Adjunctive tonic motor activation enables opioid reduction for refractory restless legs syndrome: a prospective, open-label, single-arm clinical trial.

BACKGROUND: There is a large population of restless legs syndrome (RLS) patients who are refractory to medication. Whereas experts recommend off-label opioids as an effective long-term treatment for refractory RLS, reducing opioid dose could substantially reduce side effects and risks. Tonic motor activation (TOMAC) is a nonpharmacological therapeutic device indicated for refractory RLS. Here, we investigated if TOMAC could enable opioid dose reduction for refractory RLS. METHODS: This prospective, open-label, single-arm clinical trial [NCT04698343] enrolled 20 adults taking ≤ 60 morphine milligram equivalents (MMEs) per day for refractory RLS. Participants self-administered 30-min TOMAC sessions bilaterally over the peroneal nerve when RLS symptoms presented. During TOMAC treatment, opioid dose was reduced iteratively every 2-3 weeks until Clinician Global Impression of Improvement (CGI-I) score relative to baseline exceeded 5. Primary endpoint was percent of participants who successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Secondary endpoints included mean successful percent opioid dose reduction with CGI-I ≤ 5. RESULTS: On average, participants were refractory to 3.2 medications (SD 1.6) and were taking a stable dose of opioids for 5.3 years (SD 3.9). Seventy percent of participants (70%, 14 of 20) successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Mean percent opioid dose reduction with CGI-I ≤ 5 was 29.9% (SD 23.7%, n = 20) from 39.0 to 26.8 MME per day. Mean CGI-I score at the reduced dose was 4.0 (SD 1.4), indicating no change to RLS severity. CONCLUSIONS: For refractory RLS, TOMAC enabled substantial opioid dose reduction without increased RLS symptoms. These results suggest that TOMAC has the potential to reduce the risk profile associated with opioid therapy for refractory RLS. TRIAL REGISTRATION: ClinicalTrials.gov trial number NCT04698343 registered on January 6, 2021.

Covert skill learning in a cortical-basal ganglia circuit.

We learn complex skills such as speech and dance through a gradual process of trial and error. Cortical-basal ganglia circuits have an important yet unresolved function in this trial-and-error skill learning; influential 'actor-critic' models propose that basal ganglia circuits generate a variety of behaviours during training and learn to implement the successful behaviours in their repertoire. Here we show that the anterior forebrain pathway (AFP), a cortical-basal ganglia circuit, contributes to skill learning even when it does not contribute to such 'exploratory' variation in behavioural performance during training. Blocking the output of the AFP while training Bengalese finches to modify their songs prevented the gradual improvement that normally occurs in this complex skill during training. However, unblocking the output of the AFP after training caused an immediate transition from naive performance to excellent performance, indicating that the AFP covertly gained the ability to implement learned skill performance without contributing to skill practice. In contrast, inactivating the output nucleus of the AFP during training completely prevented learning, indicating that learning requires activity within the AFP during training. Our results suggest a revised model of skill learning: basal ganglia circuits can monitor the consequences of behavioural variation produced by other brain regions and then direct those brain regions to implement more successful behaviours. The ability of the AFP to identify successful performances generated by other brain regions indicates that basal ganglia circuits receive a detailed efference copy of premotor activity in those regions. The capacity of the AFP to implement successful performances that were initially produced by other brain regions indicates precise functional connections between basal ganglia circuits and the motor regions that directly control performance.

Efficacy and safety of TOMAC for treatment of medication-naïve and medication-refractory restless legs syndrome: A randomized clinical trial and meta-analysis.

OBJECTIVE/BACKGROUND: There is a significant unmet need for safe and effective nonpharmacological therapies for restless legs syndrome (RLS). The objective was to evaluate the efficacy and safety of tonic motor activation (TOMAC) in patients with RLS. PATIENTS/METHODS: A multicenter, randomized, participant-blinded, sham-controlled trial enrolled 45 adults with primary moderate-to-severe RLS who were either medication-naïve (n = 20) or medication-refractory (n = 25). Participants were 1:1 randomized to TOMAC (n = 22) or sham (n = 23) for two weeks and instructed to self-administer 30-min TOMAC sessions when they experienced RLS symptoms. The primary outcome was mean change in International RLS Study Group Rating Scale (IRLS) total score. A subsequent meta-analysis included the present trial and a previous randomized clinical trial that enrolled medication-naïve RLS patients. RESULTS: IRLS reduction was significantly greater for TOMAC than sham (TOMAC -6.59 vs. sham -2.17; mean difference (MD) = -4.42; 95 % confidence interval [CI] -1.57 to -7.26; p = 0.0040). Subgroup analysis showed similar IRLS mean difference for medication-refractory (MD = -4.50; p = 0.02) and medication-naïve (MD = -4.40; p = 0.08) cohorts, which was significantly different from sham only for the medication-refractory cohort. Meta-analysis of combined data from 33 medication-naïve RLS patients showed a significant reduction in mean IRLS score after two weeks for TOMAC compared to sham (MD = -4.30; 95 % CI -1.36 to -7.24; p = 0.004). CONCLUSIONS: The present trial confirmed previous reports documenting efficacy and safety of TOMAC in refractory RLS and indicated similar effect sizes in refractory versus naïve subgroups. The meta-analysis demonstrated that TOMAC significantly improves RLS symptoms in naïve participants.

Lesions in a songbird vocal circuit increase variability in song syntax.

Complex skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for the syntactic ordering of actions is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered syllables, controlled in part by the songbird premotor nucleus HVC (proper name). Here, we test whether one of HVC's recurrent inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), contributes to sequencing in adult male Bengalese finches (Lonchura striata domestica). Bengalese finch song includes several patterns: (1) chunks, comprising stereotyped syllable sequences; (2) branch points, where a given syllable can be followed probabilistically by multiple syllables; and (3) repeat phrases, where individual syllables are repeated variable numbers of times. We found that following bilateral lesions of mMAN, acoustic structure of syllables remained largely intact, but sequencing became more variable, as evidenced by 'breaks' in previously stereotyped chunks, increased uncertainty at branch points, and increased variability in repeat numbers. Our results show that mMAN contributes to the variable sequencing of vocal elements in Bengalese finch song and demonstrate the influence of recurrent projections to HVC. Furthermore, they highlight the utility of species with complex syntax in investigating neuronal control of ordered sequences.

Variable sequencing is actively maintained in a well learned motor skill.

Variation in sequencing of actions occurs in many natural behaviors, yet how such variation is maintained is poorly understood. We investigated maintenance of sequence variation in adult Bengalese finch song, a learned skill with rendition-to-rendition variation in the sequencing of discrete syllables (i.e., syllable "b" might transition to "c" with 70% probability and to "d" with 30% probability). We found that probabilities of transitions ordinarily remain stable but could be modified by delivering aversive noise bursts following one transition (e.g., "b→c") but not the alternative (e.g., "b→d"). Such differential reinforcement induced gradual, adaptive decreases in probabilities of targeted transitions and compensatory increases in alternative transitions. Thus, the normal stability of transition probabilities does not reflect hardwired premotor circuitry. While all variable transitions could be modified by differential reinforcement, some were less readily modified than others; these were cases that exhibited more alternation between possible transitions than predicted by chance (i.e., "b→d " would tend to follow "b→c " and vice versa). These history-dependent transitions were less modifiable than more stochastic transitions. Similarly, highly stereotyped transitions (which are completely predictable) were not modifiable. This suggests that stochastically generated variability is crucial for sequence modification. Finally, we found that, when reinforcement ceased, birds gradually restored transition probabilities to their baseline values. Hence, the nervous system retains a representation of baseline probabilities and has the impetus to restore them. Together, our results indicate that variable sequencing in a motor skill can reflect an end point of learning that is stably maintained via continual self-monitoring.

Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms.

STUDY OBJECTIVES: Restless legs syndrome (RLS) is a prevalent sleep disorder with limited treatment options. Bilateral high-frequency noninvasive peroneal nerve stimulation (NPNS) reduces RLS symptoms. Here, we sought to characterize the mechanism of action for NPNS and identify predictors of treatment response. We hypothesized that, similar to voluntary leg movements, NPNS reduces RLS symptoms by activating leg muscles. METHODS: For 20 adults with moderate-severe RLS, we tested this hypothesis by recording surface electromyography (EMG) from the tibialis anterior leg muscle while administering NPNS at varying amplitudes to determine the minimum NPNS amplitude that evoked EMG activity (motor threshold) and maximal NPNS amplitude that was not distracting (therapeutic intensity level). Afterwards, participants self-administered NPNS (at the therapeutic intensity level) and sham control for 14 days, each in randomized order. Efficacy was defined as International RLS Study Group Rating Scale (IRLS) score difference for NPNS compared with sham. RESULTS: NPNS consistently activated leg muscles; NPNS evoked EMG activity at the therapeutic intensity level for 19 of 20 participants (mean TIL: 26.6 mA, mean MT: 18.3 mA). Evoked EMG activity was tonic (not phasic) and sustained over time. Evoked EMG activity predicted efficacy; participants with lower motor thresholds had greater IRLS improvement (r = .45, P = .046). NPNS treatment did not interfere with self-reported sleep onset (NPNS: 16% of nights; sham: 11%; P = .629) and frequently improved self-reported sleep onset (NPNS: 52% of nights; sham: 15%; P = .002). CONCLUSIONS: These results demonstrate that NPNS reduces RLS symptoms by activating afferent pathways, thereby generating tonic and sustained leg muscle activity without interfering with sleep. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT04700683; Identifier: NCT04700683. CITATION: Charlesworth JD, Adlou B, Singh H, Buchfuhrer MJ. Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms. J Clin Sleep Med. 2023;19(7):1199-1209.

Long-term efficacy and safety of tonic motor activation for treatment of medication-refractory restless legs syndrome: A 24-Week Open-Label Extension Study.

STUDY OBJECTIVES: To evaluate long-term efficacy and safety of tonic motor activation (TOMAC) for treatment of medication-refractory moderate-to-severe primary restless legs syndrome (RLS). METHODS: In the parent study (RESTFUL), adults with refractory RLS were randomized to active TOMAC or sham for 4 weeks followed by 4 weeks of open-label active TOMAC. In the extension study, earlier RESTFUL completers comprised the control group (n = 59), which was followed for 24 weeks with no TOMAC intervention, and later RESTFUL completers compromised the treatment group (n = 44), which received 24 additional weeks of open-label active TOMAC followed by no intervention for 8 weeks. The primary endpoint was Clinician Global Impressions-Improvement (CGI-I) responder rate at week 24 compared to RESTFUL entry. RESULTS: CGI-I responder rate improved from 63.6% (95% CI, 49.4 to 77.9%) at RESTFUL completion to 72.7% (95% CI, 58.2 to 83.7%) at week 24 for the treatment group versus 13.6% (95% CI, 7.0 to 24.5%) at week 24 for the control group (p < 0.0001). Mean change in International RLS Rating Scale (IRLS) score improved from -7.4 (95% CI, -5.6 to -9.2) at RESTFUL completion to -11.3 points (95% CI, -8.8 to -13.9) at week 24 for the treatment group versus -5.4 (95% CI, -3.7 to -7.2) at week 24 for control group (p = 0.0001). All efficacy endpoints partially reverted during cessation of treatment. There were no grade 2 or higher device-related adverse events. CONCLUSIONS: TOMAC remained safe and efficacious for >24 total weeks of treatment with partial reversion of benefits upon cessation. CLINICAL TRIAL: Extension Study Evaluating NTX100 Neuromodulation System for Medication-Refractory Primary RLS; clinicaltrials.gov/ct2/show/NCT05196828; Registered at ClinicalTrials.gov with the identifier number NCT05196828.

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial.

STUDY OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety/tolerability of bilateral high-frequency tonic motor activation (TOMAC) in patients with medication-refractory restless legs syndrome (RLS). METHODS: RESTFUL was a multicenter, randomized, double-blind, sham-controlled trial in adults with medication-refractory moderate-to-severe primary RLS. Participants were randomized 1:1 to active or sham TOMAC for a double-blind, 4-week stage 1 and all received active TOMAC during open-label, 4-week stage 2. The primary endpoint was the Clinical Global Impressions-Improvement (CGI-I) responder rate at the end of stage 1. Key secondary endpoints included change to International RLS Study Group (IRLS) total score from study entry to the end of stage 1. RESULTS: A total of 133 participants were enrolled. CGI-I responder rate at the end of stage 1 was significantly greater for the active versus sham group (45% vs. 16%; Difference = 28%; 95% CI 14% to 43%; p = .00011). At the end of stage 2, CGI-I responder rate further increased to 61% for the active group. IRLS change at the end of stage 1 improved for the active versus sham group (-7.2 vs. -3.8; difference = -3.4; 95% CI -1.4 to -5.4; p = .00093). There were no severe or serious device-related adverse events (AEs). The most common AEs were mild discomfort and mild administration site irritation which resolved rapidly and reduced in prevalence over time. CONCLUSIONS: TOMAC was safe, well tolerated, and reduced symptoms of RLS in medication-refractory patients. TOMAC is a promising new treatment for this population. CLINICAL TRIAL: Noninvasive Peripheral Nerve Stimulation for Medication-Refractory Primary RLS (The RESTFUL Study); clinicaltrials.gov/ct2/show/NCT04874155; Registered at ClinicalTrials.gov with the identifier number NCT04874155.

Mechanisms and time course of vocal learning and consolidation in the adult songbird.

In songbirds, the basal ganglia outflow nucleus LMAN is a cortical analog that is required for several forms of song plasticity and learning. Moreover, in adults, inactivating LMAN can reverse the initial expression of learning driven via aversive reinforcement. In the present study, we investigated how LMAN contributes to both reinforcement-driven learning and a self-driven recovery process in adult Bengalese finches. We first drove changes in the fundamental frequency of targeted song syllables and compared the effects of inactivating LMAN with the effects of interfering with N-methyl-d-aspartate (NMDA) receptor-dependent transmission from LMAN to one of its principal targets, the song premotor nucleus RA. Inactivating LMAN and blocking NMDA receptors in RA caused indistinguishable reversions in the expression of learning, indicating that LMAN contributes to learning through NMDA receptor-mediated glutamatergic transmission to RA. We next assessed how LMAN's role evolves over time by maintaining learned changes to song while periodically inactivating LMAN. The expression of learning consolidated to become LMAN independent over multiple days, indicating that this form of consolidation is not completed over one night, as previously suggested, and instead may occur gradually during singing. Subsequent cessation of reinforcement was followed by a gradual self-driven recovery of original song structure, indicating that consolidation does not correspond with the lasting retention of changes to song. Finally, for self-driven recovery, as for reinforcement-driven learning, LMAN was required for the expression of initial, but not later, changes to song. Our results indicate that NMDA receptor-dependent transmission from LMAN to RA plays an essential role in the initial expression of two distinct forms of vocal learning and that this role gradually wanes over a multiday process of consolidation. The results support an emerging view that cortical-basal ganglia circuits can direct the initial expression of learning via top-down influences on primary motor circuitry.

Noninvasive neuromodulation reduces symptoms of restless legs syndrome.

STUDY OBJECTIVES: Restless legs syndrome (RLS) is a common neurological disorder characterized by an uncontrollable nocturnal urge to move the legs and often associated with chronic sleep disturbances. The most common treatments for RLS are medications that can have debilitating side effects. Here, we evaluated a novel alternative modality of RLS treatment, noninvasive bilateral electrical stimulation of the common peroneal nerve. METHODS: To assess the impact of this noninvasive peripheral nerve stimulation (NPNS) approach to RLS symptomatology, we conducted a multisite randomized crossover study comparing NPNS to sham. RLS patients with moderate-to-severe RLS (n = 37) self-administered NPNS and sham nightly for 14 days per treatment in randomized order. RESULTS: NPNS resulted in a reduction in RLS severity of 6.81 points on the International RLS Rating Scale relative to 3.38 for sham (P < .01) and a 66% clinically significant responder rate on the Clinical Global Impressions-Improvement scale compared to 17% for sham (P < .01). Subgroup analysis indicated that medication-resistant and medication-naïve participants both exhibited similarly robust responses. There were no moderate or serious device-related adverse events. CONCLUSIONS: These results suggest that NPNS could be a promising alternative to pharmacological therapies for RLS and could provide a solution for medication-resistant RLS patients and for medication-naïve RLS patients who are unwilling or unable to take medication. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT04700683; Identifier: NCT04700683. CITATION: Buchfuhrer MJ, Baker FC, Haramandeep S, et al. Noninvasive neuromodulation reduces symptoms of restless legs syndrome. J Clin Sleep Med. 2021;17(8):1685-1694.

Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene.

Volatile organic solvent (inhalant) abuse continues to be a major health concern throughout the world. Of particular concern is the abuse of inhalants by adolescents because of its toxicity and link to illicit drug use. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. While studies have assessed outcomes of exposure to inhalants in adult male animals, there is little research on the neurobehavioral effects of inhalants in female or younger animals. In attempt to address these shortcomings, we exposed male and female Long-Evans rats to 20 min of 0, 2000, 4000, or 8000 parts per million (ppm) inhaled toluene for 10 days in rats aged postnatal (PN) day 28-39 (adolescent), PN44-PN55, or >PN70 (adult). Animals were observed individually in 29-l transparent glass cylindrical jars equipped with standard photocells that were used to measure locomotor activity. Toluene significantly increased activity as compared to air exposure in all groups of male and female rats with the magnitude of locomotor stimulation produced by 4000 ppm toluene being significantly greater for female adults than during any age of adolescence. The results demonstrate that exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous locomotor behavior in rats and that the expression of these effects appears to depend upon the postnatal age of testing and sex of the animal.

Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans.

We engineered a transdermal neuromodulation approach that targets peripheral (cranial and spinal) nerves and utilizes their afferent pathways as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) method on sympathetic physiology under different experimental conditions. The TEN method involved delivering high-frequency pulsed electrical currents to ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents. Under resting conditions, TEN significantly suppressed basal sympathetic tone compared to sham as indicated by functional infrared thermography of facial temperatures. In a different experiment, subjects treated with TEN reported significantly lower levels of tension and anxiety on the Profile of Mood States scale compared to sham. In a third experiment when subjects were experimentally stressed TEN produced a significant suppression of heart rate variability, galvanic skin conductance, and salivary α-amylase levels compared to sham. Collectively these observations demonstrate TEN can dampen basal sympathetic tone and attenuate sympathetic activity in response to acute stress induction. Our physiological and biochemical observations are consistent with the hypothesis that TEN modulates noradrenergic signaling to suppress sympathetic activity. We conclude that dampening sympathetic activity in such a manner represents a promising approach to managing daily stress.

Learning the microstructure of successful behavior.

Reinforcement signals indicating success or failure are known to alter the probability of selecting between distinct actions. However, successful performance of many motor skills, such as speech articulation, also requires learning behavioral trajectories that vary continuously over time. Here, we investigated how temporally discrete reinforcement signals shape a continuous behavioral trajectory, the fundamental frequency of adult Bengalese finch song. We provided reinforcement contingent on fundamental frequency performance only at one point in the song. Learned changes to fundamental frequency were maximal at this point, but also extended both earlier and later in the fundamental frequency trajectory. A simple principle predicted the detailed structure of learning: birds learned to produce the average of the behavioral trajectories associated with successful outcomes. This learning rule accurately predicted the structure of learning at a millisecond timescale, demonstrating that the nervous system records fine-grained details of successful behavior and uses this information to guide learning.