Low-intensity ultrasound neuromodulation: An overview of mechanisms and emerging human applications

Background

There is an emerging need for noninvasive neuromodulation techniques to improve patient outcomes while minimizing adverse events and morbidity. Low-intensity focused ultrasound (LIFUS) is gaining traction as a non-surgical experimental approach of modulating brain activity. Several LIFUS sonication parameters have been found to potentiate neural firing, suppress cortical and epileptic discharges, and alter behavior when delivered to cortical and subcortical mammalian brain regions.

Sacral Nerve Stimulation for the Treatment of Sacroiliac Joint Dysfunction: A Case Report

Introduction: Sacroiliac joint (SIJ) dysfunction is a significant contributing factor in 10–30% of individuals with lower back pain. However, definitive diagnostic methods and treatments are still controversial. Methods: We present a case of a 41‐year‐old woman with left buttock pain, referred pain to the left leg, and dyspareunia. Her visual analogue scale (VAS) pain score was 9/10. Although we performed intramuscular injection into piriformis muscle, intra‐articular injection into SIJ, and radiofrequency denervation for the treatment of SIJ pain, her pain repeatedly improved and was reaggravated. Sacral nerve stimulation to the left first sacral foramen via the retrograde cephalocaudal approach was performed. Results: Her VAS pain score decreased to 2–3/10 following sacral nerve stimulation to the left first sacral foramen via the retrograde cephalocaudal approach. Before undergoing sacral nerve stimulation, she had taken anti‐depressants, anti‐anxietics, analgesics, and anti‐convulsants. After the procedure, she required intermittent analgesics only. Conclusions: Sacral nerve stimulation with a percutaneous retrograde cephalocaudal approach is considered to be a useful therapeutic option in the treatment of intractable SIJ dysfunction.     

Neurostimulation for the Treatment of Epilepsy: A Review of Current Surgical Interventions

Objectives: Epilepsy continues to provide challenges to clinicians, as a significant proportion of patients continue to suffer from seizures despite medical and surgical treatments. Neurostimulation has emerged as a new treatment modality that has the potential to improve quality of life and occasionally be curative for patients with medically refractory epilepsy who are not surgical candidates. In order to continue to advance the frontier of this field, it is imperative to have a firm grasp of the current body of knowledge. Methods: We performed a thorough review of the current literature regarding the three main modalities of vagus nerve stimulation, deep brain stimulation, and closed‐loop stimulation (responsive neurostimulator [RNS]) for the treatment of refractory epilepsy. For each of these forms of treatment, we discuss the current understanding of the underlying mechanism of action, patient selection, outcomes to date, and associated side effects or adverse reactions. We also provide an overview of related ongoing clinical trials. Results: A total of 189 sources from 1938 to 2012 pertaining to neuromodulation for the treatment of epilepsy were reviewed. Sources included review articles, clinical trials, case reports, conference proceedings, animal studies, and government data bases. Conclusions: This review shows us how neurostimulation provides us with yet another tool with which to treat the complex disease of medically refractory epilepsy.     

Sacral Nerve and Spinal Cord Stimulation for Intractable Neuropathic Pain Caused by Spinal Cord Infarction

Central cord pain is very difficult to relieve, even with the many kinds of medical and surgical treatments available. Following spinal cord infarctions, central cord pain can develop. The problems that may arise could include limb pain, pelvic pain, difficulties voiding, and difficulties defecating. We are reporting a case of central cord pain caused by a spinal cord infarction of the conus medullaris. Limb pain was reduced by spinal cord stimulation. Voiding and defecation difficulties and pelvic pain were reduced by sacral nerve stimulation. Thus, in a case involving both intractable limb and pelvic pain, a combination therapy of these two stimulations might be an effective treatment modality.     

Prolonged electrical stimulation causes no damage to sacral nerve roots in rabbits

Previous studies have shown that, anode block electrical stimulation of the sacral nerve root can produce physiological urination and reconstruct urinary bladder function in rabbits. However, whether long-term anode block electrical stimulation causes damage to the sacral nerve root remains unclear, and needs further investigation. In this study, a complete spinal cord injury model was established in New Zealand white rabbits through T9–10 segment transection. Rabbits were given continuous electrical stimulation for a short period and then chronic stimulation for a longer period. Results showed that compared with normal rabbits, the structure of nerve cells in the anterior sacral nerve roots was unchanged in spinal cord injury rabbits after electrical stimulation. There was no significant difference in the expression of apoptosis-related proteins such as Bax, Caspase-3, and Bcl-2. Experimental findings indicate that neurons in the rabbit sacral nerve roots tolerate electrical stimulation, even after long-term anode block electrical stimulation.     

Principles of Sacral Nerve Stimulation (SNS) for the Treatment of Bladder and Urethral Sphincter Dysfunctions

Objectives. Sacral nerve stimulation (SNS) (Medtronic, Inc., Minneapolis, MN) is an exciting new treatment for refractory voiding disorders including urinary incontinence, retention, and voiding dysfunction. It is known that both voiding and continence reflex mechanisms are organized in the sacral spinal cord and that pathologic conditions can alter the balance between these two opposing mechanisms. Methods. The background and surgical technique of SNS will be presented. This will be followed by a discussion of hypotheses on how SNS works. Results. The beneficial effects of SNS are most reasonably attributed to activation of somatic afferent axons in the sacral spinal roots. This evoked afferent activity in turn modulates sensory processing and micturition reflex pathways in the spinal cord. Hyperactive voiding can be suppressed by direct inhibition of bladder preganglionic neurons as well as inhibition of interneuroneal transmission in the afferent limb of the micturition reflex. On the other hand, voiding in patients with urinary retention can be facilitated by inhibition of reflex pathways to the urethral outlet (guarding reflexes). Conclusions. SNS, a nonablative, minimally invasive technique for urologists, holds great promise for a large number of patients who suffer debilitating and refractory urinary symptoms.     

Feasibility,Safety and Efficacy of Transcutaneous Vagus Nerve Stimulation in Chronic Tinnitus: An Open Pilot Study

ObjectivesVagus nerve stimulation represents an established treatment strategy for epilepsy and affective disorders. Recently, positive effects were also shown in animals and humans with tinnitus. Here we report the results of an open pilot study exploring feasibility, safety and efficacy of tVNS in the treatment of chronic tinnitus.Study designFifty patients with chronic tinnitus underwent tVNS in an open single-armed pilot study which was conducted in two phases applying two different stimulating devices (Cerbomed CM02 and NEMOS). Clinical assessment was based on Tinnitus Questionnaire (TQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), WHO Quality of Life, and various numeric rating scales. Primary outcome was defined as change in TQ (baseline vs. final visit in week 24). The study has been registered with clinicaltrials.gov (NCT01176734).ResultsPrimary analysis indicated mean TQ reductions of 3.7 points (phase 1) and 2.8 points (phase 2) significant for the first study phase. Secondary analyses indicated a significant BDI reduction for phase 1 (uncorrected for multiple testing), but no further systematic or significant effects. Adverse events included twitching and pressure at electrode placement site. The occurrence of one hospitalization because of palpations and the development of a left bundle branch block were considered as unrelated to the intervention. Cognitive testing revealed no significant changes.ConclusionOur data demonstrate the feasibility of tVNS over a period of 6 months. There was no clinically relevant improvement of tinnitus complaints. Our data suggest tVNS to be considered safe in patients without a history of cardiac disease.     

Racial and Socioeconomic Disparities in Spinal Cord Stimulation Among the Medicare Population

IntroductionSpinal cord stimulation (SCS) is used in the treatment of many chronic pain conditions. This study investigates racial and socioeconomic disparities in SCS among Medicare patients with chronic pain.Materials and MethodsPatients over the age of 18 with a primary diagnosis of postlaminectomy syndrome (ICD-10 M96.1) or chronic pain syndrome (ICD-10 G89.4) were identified in the Center for Medicare and Medicaid Services (CMS) Medicare Claims Limited Data Set. We defined our outcome as SCS therapy by race and socioeconomic status. Multivariable logistic regression was used to determine the variables associated with SCS.ResultsWe identified 1,244,927 patients treated between 2016 and 2019 with a primary diagnosis of postlaminectomy syndrome (PLS) or chronic pain syndrome (CPS). Of these patients, 59,182 (4.8%) received SCS. Multivariable logistic regression analysis revealed that, compared with White patients, Black (OR [95%CI], 0.62 [0.6–0.65], p < 0.001), Asian (0.66 [0.56–0.76], p < 0.001), Hispanic (0.86 [0.8–0.93], p < 0.001), and North American Native (0.62 [0.56–0.69], p < 0.001) patients were significantly less likely to receive SCS. In addition, patients who were dual-eligible for Medicare and Medicaid were significantly less likely to receive SCS than those eligible for Medicare only (OR = 0.38 [95% CI: 0.37–0.39], p < 0.001).ConclusionsThis study suggests that racial and socioeconomic disparities exist in SCS among Medicare and Medicaid patients with PLS and CPS. Further work is required to elucidate the complex etiology underlying these findings.     

Economic evaluations of nonpharmacological treatments for drug-resistant epilepsy: A systematic review

This study was undertaken to systematically identify and critically appraise all published full economic evaluations assessing the cost-effectiveness of nonpharmacological interventions for patients with drug-resistant epilepsy. The Population, Intervention, Comparison, Outcome, Study criteria was used to design search strategies for the identification and selection of relevant studies. Literature search was performed using the MEDLINE (via PubMed), Embase, International Health Technology Assessment, National Institute for Health Research Economic Evaluation Database, and Cost-Effectiveness Analysis Registry databases to identify articles published between January 2000 and May 2023. Web of Science was additionally used to perform forward and backward referencing. Title, abstract, and full-text screening was performed by two independent researchers. The Consensus Health Economic Criteria (CHEC) checklist and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 were applied for quality assessment. A total of 4470 studies were identified, of which 18 met our inclusion criteria. Twelve of the studies conducted model-based economic evaluation, and others were trial-based. Three studies showed that epilepsy surgery was cost-effective in adults, whereas this remained inconclusive for children (two positive, three negative). Three studies showed negative economic outcome for ketogenic diet in children. One of four studies showed positive results for self-management. For vagus nerve stimulation, one study showed positive results in adults and another one negative results in children. One recent study showed cost-effectiveness of responsive neurostimulation (RNS) in adults. Finally, one study showed promising but inconclusive results for deep brain stimulation (DBS). The mean scores for risk of bias assessment (based on CHEC) and for reporting quality (CHEERS 2022) were 95.8% and 80.5%, respectively. This review identified studies that assessed the cost-effectiveness of nonpharmacological treatments in both adults and children with drug-resistant epilepsy, suggesting that in adults, epilepsy surgery, vagus nerve stimulation, and RNS are cost-effective, and that DBS and self-management appear to be promising. In children, the cost-effectiveness of epilepsy surgery remains inconclusive. Finally, the use of ketogenic diet was shown not to be cost-effective. However, limited long-term data were available for newer interventions (i.e., ketogenic diet, DBS, and RNS).     

Central distribution of afferent and efferent components of the pudendal nerve in cat

Central distribution of afferent and efferent components of the pudendal nerve was examined in the cat by the HRP method after applying HRP to the central cut end of the pudendal nerve. Retrogradely labeled neuronal cell bodies were located primarily in the feline homologue of the Onuf's X nucleus, constituting a slender longitudinal cell column in the ventral horn of the S1 and S2 cord segments. The Onuf's nucleus was present constantly from middle S1 to high S2 cord segments, and occasionally extended rostrally to high S1 or low L7, and caudally to middle S2, low S2, or high S3 cord segments. No sex differences were observed in the distribution pattern, number, and soma size of labeled neurons in the Onuf's nucleus. Transganglionically labeled dorsal root fibers were found to terminate ipsilaterally in the lamina I of the dorsal horn at levels of lower lumbar, sacral, and higher coccygeal cord segments and the gracile nucleus, and bilaterally with an ipsilateral predominance in the dorsal commissural gray and laminae III, IV, V, and VI of the dorsal horn at levels of lower lumbar, sacral, and higher coccygeal cord segments. Some labeled dorsal root fibers appeared to end ipsilaterally in the regions where the sacral parasympathetic preganglionic neurons have been shown to be located.     

Differential fatigue of paralyzed thenar muscles by stimuli of different intensities

Muscles paralyzed by injury or disease fatigue excessively when stimulated. This study examined whether the first few paralyzed thenar motor units recruited by electrical stimulation of the median nerve were more fatigue resistant than the total thenar motor unit population. The paralyzed thenar muscles of four subjects with chronic cervical spinal cord injury were fatigued by a 2-min intermittent 40-HZ protocol on 2 days. One experiment involved submaximal stimulation, the other supramaximal stimulation. These stimuli resulted in activation of part and all of the thenar muscles, respectively. Relative force loss, force-time integral decline, and slowing of half-relaxation time were always significantly less when only part rather than all of the muscles was fatigued. The part of the paralyzed muscles that was activated was also relatively fatigue resistant compared with control single thenar motor units. Thus, a reversal of recruitment order from fatigable to fatigue-resistant units cannot explain the extreme fatigability of paralyzed muscles. Use of submaximal stimulation during functional electrical stimulation may therefore help to reduce muscle fatigue because it recruits the more fatigue-resistant units.     

Central distribution of efferent and afferent components of the pudendal nerve in macaque monkeys

Central distribution of efferent and afferent components of the pudendal nerve was studied by the horseradish peroxidase (HRP) method in 13 macaque monkeys, i.e., in nine Japanese monkeys (Macaca fuscata), two rhesus monkeys (Macaca mulatta), and two crab-eating monkeys (Macaca fascicularis). The enzyme was applied to the central cut end of the pudendal nerve; then the monkeys were allowed to survive for 36 to 72 hr. Retrogradely labeled neuronal cell bodies of pudendal motoneurons constituted a slender longitudinal cell column in the ventral horn. The cell column extended from high or middle S1 to high or middle S2 in eight monkeys, from middle or low L7 to high S2 in four monkeys, and from high L7 to middle S1 in a monkey. The cell column appeared to correspond to Onuf's X nucleus in man. No sex difference was recognized in the position of the cell column. The average number of HRP-labeled pudendal motoneurons was larger in male than in female adult Japanese monkeys, whereas no sex difference was found in the average soma diameter of the pudendal motoneurons. Transganglionically labeled axons entered into the spinal cord through the S1 and S2 dorsal roots in 12 monkeys and through the L7 and S1 dorsal roots in one monkey. Labeled axons were distributed ipsilaterally in laminae I-VI and X of the spinal cord at the same and adjacent levels of entry of HRP-labeled dorsal root fibers (from L7 to S3 in 12 monkeys and from L6 to S3 in one monkey).(ABSTRACT TRUNCATED AT 250 WORDS)     

迷走神经刺激治疗难治性癫(附12例分析)

目的探讨迷走神经刺激术(VNS)治疗顽固性癫的治疗效果和机制。方法回顾性分析12例顽固性癫病人的手术经验。其中脑炎后继发性癫3例,Lenonx-Castaut综合征(LGS)3例,原因不明6例。均行VNS治疗,手术将迷走神经刺激电极缠绕于迷走神经干上,在左腋前线作一皮肤切口,将刺激器置入皮下并与刺激电极相连接。术后2周开机,刺激电流从0.25mA逐渐调至1.5mA,刺激时间为30s,间歇(180～5)min,脉宽500～1000μs,频率30Hz。结果术后3个月,本组癫发作频率平均减少46%;术后随访1年以上5例,癫发作频率平均减少60%以上,且发作程度减轻,全身强直-阵挛性发作明显减少,精神状态改善。结论VNS手术创伤小,副作用少,术后能减少发作的频率,提高生活质量,对不适合开颅手术的难治性癫是一种安全有效、耐受性良好的治疗方法。     

A proposed guideline for vagus nerve stimulator handling in palliative care and after death

Vagus nerve stimulation (VNS) is often used for patients with drug-resistant epilepsy. Although this intervention may improve seizure control and mood, a number of factors must be considered when patients with VNS near end of life. We reviewed relevant literature to create a proposed guideline for management of patients with VNS in palliative care and after death. VNS has multiple possible side effects, including cough and swallowing difficulties. For patients with neurologic disease in palliative care, such adverse effects can severely affect quality of life and increase the risk for complications such as aspiration pneumonia. Patients with VNS should be screened regularly for such side effects, and VNS parameters should be adjusted if they are identified. If a patient requires urgent cardiac resuscitation involving external defibrillation, the VNS should be interrogated immediately afterwards to evaluate its function. During defibrillation, paddles should be placed perpendicular to the VNS, and as far as possible away from it. The VNS can be acutely turned off by taping the magnet to the patient's chest, thereby preventing any possible interference with restoration of a normal heart rhythm. After death, any staff involved with handling the body should be notified that a VNS is in place. The device must be removed prior to cremation, as it can explode with high heat. If the cause of death is unclear, a full postmortem examination should be undertaken, per sudden unexpected death in epilepsy guidelines. If there is concern about device malfunction, the device should be returned to the manufacturer for evaluation.