Gold Coast diagnostic criteria increase sensitivity in amyotrophic lateral sclerosis

ObjectiveThis study evaluates diagnostic accuracy of the proposed ‘Gold Coast’ (GC) diagnostic criteria for amyotrophic lateral sclerosis (ALS).MethodsFive European centres retrospectively sampled consecutive patients referred for electromyography on suspicion of ALS. Patients were classified according to the GC criteria, the revised El Escorial (rEE) criteria and the Awaji (AW) criteria without and with the ‘Possible’ category (+ Poss). Reference standard was ALS confirmed by disease progression at follow-up.ResultsOf 404 eligible patients 272 were diagnosed as ALS, 94 had mimicking disorders, 35 were lost for follow-up, and three had insufficient data. Sensitivity for the GC criteria was 88.2% (95% CI: 83.8-91.8%), which was higher than for previous criteria, of which the AW + Poss criteria reached the highest sensitivity of 77.6% (95% CI: 72.2–82.4%) (p < 0.001). Specificity was high for all criteria. The increase in sensitivity for the GC criteria was mainly due to the inclusion of 28 patients with progressive muscular atrophy (PMA).ConclusionsThe simpler GC criteria increase the sensitivity, primarily due to considering PMA as a form of ALS with high specificity preserved.SignificanceThis validation study supports that GC criteria should be used in clinical practice and may be used for inclusion in trials.     

Relationship between EMG-detected and ultrasound-detected fasciculations in amyotrophic lateral sclerosis: A prospective cohort study

ObjectivesFasciculation potentials (FP) are an important consideration in the electrophysiological diagnosis of ALS. Muscle ultrasonography (MUS) has a higher sensitivity in detecting fasciculations than electromyography (EMG), while in some cases, it is unable to detect EMG-detected fasciculations. We aimed to investigate the differences of FP between the muscles with and without MUS-detected fasciculations (MUS-fas).MethodsThirty-one consecutive patients with sporadic ALS were prospectively recruited and in those, both needle EMG and MUS were performed. Analyses of the amplitude, duration, and number of phases of EMG-detected FPs were performed for seven muscles per patient, and results were compared between the muscles with and without MUS-fas in the total cohort.ResultsThe mean amplitude and phase number of FP were significantly lower in patients with EMG-detected FP alone (0.39 ± 0.25 mV and 3.21 ± 0.88, respectively) than in those with both FP and MUS-fas (1.22 ± 0.92 mV and 3.74 ± 1.39, respectively; p < 0.0001 and p = 0.017, Welch’s t-test).ConclusionSmall FP may be undetectable with MUS. MUS cannot replace EMG in the diagnostic approach for ALS.SignificanceClinicians should use a combination of EMG and MUS for the detection and quantitative analysis of fasciculation in ALS.     

Peripheral nerve imaging in amyotrophic lateral sclerosis

We systematically identified and reviewed 29 studies of peripheral nerve ultrasound or magnetic resonance imaging (MRN) in amyotrophic lateral sclerosis (ALS). The majority of the ultrasound studies reported smaller nerves and nerve roots in ALS compared to healthy controls, but there was a large overlap of the cross-sectional nerve area between ALS and controls. Most of the MRN studies confirmed nerve abnormalities demonstrating slight T2 hyperintensities and, sometimes, mild enlargement of more proximal nerve segments (plexus, roots) in ALS. The size of the proximal nerve segments, i.e. nerve roots, is thus somewhat incongruent between nerve ultrasound and MRN in ALS. Peripheral nerve ultrasound has the potential to differentiate between ALS and multifocal motor neuropathy (MMN) in that patients with MMN have significantly larger nerves. Conversely, there is an overlap of MRN abnormalities in ALS and MMN, restricting the techniques’ utility in the clinical setting. A subgroup of patients with ALS seems to reveal a sonographic nerve pattern suggesting peripheral nerve inflammation. In the future, combined imaging with nerve ultrasound and MRN assessing parameters such as blood flow or textural markers may aid in the understanding of the deep nerve microstructure down to the fascicle level, and thus, in the classification of the nerve state as more degenerative or more inflammatory in ALS. This systematic review provides evidence that nerve imaging abnormalities are common in ALS.     

The evolving role of surface electromyography in amyotrophic lateral sclerosis: A systematic review

ObjectiveAmyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads to inexorable motor decline and a median survival of three years from symptom onset. Surface EMG represents a major technological advance that has been harnessed in the development of novel neurophysiological biomarkers. We have systematically reviewed the current application of surface EMG techniques in ALS.MethodsWe searched PubMed to identify 42 studies focusing on surface EMG and its associated analytical methods in the diagnosis, prognosis and monitoring of ALS patients.ResultsA wide variety of analytical techniques were identified, involving motor unit decomposition from high-density grids, motor unit number estimation and measurements of neuronal hyperexcitability or neuromuscular architecture. Some studies have proposed specific diagnostic and prognostic criteria however clinical calibration in large ALS cohorts is currently lacking. The most validated method to monitor disease is the motor unit number index (MUNIX), which has been implemented as an outcome measure in two ALS clinical trials.ConclusionSurface EMG offers significant practical and analytical flexibility compared to invasive techniques. To capitalise on this fully, emphasis must be placed upon the multi-disciplinary collaboration of clinicians, bioengineers, mathematicians and biostatisticians.SignificanceSurface EMG techniques can enrich effective biomarker development in ALS.     

Vestibular evoked myogenic potentials and their clinical utility in patients with amyotrophic lateral sclerosis

ObjectiveTo evaluate the diagnostic value of vestibular evoked myogenic potentials (VEMPs) in the assessment of brainstem function integrity in patients with amyotrophic lateral sclerosis (ALS).MethodsThis was a prospective case-control study including 30 definite or probable ALS patients divided into two groups (with or without brainstem involvement) and 30 healthy controls. Cervical (c-), masseter (m-) and ocular VEMP (o-VEMP) measurements were obtained for all the participants.ResultsThe c-VEMP mean p13 and n23 were significantly prolonged in the ALS patients. The interside peak differences in p13 and n23 of c-VEMP and in n10 and p15 of o-VEMP were significantly prolonged. The rates of alteration in c-VEMP, m-VEMP and o-VEMP in the ALS patients were 67%, 40%, and 45%, respectively. The ALS patients with brainstem involvement had a significantly higher percentage of VEMP abnormalities than did those without brainstem involvement (p = 0.027).Conclusionsc-VEMP is a sensitive tool to detect lower levels of brainstem involvement. Impairments in o-VEMP and m-VEMP indicate involvement of the upper brainstem. The use of combined VEMPs may provide useful insights into the pathophysiological mechanism of ALS.SignificanceVEMPs may be useful in the evaluation of brainstem dysfunction in ALS patients.     

Enlarged high frequency oscillations of the median nerve somatosensory evoked potential and survival in amyotrophic lateral sclerosis

ObjectiveA large N20 and P25 of the median nerve somatosensory evoked potential (SEP) predicts short survival in amyotrophic lateral sclerosis (ALS). We investigated whether high frequency oscillations (HFOs) over N20 are enlarged and associated with survival in ALS.MethodsA total of 145 patients with ALS and 57 healthy subjects were studied. We recorded the median nerve SEP and measured the onset-to-peak amplitude of N20 (N20o-p), and peak-to-peak amplitude between N20 and P25 (N20p-P25p). We obtained early and late HFO potentials by filtering SEP between 500 and 1 kHz, and measured the peak-to-peak amplitude. We followed up patients until endpoints (death or tracheostomy) and analyzed the relationship between SEP or HFO amplitudes and survival using a Cox analysis.ResultsPatients showed larger N20o-p, N20p-P25p, and early and late HFO amplitudes than the control values. N20p-P25p was associated with survival periods (p = 0.0004), while early and late HFO amplitudes showed no significant association with survival (p = 0.4307, and p = 0.6858, respectively).ConclusionsThe HFO amplitude in ALS is increased, but does not predict survival.SignificanceThe enlarged HFOs in ALS might be a compensatory phenomenon to the hyperexcitability of the sensory cortex pyramidal neurons.     

Altered motor cortical plasticity in patients with hepatic encephalopathy: A paired associative stimulation study

ObjectiveHepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE.Methods23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups.ResultsMEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity.ConclusionsOur study revealed reduced synaptic plasticity of the primary motor cortex in HE.SignificanceReduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients.     

Advancing disease monitoring of amyotrophic lateral sclerosis with the compound muscle action potential scan

ObjectiveTo determine which compound muscle action potential (CMAP) scan-derived electrophysiological markers are most sensitive for monitoring disease progression in amyotrophic lateral sclerosis (ALS), and whether they hold value for clinical trials.MethodsWe used four independent patient cohorts to assess longitudinal patterns of a comprehensive set of electrophysiological markers including their association with the ALS functional rating scale (ALSFRS-R). Results were translated to trial sample size requirements.ResultsIn 65 patients, 225 thenar CMAP scan recordings were obtained. Electrophysiological markers showed extensive variation in their longitudinal trajectories. Expressed as standard deviations per month, motor unit number estimation (MUNE) values declined by 0.09 (CI 0.07–0.12), D50, a measure that quantifies CMAP scan discontinuities, declined by 0.09 (CI 0.06–0.13) and maximum CMAP by 0.05 (CI 0.03–0.08). ALSFRS-R declined fastest (0.12, CI 0.08 – 0.15), however the between-patient variability was larger compared to electrophysiological markers, resulting in larger sample sizes. MUNE reduced the sample size by 19.1% (n = 388 vs n = 314) for a 6-month study compared to the ALSFRS-R.ConclusionsCMAP scan-derived markers show promise in monitoring disease progression in ALS patients, where MUNE may be its most suitable derivate.SignificanceMUNE may increase clinical trial efficiency compared to clinical endpoints.     

Practice-dependent motor cortex plasticity is reduced in non-disabled multiple sclerosis patients

ObjectivesSkill acquisition after motor training involves synaptic long-term potentiation (LTP) in primary motor cortex (M1). In multiple sclerosis (MS), LTP failure ensuing from neuroinflammation could contribute to worsen clinical recovery. We therefore addressed whether practice-dependent plasticity is altered in MS.MethodsEighteen relapsing-remitting (RR)-MS patients and eighteen healthy controls performed 600 fast abductions of index finger in 30 blocks of 20 movements. Before and after practice, transcranial magnetic stimulation (TMS) was delivered over the hot spot of the trained first dorsal interosseous muscle. Movements kinematics, measures of cortical excitability, and the input/output curves of motor evoked potentials (MEPs) were assessed.ResultsKinematic variables of movement improved with practice in patients and controls to a similar extent, although patients showed lower MEPs amplitude increase after practice. Practice did not change the difference in resting motor threshold values observed between patients and controls, nor did modulate short-interval intracortical inhibition. Clinical/radiological characteristics were not associated to practice-dependent effects.ConclusionsPractice-induced reorganization of M1 is altered in non-disabled RR-MS patients, as shown by impaired MEPs modulation after motor learning.SignificanceThese findings suggest that in RR-MS physiological mechanisms of practice-dependent plasticity are altered.     

Altered supraspinal motor networks in survivors of poliomyelitis: A cortico-muscular coherence study

ObjectivePoliomyelitis results in changes to the anterior horn cell. The full extent of cortical network changes in the motor physiology of polio survivors has not been established. Our aim was to investigate how focal degeneration of the lower motor neurons (LMN) in infancy/childhood affects motor network connectivity in adult survivors of polio.MethodsSurface electroencephalography (EEG) and electromyography (EMG) were recorded during an isometric pincer grip task in 25 patients and 11 healthy controls. Spectral signal analysis of cortico-muscular (EEG-EMG) coherence (CMC) was used to identify the cortical regions that are functionally synchronous and connected to the periphery during the pincer grip task.ResultsA pattern of CMC was noted in polio survivors that was not present in healthy individuals. Significant CMC in low gamma frequency bands (30–47 Hz) was observed in frontal and parietal regions.ConclusionThese findings imply a differential engagement of cortical networks in polio survivors that extends beyond the motor cortex and suggest a disease-related functional reorganisation of the cortical motor network.SignificanceThis research has implications for other similar LMN conditions, including spinal muscular atrophy (SMA). CMC has potential in future clinical trials as a biomarker of altered function in motor networks in post-polio syndrome, SMA, and other related conditions.     

Altered sensorimotor integration in multiple sclerosis: A combined neurophysiological and functional MRI study

ObjectiveTo explore whether abnormal thalamic resting-state functional connectivity (rsFC) contributes to altered sensorimotor integration and hand dexterity impairment in multiple sclerosis (MS).MethodsTo evaluate sensorimotor integration, we recorded kinematic features of index finger abductions during somatosensory temporal discrimination threshold (STDT) testing in 36 patients with relapsing-remitting MS and 39 healthy controls (HC). Participants underwent a multimodal 3T structural and functional MRI protocol.ResultsPatients had lower index finger abduction velocity during STDT testing compared to HC. Thalamic rsFC with the precentral and postcentral gyri, supplementary motor area (SMA), insula, and basal ganglia was higher in patients than HC. Intrathalamic rsFC and thalamic rsFC with caudate and insula bilaterally was lower in patients than HC. Finger movement velocity positively correlated with intrathalamic rsFC and negatively correlated with thalamic rsFC with the precentral and postcentral gyri, SMA, and putamen.ConclusionsAbnormal thalamic rsFC is a possible substrate for altered sensorimotor integration in MS, with high intrathalamic rsFC facilitating finger movements and increased thalamic rsFC with the basal ganglia and sensorimotor cortex contributing to motor performance deterioration.SignificanceThe combined study of thalamic functional connectivity and upper limb sensorimotor integration may be useful in identifying patients who can benefit from early rehabilitation to prevent upper limb motor impairment.     

Intensified electrical stimulation targeting lateral and medial prefrontal cortices for the treatment of social anxiety disorder: A randomized,double-blind,parallel-group,dose-comparison study

BackgroundSocial Anxiety Disorder (SAD) is the most common anxiety disorder while remains largely untreated. Disturbed amygdala-frontal network functions are central to the pathophysiology of SAD, marked by hypoactivity of the lateral prefrontal cortex (PFC), and hypersensitivity of the medial PFC and the amygdala. The objective of this study was to determine whether modulation of the dorsolateral and medial PFC activity with a novel intensified stimulation protocol reduces SAD core symptoms, improves treatment-related variables, and reduces attention bias to threatening stimuli.MethodsIn this randomized, sham-controlled, double-blind trial, we assessed the efficacy of an intensified stimulation protocol (20 min, twice-daily sessions with 20 min intervals, 5 consecutive days) in two intensities (1 vs 2 mA) compared to sham stimulations. 45 patients with SAD were randomized in three tDCS arms (1-mA, 2-mA, sham). SAD symptoms, treatment-related variables (worries, depressive state, emotion regulation, quality of life), and attention bias to threatening stimuli (dot-probe paradigm) were assessed before and right after the intervention. SAD symptoms were also assessed at 2-month follow-up.ResultsBoth 1-mA and 2-mA protocols significantly reduced fear/avoidance symptoms, worries and improved, emotion regulation and quality of life after the intervention compared to the sham group. Improving effect of the 2-mA protocol on avoidance symptoms, worries and depressive state was significantly larger than the 1-mA group. Only the 2-mA protocol reduced attention bias to threat-related stimuli, the avoidance symptom at follow-up, and depressive states, as compared to the sham group.ConclusionsModulation of lateral-medial PFC activity with intensified stimulation can improve cognitive control, motivation and emotion networks in SAD and might thereby result in therapeutic effects. These effects can be larger with 2-mA vs 1-mA intensities, though a linear relationship between intensity and efficacy should not be concluded. Our results need replication in larger trials.     

Differentiating transcranial magnetic stimulation cortical and auditory responses via single pulse and paired pulse protocols: A TMS-EEG study

ObjectiveWe measured the neurophysiological responses of both active and sham transcranial magnetic stimulation (TMS) for both single pulse (SP) and paired pulse (PP; long interval cortical inhibition (LICI)) paradigms using TMS-EEG (electroencephalography).MethodsNineteen healthy subjects received active and sham (coil 90° tilted and touching the scalp) SP and PP TMS over the left dorsolateral prefrontal cortex (DLPFC). We measured excitability through SP TMS and inhibition (i.e., cortical inhibition (CI)) through PP TMS.ResultsCortical excitability indexed by area under the curve (AUC_(25-275ms)) was significantly higher in the active compared to sham stimulation (F(1,18) = 43.737, p < 0.001, η² = 0.708). Moreover, the amplitude of N100-P200 complex was significantly larger (F(1,18) = 9.118, p < 0.01, η² = 0.336) with active stimulation (10.38 ± 9.576 µV) compared to sham (4.295 ± 2.323 µV). Significant interaction effects were also observed between active and sham stimulation for both the SP and PP (i.e., LICI) cortical responses. Finally, only active stimulation (CI = 0.64 ± 0.23, p < 0.001) resulted in significant cortical inhibition.ConclusionThe significant differences between active and sham stimulation in both excitatory and inhibitory neurophysiological responses showed that active stimulation elicits responses from the cortex that are different from the non-specific effects of sham stimulation.SignificanceOur study reaffirms that TMS-EEG represents an effective tool to evaluate cortical neurophysiology with high fidelity.     

Sleep modulates effective connectivity: A study using intracranial stimulation and recording

ObjectiveSleep is an active process with an important role in memory. Epilepsy patients often display a disturbed sleep architecture, with consequences on cognition. We aimed to investigate the effect of sleep on cortical networks’ organization.MethodsWe analyzed cortico-cortical evoked responses elicited by single pulse electrical stimulation (SPES) using intracranial depth electrodes in 25 patients with drug-resistant focal epilepsy explored using stereo-EEG. We applied the SPES protocol during wakefulness and NREM – N2 sleep. We analyzed 31,710 significant responses elicited by 799 stimulations covering most brain structures, epileptogenic or non-epileptogenic. We analyzed effective connectivity between structures using a graph-theory approach.ResultsSleep increases excitability in the brain, regardless of epileptogenicity. Local and distant connections are differently modulated by sleep, depending on the tissue epileptogenicity.In non-epileptogenic areas, frontal lobe connectivity is enhanced during sleep. There is increased connectivity between the hippocampus and temporal neocortex, while perisylvian structures are disconnected from the temporal lobe. In epileptogenic areas, we found a clear interhemispheric difference, with decreased connectivity in the right hemisphere during sleep.ConclusionsSleep modulates brain excitability and reconfigures functional brain networks, depending on tissue epileptogenicity.SignificanceWe found specific patterns of information flow during sleep in physiologic and pathologic structures, with possible implications for cognition.     

Dissociating the causal role of left and right dorsal premotor cortices in planning and executing bimanual movements – A neuro-navigated rTMS study

BackgroundThe dorsal premotor cortex (PMd) is a key region in bimanual coordination. However, causal evidence linking PMd functionality during motor planning and execution to movement quality is lacking.ObjectiveWe investigated how left (PMd_L) and right PMd (PMd_R) are causally involved in planning and executing bimanual movements, using short-train repetitive transcranial magnetic stimulation (rTMS). Additionally, we explored to what extent the observed rTMS-induced modulation of performance could be explained by rTMS-induced modulation of PMd-M1 interhemispheric interactions (IHI).MethodsTwenty healthy adults (mean age ± SD = 22.85 ± 3.73 years) participated in two sessions, in which either PMd_L or PMd_R was targeted with rTMS (10 Hz) in a pseudo-randomized design. PMd functionality was transiently modulated during the planning or execution of a complex bimanual task, whereby the participant was asked to track a moving dot by controlling two dials. The effect of rTMS on several performance measures was investigated. Concurrently, rTMS-induced modulation of PMd-M1 IHI was measured using a dual-coil paradigm, and associated with the rTMS-induced performance modulation.ResultsrTMS over PMd_L during planning increased bilateral hand movement speed (p = 0.03), thereby improving movement accuracy (p = 0.02). In contrast, rTMS over PMd_R during both planning and execution induced deterioration of movement stability (p = 0.04). rTMS-induced modulation of PMd-M1 IHI during planning did not predict rTMS-induced performance modulation.ConclusionThe current findings support the growing evidence on PMd_L dominance during motor planning, as PMd_L was crucially involved in planning the speed of each hand, subserving bimanual coordination accuracy. Moreover, the current results suggest that PMd_R fulfills a role in continuous adjustment processes of movement.     

Cortical mechanisms underlying variability in intermittent theta-burst stimulation-induced plasticity: A TMS-EEG study

ObjectiveTo test the hypothesis that intermittent theta burst stimulation (iTBS) variability depends on the ability to engage specific neurons in the primary motor cortex (M1).MethodsIn a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects.ResultsThe facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS.ConclusionsThe results show that variability in iTBS-associated plasticity depends on baseline corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations.SignificanceThese observations can be used to optimize iTBS investigational and therapeutic applications.     

Postoperative navigated transcranial magnetic stimulation to predict motor recovery after surgery of tumors in motor eloquent areas

ObjectiveTo know whether motor deficits after tumor surgery are transient is reassuring for the patient and crucial for planning rehabilitation and adjuvant treatment. We analyze the value of postoperative MRI navigated transcranial magnetic stimulation (nTMS) compared to intraoperative MEP monitoring in predicting recovery of motor function.MethodsRetrospective series of nTMS mappings within 14 days after surgery for supratentorial tumors (09/2014–05/2018). All patients with motor deficits of Medical-Research-Council-Grade (MRCS) 0–4- were included.ResultsWe performed nTMS mapping on average 3.8 days after surgery and recorded nTMS MEP in 11 of 13 patients. Motor strength recovered to at least MRCS 4 within one month if postoperative nTMS elicited MEPs (positive predictive value 90.9%). If nTMS did not elicit MEPs, the patient did not recover (negative predictive value 100%). Intraoperative MEP and postoperative nTMS were equally predictive for long-term motor recovery. In cases of intraoperative MEP alteration/signal loss, but a positive postoperative nTMS mapping, 2/3 patients demonstrated a good motor recovery.ConclusionnTMS may predict long-term motor recovery of patients suffering from severe motor deficits directly after resection of tumors located in motor eloquent areas.SignificanceIn cases of intraoperative MEP alterations, postoperative nTMS may clarify the potential for motor recovery.