episodic memories observed in aging and Alzheimer's disease (AD). Finally, we described how exercise may be a fundamental tool to prevent or decrease neurodegeneration.

Emerging Functions of Neuromodulation during Sleep.

Neuromodulators act on multiple timescales to affect neuronal activity and behavior. They function as synaptic fine-tuners and master coordinators of neuronal activity across distant brain regions and body organs. While much research on neuromodulation has focused on roles in promoting features of wakefulness and transitions between sleep and wake states, the precise dynamics and functions of neuromodulatory signaling during sleep have received less attention. This review discusses research presented at our minisymposium at the 2024 Society for Neuroscience meeting, highlighting how norepinephrine, dopamine, and acetylcholine orchestrate brain oscillatory activity, control sleep architecture and microarchitecture, regulate responsiveness to sensory stimuli, and facilitate memory consolidation. The potential of each neuromodulator to influence neuronal activity is shaped by the state of the synaptic milieu, which in turn is influenced by the organismal or systemic state. Investigating the effects of neuromodulator release across different sleep substates and synaptic environments offers unique opportunities to deepen our understanding of neuromodulation and explore the distinct computational opportunities that arise during sleep. Moreover, since alterations in neuromodulatory signaling and sleep are implicated in various neuropsychiatric disorders and because existing pharmacological treatments affect neuromodulatory signaling, gaining a deeper understanding of the less-studied aspects of neuromodulators during sleep is of high importance.

Clinical Efficacy of Auricular Vagus Nerve Stimulation in the Treatment of Chronic and Acute Pain: A Systematic Review and Meta-analysis.

INTRODUCTION: Current guidelines for pain treatment recommend a personalized, multimodal and interdisciplinary approach as well as the use of a combination of drug and non-drug therapies. Risk factors for chronification should already be reduced in patients with acute pain, e.g., after surgery or trauma. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy in the multimodal treatment of chronic and acute pain. The aim of this systematic review and meta-analysis is to evaluate the clinical efficacy and safety of aVNS in treating chronic and acute pain conditions. METHODS: A systematic literature search was performed regarding the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence (Jadad scale), scientific validity and risk of bias (RoB 2 tool) and analyzed regarding indication, method, stimulation parameters, duration of treatment and efficacy and safety. A meta-analysis on (randomized) controlled trials (using different comparators) was performed for chronic and acute pain conditions, respectively, including subgroup analysis for percutaneous (pVNS-needle electrodes) and transcutaneous (tVNS-surface electrodes) aVNS. The visual analog pain scale (VAS) was defined as primary efficacy endpoint. RESULTS: A total of n = 1496 patients were treated with aVNS in 23 identified and analyzed studies in chronic pain, 12 studies in acute postoperative pain and 7 studies in experimental acute pain. Of these, seven studies for chronic pain and six studies for acute postoperative pain were included in the meta-analysis. In chronic pain conditions, including back pain, migraine and abdominal pain, a statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control treatment with an effect size Hedges' g/mean difference of - 1.95 (95% confidence interval [CI]: - 3.94 to 0.04, p = 0.008) could be shown and a more favorable effect in pVNS compared to tVNS (- 5.40 [- 8.94; - 1.85] vs. - 1.00 [- 1.55; - 0.44]; p = 0.015). In acute pain conditions, single studies showed significant improvements with aVNS, e.g., in kidney donor surgery or tonsillectomy but, overall, a non-statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control with - 0.70 [- 2.34; 0.93] (p = 0.15) could be observed in the meta-analysis. In acute pain results vary greatly between studies depending especially on co-medication and timepoints of assessment after surgery. A significant reduction in analgesics or opiate intake was documented in most studies evaluating this effect in chronic and acute pain. In 3 of the 12 randomized controlled trials in patients with chronic pain, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated. CONCLUSION: This systematic review and meta-analysis indicate that aVNS can be an effective and safe non-drug treatment in patients with specific chronic and acute postoperative pain conditions. Further research is needed to identify the influence of simulation parameters and find optimal and standardized treatment protocols while considering quality-of-life outcome parameters and prolonged follow-up periods. A more standardized approach and harmonization in study designs would improve comparability and robustness of outcomes.

Sacral neuromodulation for Organophosphate-induced delayed neuropathy neurogenic lower urinary tract dysfunction: a case report.

BACKGROUND: Organophosphate-Induced Delayed Neuropathy (OPIDN) is a rare neurological disorder triggered by exposure to organophosphorus compounds. These compounds exert their neurotoxic effects by impacting the nervous system, leading to systemic manifestations. Urinary system symptoms are infrequently observed in clinical settings. Currently, effective therapeutic interventions for OPIDN-related urinary symptoms are lacking. Sacral nerve modulation therapy, an FDA-approved approach for managing lower urinary tract symptoms, presents as a promising option. Herein, we present a case of OPIDN-induced lower urinary tract obstruction successfully treated with sacral nerve modulation therapy, resulting in substantial symptom relief. CASE REPORT: A 27-year-old male patient presented with severe bilateral hydronephrosis, attributed to low bladder compliance and accompanied by a fever persisting for 6 days. The patient's medical history revealed accidental ingestion of organophosphate pesticide (Dimethoate) with no concomitant underlying diseases. In consideration of the potential for OPIDN, surgical intervention in the form of sacral neuromodulation (phase I) was undertaken. Subsequent evaluation one month post-surgery revealed notable improvements in both bladder compliance and bilateral hydronephrosis, necessitating sacral neuromodulation (phase II). Presently, following a 5-month follow-up period, the patient remains asymptomatic and in favorable health. CONCLUSION: This patient achieved long-term relief using sacral neuromodulation.

Adenosine Metabolism Pathway Alterations in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia (n = 20) and sex- and age-matched control subjects without psychiatric illness (n = 20) was obtained from the Bronx-Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components-adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5'-nucleotidase (NT5E)-were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups (p > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann-Whitney U = 86; p < 0.05), a finding significantly driven by disease (t(17) = 3.289; p < 0.05). Correlation analyses also demonstrated significant associations (n = 12) between the expression of several adenosine pathway components (p < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the "mild" clinical dementia rating (CDR) bin compared with males in the "none" CDR bin (F(2, 13) = 5.212; p < 0.05). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects (p > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia's pathology.

Clinical pain management: Current practice and recent innovations in research.

Chronic pain affects one in five adults. It is not only a major cause of disability for individual patients but also a driver of costs for entire healthcare systems. Treatment of pain remains a challenge, and the use of opioids has further led to a concurrent opioid epidemic. In this review, we discuss current standard treatment options for chronic pain, including pharmacological, behavioral, and interventional treatments. In addition, we review ongoing research in different areas that will potentially unlock new therapies.

Pain tolerance and the thresholds of human sensory and motor axons to single and repetitive bursts of kilohertz-frequency stimulation.

Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier frequency is thought to be less painful than conventional pulsed currents by reducing the sensitivity of pain receptors. However, no purported benefit has been shown unequivocally. We compared the effects of carrier-frequency stimulation and conventional stimulation on pain tolerance and the thresholds for sensory and motor axons in twelve participants. The ulnar nerve was stimulated transcutaneously with a conventional single pulse and 5 and 10 kHz carrier-frequency waveforms that had 5 and 10 pulses, respectively, when delivered in bursts of ∼1 ms duration. Phase durations were adjusted across waveform types to match the total charge for a given current amplitude. Single bursts of stimulation were delivered from 1 mA up until no longer tolerable. This was repeated with repetitive bursts of stimulation at 20 Hz for 1 s. Participants tolerated higher current amplitudes with both carrier-frequency waveforms than conventional stimulation, with repetitive bursts more painful than single bursts. However, compared to conventional stimulation, carrier-frequency waveforms required more current to produce sensory and motor-threshold responses and to obtain a maximal motor response (Mmax). When the current at pain tolerance was normalised to the current at Mmax, participants tolerated lower stimulus intensities with carrier-frequency waveforms than conventional stimulation. These findings indicate that there is little to no benefit in using carrier-frequency waveforms to minimise the discomfort from electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in the activation of sensory and motor axons. KEY POINTS: Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier-frequency waveform is thought to be less painful than conventional pulsed currents. For ulnar nerve stimulation, when stimulus waveforms were matched for total phase charge, participants tolerated higher current amplitudes with carrier-frequency stimulation than conventional stimulation. However, compared to conventional stimulation, carrier-frequency waveforms required more current to produce a threshold response in both sensory and motor axons and to produce a maximal motor response (Mmax). When current at pain tolerance was normalised to current at Mmax, participants tolerated lower stimulus intensities with carrier-frequency waveforms than conventional stimulation. Carrier-frequency waveforms provide little to no benefit in minimising the discomfort from transcutaneous electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in activating sensory and motor axons.

Transcranial direct-current stimulation of core language areas facilitates novel word acquisition.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that can alter the state of the stimulated brain area and thereby affect neurocognitive processes and resulting behavioural performance. Previous studies have shown disparate results with respect to tDCS effects on language function, particularly with respect to language learning and word acquisition. To fill this gap, this study aimed at systematically addressing the effects of tDCS of core left-hemispheric language cortices on the brain mechanisms underpinning two main neurocognitive strategies of word learning: implicit inference-based Fast Mapping (FM) and direct instruction-based Explicit Encoding (EE). Prior to a word-learning session, 160 healthy participants were given 15 min of either anodal or cathodal tDCS of Wernicke's or Broca's areas, or a control sham (placebo) stimulation, using a between-group design. Each participant then learned 16 novel words (8 through FM and 8 through EE) in a contextual word-picture association session. Moreover, these words were learnt either perceptually via auditory exposure combined with a graphical image of the novel object, or in an articulatory mode, where the participants additionally had to overtly articulate the novel items. These learning conditions were fully counterbalanced across participants, stimuli and tDCS groups. Learning outcomes were tested at both lexical and semantic levels using two tasks: recognition and word-picture matching. EE and FM conditions produced similar outcomes, indicating comparable efficiency of the respective learning strategies. At the same time, articulatory learning produced generally better results than non-articulatory exposure, yielding higher recognition accuracies and shorter latencies in both tasks. Crucially, real tDCS led to global outcome improvements, demonstrated by faster (compared to sham) reactions, as well as some accuracy changes. There was also evidence of more specific tDCS effects: better word-recognition accuracy for EE vs. FM following cathodal stimulation as well as more expressed improvements in recognition accuracy and reaction times for anodal Broca's and cathodal Wernicke's stimulation, particularly for unarticulated FM items. These learning mode-specific effects support the notion of partially distinct brain mechanisms underpinning these two learning strategies. Overall, numerically largest improvements were observed for anodal Broca's tDCS, whereas the least expressed benefits of tDCS for learning were measured after anodal Wernicke stimulation. Finally, we did not find any inhibitory effects of either tDCS polarity in any of the comparisons. We conclude that tDCS of core language areas exerts a general facilitatory effect on new word acquisition with some limited specificity to learning protocols - the result that may be of potential applied value for future research aimed at ameliorating learning deficits and language disorders.

Motor Response Matters: Lead Placement and Urologic Efficacy Linked in Sacral Neuromodulation.

OBJECTIVES: This study aimed to characterize the pelvic floor muscles (PFM) motor response provoked during sacral neuromodulation (SNM) lead placement, determining its utility in improving therapy delivery. MATERIALS AND METHODS: A prospective pilot study (January 2018-September 2021) was performed including patients with overactive bladder or nonobstructive urinary retention-a very homogeneous group without any medical history interfering with bladder function-who underwent SNM. An external pulse generator was connected for three weeks. Success was defined as ≥50% improvement. PFM electromyography was recorded using a multiple array probe. Differences in electrical PFM motor response (peak-to-peak amplitude, area under the curve [AUC] or latency) among different electrical stimulation levels up to 10V (and the clinically relevant intensities up to 3V) and different parts (four sides, three depths) of the pelvic floor were modeled using linear mixed model analysis (LMM). RESULTS: The study population comprised 26 women (overall success 81%). With increasing improvement in voiding diary data, higher peak-to-peak amplitudes and AUC were seen for up to 10V stimulation intensities (LMM: p value 0.0046 and 0.0043, respectively) and up to 3V stimulation intensities (LMM: p value 0.0261 and 0.0416, respectively). Subanalysis of the different parts of the PFM showed all different sides (first corrected p value < 0.0125) and depths (first corrected p value < 0.0167) presented with statistically significant differences in favor of those with higher percentage improvement for the 10V and 3V analyses, with only two exceptions: peak-to-peak amplitude at the posterior layer at the clinically relevant stimulation intensities (LMM: p value: 0.0752) and AUC at the posterior layer for the stimulation intensities on 10V (LMM: p value: 0.0557). No statistically significant differences were found for the overall mean peak-to-peak amplitude and AUC based on dichotomous outcome (responders vs nonresponders). CONCLUSIONS: Intraoperative PFM electromyography obtained during lead placement aids in more accurate targeting of the lead to the nerve. To our knowledge, this is the first study to correlate tined lead placement based on electrodiagnostic testing and outcome in SNM. It has been proved to be a reliable measurement tool, serving as a physiological biomarker of treatment response during the test phase. A strong motor response can make the surgeon confident that the correct position of the lead has been established for maximal benefit.