Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Effects of different vibration frequencies on spinal cord reflex circuits and thermoalgesic perception.

OBJECTIVES: We studied the effect of different vibration frequencies on spinal cord excitability and heat pain perception. We hypothesized that the effects of vibration on spinal cord reflexes, and, also those on heat pain perception, depend on vibration frequency. METHODS: In 9 healthy subjects, we applied vibration over the tibialis anterior muscle at three different frequencies (50, 150, or 250 Hz) on spinal cord reflex excitably, tested with the H reflex and the T wave in the soleus muscle, as well as on sensory and pain perception, tested by measuring warm perception (WT) and heat pain perception thresholds, (HPT) in sites rostral and caudal to vibration. Exams were carried out before, during, and after vibration. RESULTS: The amplitude of the H reflex and T wave significantly decreased during vibration in comparison to baseline. Low frequencies (50 and 150Hz) induced greater reflex suppression than high frequency (250Hz). No significant changes were observed on WT and HPT. CONCLUSIONS: The effects of vibratory stimulation can be summarized as frequency-related suppression of the spinal cord excitability without an effect on warm and heat pain perception. The present results may help to design vibration-related interventions intended to diminish spinal cord reflex excitability in spastic patients.

Intermittent tACS during a visual task impacts neural oscillations and LZW complexity.

Little is known about how transcranial alternating current stimulation (tACS) interacts with brain activity. Here, we investigate the effects of tACS using an intermittent tACS-EEG protocol and use, in addition to classical metrics, Lempel-Ziv-Welch complexity (LZW) to characterize the interactions between task, endogenous and exogenous oscillations. In a cross-over study, EEG was recorded from thirty participants engaged in a change-of-speed detection task while receiving multichannel tACS over the visual cortex at 10 Hz, 70 Hz and a control condition. In each session, tACS was applied intermittently during 5 s events interleaved with EEG recordings over multiple trials. We found that, with respect to control, stimulation at 10 Hz ([Formula: see text]) enhanced both [Formula: see text] and [Formula: see text] power, [Formula: see text]-LZW complexity and [Formula: see text] but not [Formula: see text] phase locking value with respect to tACS onset ([Formula: see text]-PLV, [Formula: see text]-PLV), and increased reaction time (RT). [Formula: see text] increased RT with little impact on other metrics. As trials associated with larger [Formula: see text]-power (and lower [Formula: see text]-LZW) predicted shorter RT, we argue that [Formula: see text] produces a disruption of functionally relevant fast oscillations through an increase in [Formula: see text]-band power, slowing behavioural responses and increasing the complexity of gamma oscillations. Our study highlights the complex interaction between tACS and endogenous brain dynamics, and suggests the use of algorithmic complexity inspired metrics to characterize cortical dynamics in a behaviorally relevant timescale.

Noninvasive Brain Stimulation and Noninvasive Peripheral Stimulation for Neglect Syndrome Following Acquired Brain Injury.

OBJECTIVE: Hemispatial neglect is a frequent condition usually following nondominant hemispheric brain injury. It strongly affects rehabilitation strategies and everyday life activities. It is associated with behavioral and cognitive disability with a strong impact on patient's life. METHODS: We reviewed the published literature on the use of noninvasive brain stimulation, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), and of noninvasive peripheral muscle stimulation, as therapeutic strategies for rehabilitation of neglect after acquired brain injury, such as in stroke or in traumatic injuries. The studies were grouped as controlled or uncontrolled studies in each stimulation techniques. RESULTS: Thirty-four studies were identified and 16 on rTMS, 10 on tDCS, and 8 on vibration. All studies were conducted in adult patients who suffered a stroke, except for one that was conducted in a patient suffering traumatic acquired brain injury and another that was conducted in a patient with brain tumor. In spite of significant variability in treatment protocols, patients' features and assessment of neglect, improvement was reported in almost all studies with no side-effects. CONCLUSIONS: Noninvasive brain stimulation and neuromuscular vibration are promising therapeutic neuromodulatory approaches for neglect. Further randomized-controlled studies are needed to corroborate their effectiveness as separate and combined techniques.

Unilateral pallidal stimulation for disabling dystonia due to Rasmussen's disease.

OBJECTIVE: To describe an adult patient with Rasmussen's disease with focal dystonia as the most disabling symptom and the good response to unilateral globus pallidus internus (GPi) deep brain stimulation (DBS). METHODS: Retrospective review of clinical records and diagnostic tests. RESULTS: The patient had displayedmild focal seizures with sensory and motor symptoms on the left arm and hemiface since the age of 22. Ten years later she experienced abrupt onset of focal left dystonia involving mainly the leg. Brain MRI showed progressive right hemisphere atrophy, and  18 fluorodeoxyglucose-positron emission tomography (18FDG-PET) showed right hypometabolism mainly over the frontal and insular regions. Brain biopsy confirmed chronic encephalitis. The dystonia became very severe and made walking extremely difficult. Different treatments including dopaminergic, anticholinergic, immunomodulatory drugs and botulinum toxin were ineffective. Finally the patient was treated with unilateral GPi DBS. Shortly after the onset of the stimulation, the dystonia started to improve. Parameters have been adjusted, and 18 months after surgery the patient is able to walk and run unaided, although a mild left leg dystonia persists. CONCLUSION: Rasmussen's disease may be difficult to diagnose in adult patients. Associated movement disorders may be more disabling than seizures. Focal dystonia may be treated successfully with DBS.

Prepulse inhibition of the blink reflex is abnormal in functional movement disorders.

BACKGROUND: Patients with functional movement disorders also typically have functional somatic symptoms, including pain, fatigue, and sensory disturbance. A potentially unifying mechanism for such symptoms is a failure in processing of sensory inputs. Prepulse inhibition is a neurophysiological method that allows for the study of preconscious somatosensory processing. OBJECTIVE: The objective of this study was to assess prepulse inhibition in patients with functional movement disorders and healthy control subjects. METHODS: We analyzed the effect of a weak electrical stimulus to the index finger (prepulse) on the magnitude of the R2 response of the blink reflex induced by electrical stimuli delivered to the supraorbital nerve in 22 patients with clinically established functional movement disorders and 22 matched controls. Pain, depression, anxiety, and obsessive-compulsive symptoms were assessed using self-rated questionnaires. In addition, in patients we assessed motor symptom severity. RESULTS: Prepulses suppressed the R2 response of the blink reflex in both groups, by 36.4% (standard deviation: 25.6) in patients and by 67.3% (standard deviation: 16.4) in controls. This difference was significant (P < 0.001). There was no significant correlation between motor and nonmotor symptom measures and prepulse inhibition size. CONCLUSIONS: Impaired prepulse inhibition of the blink reflex suggests an abnormal preconscious processing of somatosensory inputs, which can be interpreted within predictive coding accounts of both functional movement disorders and functional somatic syndromes. Our results, along with previous findings of a reduced prepulse inhibition in fibromyalgia syndrome, support a possible unified pathophysiology across functional neurological and somatic syndromes with noteworthy implications for diagnostic classification and development of novel biomarkers and treatments. © 2019 International Parkinson and Movement Disorder Society.

Jendrassik maneuver effect on spinal and brainstem reflexes.

The effect of Jendrassik Maneuver (JM) has been extensively studied on monosynaptic reflexes in numerous muscles below the level at which the maneuver was performed. Here we hypothesize that the effect of JM could be observed also on other reflexes, indicating a widespread influence of performing a motor act such as the JM. We examined polysynaptic reflexes caudal (i.e., the withdrawal reflex of the lower extremities) and rostral (i.e., the blink reflex to supraorbital nerve stimulation) to the level of JM contraction. We have assessed soleus tendon (T) reflex; withdrawal reflex in tibialis anterior and soleus muscle; blink reflex (BR), blink reflex excitability recovery curve (BR-ER) and prepulse inhibition of the blink reflex. Our results showed that (1) T-reflex amplitude increased during JM and decreased just after and 15 min after JM; (2) no change in the withdrawal reflex; (3) R2 area of BR reduced significantly just after or 15 min after JM; (4) Prepulse inhibition in BR reduced significantly during JM; (5) no change in BR-ER. Our results indicate that JM leads to generalized effects on neural excitability at both caudal and rostral levels. Furthermore, JM has a selective effect on excitability of reflex circuitries.

Botulinum Toxin Type A Improves Function According to Goal Attainment in Adults with Poststroke Lower Limb Spasticity in Real Life Practice.

INTRODUCTION: Botulinum toxin type A (BoNT-A) is an effective and well-tolerated treatment for adult lower limb spasticity. However, data are inadequate to determine BoNT-A efficacy for active function. This study evaluated functional goal achievement (measured by goal attainment scaling [GAS]) following lower limb BoNT-A injection in clinical practice. METHODS: Phase 4, postmarketing, multicenter, prospective, observational study (NCT01444794) in adults with poststroke lower limb spasticity receiving one BoNT-A injection cycle. Assessments were at baseline (pretreatment), 1 month ±7 days (visit 1), and 3-5 months posttreatment (visit 2). Primary outcome measure was GAS; additional assessments included Modified Ashworth Scale, Demeurisse Motricity Index, 10-meter walk test, and Disability Assessment Scale. RESULTS: Of 100 enrolled patients, 94 completed the study. Most common primary treatment goals at baseline were improving mobility (57.5%) and positioning (18.1%). At visit 2, 88.3% achieved their primary goal; 87.0% (n = 47/54) for mobility, and 100.0% (n = 17/17) for positioning. In total, 79.1% of patients achieved their secondary goals. Two factors were predictive of primary goal achievement: time since stroke onset (OR 0.907; 95% CI 0.827-0.995; p = 0.038); and absence of stiff knee spasticity pattern (OR 0.228; 95% CI 0.057-0.911; p = 0.036). All functional scales showed improvements; walking speed (mean [SD]) improved by 0.06 (0.13) and 0.05 (0.20) m/s at visits 1 and 2, respectively. CONCLUSIONS: BoNT-A injection for lower limb spasticity led to high goal achievement rates in patient-centered GAS evaluation and functional and symptomatic improvements. BoNT-A may therefore deliver clinically meaningful functional improvements in real-life practice.

Double peak sensory nerve action potentials to single stimuli in nerve conduction studies.

INTRODUCTION: In humans, sensory nerve action potentials (SNAPs) can show 2 separate deflections, i.e., double peak potentials (DPp), which necessarily means that 1 peak is delayed with respect to the other. DPps may have various origins and be due to either physical or physiological properties. METHODS: We review the nature of commonly encountered DPps in clinical practice, provide the most likely interpretations for their physiological origin, and assess their reproducibility and clinical utility. RESULTS: We classified the DPps into 3 categories: (1) simultaneous anodal and cathodal stimulation. (2) simultaneous recording from 2 different nerves at the same site, and (3) SNAP desynchronization. CONCLUSIONS: Although the recording of DPps is not a standardized neurophysiological method, their study brings interesting cues about the physiology of nerve stimulation and paves the way for clinical application of such an observation. Muscle Nerve 55: 619-625, 2017.

Anodal sensory nerve action potentials: From physiological understanding to potential clinical applicability.

INTRODUCTION: Low-intensity electrical stimuli of digital nerves may generate a double peak potential (DPp), composed of a cathodal (caAP) and an anodal (anAP) potential in orthodromic recordings. METHODS: We studied the effects on caAP and anAP of stimuli of variable intensity, duration, and frequency. We also applied a conditioning stimulus to study potential differences in recovery time. RESULTS: The anAP was obtained in 33 of 40 healthy subjects (82.5%) and 4 of 20 patients with various types of sensory neuropathies (20%). Changes in stimulus duration and intensity had reciprocal effects on the amplitude of the anAP and the caAP. There were significant differences in recovery time between caAP and anAP after a conditioning stimulus. CONCLUSION: The caAP and anAP are 2 interdependent waveforms generated by different effects of the same stimulus over axons at the verge of depolarization. Muscle Nerve 53: 897-905, 2016.

Placebo-controlled study of rTMS combined with Lokomat® gait training for treatment in subjects with motor incomplete spinal cord injury.

High-frequency rTMS combined with gait training improves lower extremity motor score (LEMS) and gait velocity in SCI subjects who are able to walk over ground. The aim of this study was to optimize the functional outcome in early phases of gait rehabilitation in SCI using rTMS as an additional treatment to physical therapy. The present study included 31 motor incomplete SCI subjects randomized to receive real or sham rTMS, just before Lokomat gait training (15 subjects for real, 16 for sham rTMS). rTMS consisted of one daily session for 20 days over vertex (at 20 Hz). The subjects were evaluated using modified Ashworth scale (MAS) for spasticity, upper and lower extremity motor score (UEMS and LEMS, respectively), ten meters walking test (10MWT) and Walking Index for SCI (WISCI-II) for gait at baseline, after last rTMS session, and during follow-up. UEMS and LEMS improved significantly after last session in both groups and during follow-up period. The improvement was greater in real than in sham rTMS group. At follow-up, 71.4 % of the subjects after real rTMS and 40 % of the subjects after sham rTMS could perform 10MWT without significant differences in gait velocity, cadence, step length and WISCI-II between both groups. We conclude that 20 sessions of daily high-frequency rTMS combined with Lokomat gait training can lead to clinical improvement of gait in motor incomplete SCI. Such combined treatment improved motor strength in lower extremity in incomplete SCI subjects and in upper extremity in those with cervical SCI.

Is electromyography a predictive test of patient response to biofeedback in the treatment of fecal incontinence?

AIM: Biofeedback is effective in more than 70% of patients with fecal incontinence. However, reliable predictors of successful treatment have not been identified. The aim was to identify clinical variables and diagnostic tests, particularly electromyography, that could predict a successful outcome. METHODS: We included 135 consecutive women with fecal incontinence treated with biofeedback. Clinical evaluation, manometry, ultrasonography, electromyography, and pudendal nerve terminal motor latency were performed before therapy. Treatment outcome was assessed using a symptoms diary, Wexner incontinence score and the patient's subjective perception. RESULTS: According to the symptoms diaries, 106 (78.5%) women had a good clinical result and 29 (21.5%) had a poor result. There were no differences in age, severity and type of fecal incontinence. Maximum resting pressure (39.3 ± 19.1 mmHg vs. 33.7 ± 20.2 mmHg; P = 0.156) and maximum squeeze pressure (91.8 ± 33.2 mmHg vs. 79.8 ± 31.2 mmHg; P = 0.127) were higher in patients having good clinical outcome although the difference was not significant. There were no differences in the presence of sphincter defects or abnormalities in electromyographic recordings. Logistic regression analysis found no independent predictive factor for good clinical outcome. CONCLUSIONS: Biofeedback is effective in more than 75% of patients with fecal incontinence. Clinical characteristics of patients and results of baseline tests have no predictive value of response to therapy. Specifically, we found no association between severity of electromyographic deficit and clinical response.

Defective sensorimotor integration in preparation for reaction time tasks in patients with multiple sclerosis.

Slowness of voluntary movements in patients with multiple sclerosis (MS) may be due to various factors, including attentional and cognitive deficits, delays in motor conduction time, and impairment of specific central nervous system circuits. In 13 healthy volunteers and 20 mildly disabled, relapsing-remitting MS patients, we examined simple reaction time (SRT) tasks requiring sensorimotor integration in circuits involving the corpus callosum and the brain stem. A somatosensory stimulus was used as the imperative signal (IS), and subjects were requested to react with either the ipsilateral or the contralateral hand (uncrossed vs. crossed SRT). In 33% of trials, a startling auditory stimulus was presented together with the IS, and the percentage reaction time change with respect to baseline SRT trials was measured (StartReact effect). The difference between crossed and uncrossed SRT, which requires interhemispheric conduction, was significantly larger in patients than in healthy subjects (P = 0.021). The StartReact effect, which involves activation of brain stem motor pathways, was reduced significantly in patients with respect to healthy subjects (uncrossed trials: P = 0.015; crossed trials: P = 0.005). In patients, a barely significant correlation was found between SRT delay and conduction abnormalities in motor and sensory pathways (P = 0.02 and P = 0.04, respectively). The abnormalities found specifically in trials reflecting interhemispheric transfer of information, as well as the evidence for reduced subcortical motor preparation, indicate that a delay in reaction time execution in MS patients cannot be explained solely by conduction slowing in motor and sensory pathways but suggest, instead, defective sensorimotor integration mechanisms in at least the two circuits examined.

Influence of spinal cord lesion level and severity on H-reflex excitability and recovery curve.

INTRODUCTION: Changes in spinal reflexes can result from alterations in the spinal cord and descending pathways. We studied whether H-reflex excitability and its recovery depend on the level and/or severity of spinal cord injury (SCI). METHODS: The soleus Hmax and Mmax responses and the H-reflex recovery curve (HRC) at interstimulus intervals (ISIs) ranging from 50 to 1,000 ms were recorded in 38 SCI individuals and 18 healthy subjects. RESULTS: Amplitude of Mmax correlated with level and severity of lesion (smaller amplitude correlated with more severe SCI or with more caudal lesion). Hmax/Mmax correlated only with age in the SCI group. HRC was increased significantly in complete SCI at ISIs < 500 ms and in incomplete SCI at ISIs > 200 ms with respect to healthy subjects. CONCLUSIONS: The changes in spinal reflexes as measured by the H-reflex and its recovery curve after SCI depend on the severity, but not on the level of the lesion.

Cutaneous autonomic denervation in Parkinson's disease.

Numerous studies have detailed involvement of the peripheral autonomic nervous system (PANS) in Parkinson's disease (PD). We assessed autonomic innervation of dermal annexes through quantitative fluorescence measurement from skin obtained via punch biopsies at distal leg region in PD and control subjects. We defined a ratio between the area corresponding to protein gen product (PGP) immunoreactivity and the area corresponding to blood vessel or sweat gland as a quantitative measure of autonomic innervation. Presence of alpha-synuclein (AS) deposits in dermis and hypodermis was also assessed by immunohistochemistry. Skin biopsies form six PD patients and six healthy controls were studied. Autonomic innervation scores were lower in PD than in controls in both blood vessels and sweat glands. No AS or phosphorylated AS (pAS) immunoreactivity was detected in dermis or hypodermis in any of the studied subjects. The results of this investigation suggest that autonomic innervation of dermal annexes in living patients with PD is reduced compared to controls. AS or pAS deposits were not found in dermis or hypodermis suggesting that distal leg skin study is not useful for in vivo detection of AS in PD.

Effects of postural and voluntary muscle contraction on modulation of the soleus H reflex by transcranial magnetic stimulation.

Modulation of spinal reflexes depends largely on the integrity of the corticospinal tract. A useful method to document the influence of descending tracts on reflexes is to examine the effects of transcranial magnetic stimulation (TMS) on the soleus H reflex elicited by posterior tibial nerve electrical stimuli (PTS). In 12 healthy volunteers, we investigated how postural or voluntary muscle contraction modified such descending modulation. We first characterized the effects of TMS at 95 % of motor threshold for leg responses on the H reflex elicited by a preceding PTS at inter-stimuli intervals (ISIs) between 0 and 120 ms at rest and, then, during voluntary plantar flexion (pf), dorsal flexion (df), and standing still (ss). During pf, there was an increase in the facilitation of the H reflex at ISIs 0-20 ms. During df, there were no effects of TMS on the H reflex. During ss, there was inhibition at ISIs 40-60 ms. Our observations suggest that muscle contraction prevails over the baseline effects of TMS on the soleus H reflex. While contraction of the antagonist (df) suppressed most of the effects, contraction of the agonist had different effects depending on the type of activity (pf or ss). The characterization of the interaction between descending corticospinal volleys and segmental peripheral inputs provides useful information on motor control for physiological research and further understanding of the effects of spinal cord lesions.

Temporal profile of the effects of regional anesthesia on the cutaneous reflexes of foot muscles.

We analyzed the effects of an anesthetic sciatic nerve block on the cutaneomuscular reflex (cMR) and the cutaneous silent period (cSP) of foot muscles, in order to investigate further the type of fibers involved in their generation. In 14 neurologically normal patients with indication for surgical treatment of hallux valgus, we recorded from the extensor digitorum brevis muscle the reflex responses elicited by high-intensity electrical stimulation of the big toe at various time periods, ranging from 0 to 20 min, after ultrasound-guided sciatic nerve popliteal anesthetic block. The first effect was a delay in cSP onset latency, with no changes in end latency. The cMR remained unaltered up to when subjects were no longer able to maintain the contraction. The effects of local anesthetics on peripheral nerves allow for recognition of the different types of fibers contributing to the cMR and the cSP in muscles of the lower limb.

The effects of transcranial direct current stimulation on conscious perception of sensory inputs from hand palm and dorsum.

Conscious perception of sensory signals depends in part on stimulus salience, relevance and topography. Letting aside differences at skin receptor level and afferent fibres, it is the CNS that makes a contextual selection of relevant sensory inputs. We hypothesized that subjective awareness (AW) of the time at which a sensory stimulus is perceived, a cortical function, may be differently modified by cortical stimulation, according to site and type of the stimulus. In 24 healthy volunteers, we examined the effects of transcranial direct current stimulation (tDCS) on the assessment of AW to heat pain or weak electrical stimuli applied to either the hand palm or dorsum. We also recorded the vertex-evoked potentials to the same stimuli. The assessment was done before, during and after cathodal or anodal tDCS over the parietal cortex contralateral to the hand receiving the stimuli. At baseline, AW to thermal stimuli was significantly longer for palm than for dorsum (P < 0.01), while no differences between stimulation sites were observed for the electrical stimuli. Both cathodal and anodal tDCS caused a significant shortening of AW to thermal stimuli in the palm but not in the dorsum, and no effects on AW to electrical stimuli. Longer AW in the palm than in the dorsum may be attributable to differences in skin thickness. However, the selectivity of the effects of tDCS on AW to thermal stimulation of the glabrous skin reflects the specificity of CNS processing for site and type of sensory inputs.

Neural control of blinking.

Blinking is a motor act characterized by the sequential closing and opening of the eyelids, which is achieved through the reciprocal activation of the orbicularis oculi and levator palpebrae superioris muscles. This stereotyped movement can be triggered reflexively, occur spontaneously, or voluntarily initiated. During each type of blinking, the neural control of the antagonistic interaction between the orbicularis oculi and levator palpebrae superioris muscles is governed by partially overlapping circuits distributed across cortical, subcortical, and brainstem structures. This paper provides a comprehensive overview of the anatomical and physiological foundations underlying the neural control of blinking. We describe the infra-nuclear apparatus, as well as the supra-nuclear control mechanisms, i.e., how cortical, subcortical, and brainstem structures regulate and coordinate the different types of blinking.

The blink reflex and its modulation - Part 2: Pathophysiology and clinical utility.

The blink reflex (BR) is integrated at the brainstem; however, it is modulated by inputs from various structures such as the striatum, globus pallidus, substantia nigra, and nucleus raphe magnus but also from afferent input from the peripheral nervous system. Therefore, it provides information about the pathophysiology of numerous peripheral and central nervous system disorders. The BR is a valuable tool for studying the integrity of the trigemino-facial system, the relevant brainstem nuclei, and circuits. At the same time, some neurophysiological techniques applying the BR may indicate abnormalities involving structures rostral to the brainstem that modulate or control the BR circuits. This is a state-of-the-art review of the clinical application of BR modulation; physiology is reviewed in part 1. In this review, we aim to present the role of the BR and techniques related to its modulation in understanding pathophysiological mechanisms of motor control and pain disorders, in which these techniques are diagnostically helpful. Furthermore, some BR techniques may have a predictive value or serve as a basis for follow-up evaluation. BR testing may benefit in the diagnosis of hemifacial spasm, dystonia, functional movement disorders, migraine, orofacial pain, and psychiatric disorders. Although the abnormalities in the integrity of the BR pathway itself may provide information about trigeminal or facial nerve disorders, alterations in BR excitability are found in several disease conditions. BR excitability studies are suitable for understanding the common pathophysiological mechanisms behind various clinical entities, elucidating alterations in top-down inhibitory systems, and allowing for follow-up and quantitation of many neurological syndromes.