Figure 4 - uploaded by Matthew C Kiernan
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Group data in 16 patients with amyotrophic lateral sclerosis (ALS) and 25 normal controls (A) revealed a significant reduction in the strength–duration time constant in patients with ALS compared with controls after a maximum voluntary contraction (MVC) of 60 s duration. (B) Superexcitability, a sensitive parameter of membrane potential, was increased in patients with ALS and controls after MVC. The filled bar represents the period of MVC.
Source publication
While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuri...
Contexts in source publication
Context 1
... increase in threshold was accompanied by a reduction in t SD ( fig 2D) and an increase in superexcitability ( fig 2C), as illustrated for a representative ALS patient. Group data confirmed a significant reduction in t SD in patients with ALS post-MVC compared with controls (peak reduction in ALS 0.79 (0.04); controls 0.90 (0.02), 95% CI controls 0.70 to 1.10; p,0.01) ( fig 4A). The reduction in t SD was accompanied by an increase in superexcitability in both ALS and normal controls following MVC ( fig 4B). ...
Context 2
... data confirmed a significant reduction in t SD in patients with ALS post-MVC compared with controls (peak reduction in ALS 0.79 (0.04); controls 0.90 (0.02), 95% CI controls 0.70 to 1.10; p,0.01) ( fig 4A). The reduction in t SD was accompanied by an increase in superexcitability in both ALS and normal controls following MVC ( fig 4B). These changes in t SD and super- excitability were consistent with hyperpolarisation of the axonal membrane 17 19 and correlated with an increase in threshold for both patients with ALS and controls ( fig 5A, B). ...
Citations
... Of which, 10 studies did not report the prevalence of fatigue. Among the studies that reported fatigue prevalence, six studies did not provide criteria for defining ALS patients [21][22][23][24][25][26], six studies relied on patient self-report of fatigue presence without using a validated measure [27][28][29][30][31][32], two studies did not establish a specific cut-off value [12,33], one study used a physiological measurement [34], and one study had the same participants of an included study [35]. Finally, 11 studies with 1072 ALS patients met the inclusion criteria and were included in this review [7,9,[36][37][38][39][40][41][42][43][44]. ...
This systematic review and meta-analysis aimed to determine the frequency and correlates of fatigue in patients with amyotrophic lateral sclerosis (ALS).
Three databases were searched up to 2nd May 2023 to identify studies reporting fatigue frequency in ALS. Studies included had to identify ALS patients through one of ALS diagnostic criteria and measure fatigue by a validated tool with a specific cut-off value. Meta-analysis was conducted using RStudio's "meta" package with a random-effects model. Subgroup analyses and meta-regression explored the relationship between fatigue frequency in ALS and different covariates.
Eleven studies, compromising 1072 patients, met the inclusion criteria and were included in our analysis. The pooled frequency of fatigue across all studies was 48% (95% CI = 40% to 57%). Our subgroup analysis based on the ALSFRS-R revealed a higher frequency of fatigue in studies with lower scores (< 30) compared to those with higher scores (≥ 30), with a pooled frequency of 62% (95% CI = 43% to 79%) and 43% (95% CI = 37% to 49%), respectively. Also, the meta-regression analysis showed a significant negative association between fatigue and ALSFRS-R mean (P = 0.02). The included studies reported an association between fatigue and lower functional status and poorer quality of life in patients with ALS.
Our findings suggest that fatigue is prevalent in almost half of ALS patients and is associated with lower functional status and poorer quality of life, highlighting the importance of assessing and managing fatigue in ALS patients.
... Some previous studies using neurophysiological measures, such as sustained isometric muscle contraction, to assess the severity of the physical component of fatigue in ALS patients, revealed predominant correlations of lower motor neuron impairment with fatigue (Vucic et al., 2007), although these measures have been shown to extend to more sites than those affected by clinical motor weakness (Sanjak et al., 2001). Additionally, further studies explored the correlations between measures of the severity of fatigue with some clinical features monitored in ALS (Chiò et al., 2021), such as motor functional status (Panitz et al., 2015), quality of life Young et al., 2022), respiratory (Vogt et al., 2020), and sleep dysfunction (Lo Coco & La Bella, 2012). ...
Introduction
Fatigue is defined as a symptom of exhaustion unexplained by drug effects or psychiatric disorders and comprises two main components (i.e., central or “mental” and peripheral or “physical” components), both influencing global disability in amyotrophic lateral sclerosis (ALS). We aim at investigating the clinical correlations between “physical” and “mental” components of fatigue, measured by the Multidimensional Fatigue Inventory scale, and motor and cognitive/behavioral disability in a large sample of patients with ALS. We also investigated the correlations between these measures of fatigue and resting‐state functional connectivity of brain functional magnetic resonance imaging (RS‐fMRI) large‐scale networks in a subset of patients.
Methods
One hundred and thirty ALS patients were assessed for motor disability, cognitive and behavioral dysfunctions, fatigue, anxiety, apathy, and daytime sleepiness. Moreover, the collected clinical parameters were correlated with RS‐fMRI functional connectivity changes in the large‐scale brain networks of 30 ALS patients who underwent MRI.
Results
Multivariate correlation analysis revealed that “physical” fatigue was related to anxiety and respiratory dysfunction, while “mental” fatigue was related to memory impairment and apathy. Moreover, the mental fatigue score was directly related to functional connectivity in the right and left insula (within the salience network), and inversely related to functional connectivity in the left middle temporal gyrus (within the default mode network).
Conclusions
Although the “physical” component of fatigue may be influenced by the disease itself, in ALS the “mental” component of fatigue correlates with cognitive and behavioral impairment, as well as with alterations of functional connectivity in extra‐motor networks.
... The included studies were: Kanai et al. (2006), CMAP >5mV; Brum (2015), CMAP >2.84mV (Group 1); Menon (2015); and Iwai (2016), CMAP >5mV. The forest plots for measures that had significant pooled effect in the sensitivity analysis are shown in Figures 2-5.Strength-Duration PropertiesData from 21 studies was analyzed to compare SDTC (ALS = 678, HC = 558).29,30,[41][42][43][44][45][46][58][59][60][61][62][65][66][67][68][69][70][71][72] SDTC was significantly longer in ALS patients compared to HCs, with a mean difference of 0.05 ms (95%CI: 0.04 to 0.06) and minimal heterogeneity (I 2 =3%,Figure 2). ...
... Summary statistics for axonal excitability indices reported by four or more studies. Indices descending rank ordered (top to bottom) for overall effect (Z).Compound Muscle Action PotentialNineteen studies reported maximum CMAP amplitude (ALS = 644, HC = 533), with marked heterogeneity (I 2 =88%).30,41,42,[44][45][46][58][59][60][61][62][63][64][65][66][67][68][69][70] CMAP is significantly reduced in ALS patients compared to HCs, Four studies included ALS patients with similar CMAP to HCs, suggesting testing was done earlier in the disease course (Z=1.62, ...
Objective
To determine which nerve excitability outcome measures are potential biomarkers for ALS via systematic review and meta-analysis.
Methods
Potential studies were identified from the following databases: MEDLINE, PubMed Central, CINAHL Plus, EMBASE, HealthSTAR, Scopus, and Web of Science up to March 2020. Only studies performed in human participants and assessing median motor axons were included. Forest Plot analyses using a random-effects model to determine pooled effect (Z-score), heterogeneity (I ² ) and Cohen’s d were used to identify potential biomarkers.
Results
From 2866 studies, 26 (patients=942, controls=719) were used in the systematic review and 23 in the meta-analysis. Seven axonal excitability indices met the three criteria for: significant Z-score, heterogeneity I ² <40% and Cohen’s d >0.2 (in descending rank order): TEd 90-100 ms, strength-duration time constant (SDTC), superexcitability, TEd 40-60 ms, resting I/V slope, 50% depolarizing, and subexcitability. A sensitivity analysis restricted to patients with ‘early’ ALS indicated that four indices are potential early biomarkers of ALS (Z ranging from 2.99 to 2.16, in descending rank order): TEd 10-20 ms, TEd 90-100 ms, superexcitability, and SDTC.
Conclusion
Seven excitability indices differentiate ALS patients from healthy controls, four of which may serve as early biomarkers for ALS. The candidate biomarkers may be used to monitor disease progression, predict survivability, and measure treatment response in clinical trials. High quality diagnostic test accuracy studies are warranted to firmly establish the utility of these indices in individuals suspected of an ALS diagnosis.
... The origin of fatigue in ALS is multifactorial. From the pathophysiological point of view, proposed mechanisms are decreased physical resistance associated with reduction of maximum oxygen consumption (VO2 max), muscular modifications due to disuse, and impairment in the excitationcontraction coupling [144][145][146][147]. ...
... Several questionnaires have been utilized to determine the frequency and severity of fatigue in ALS (Table 3). When assessed with neurophysiological measures, fatigue severity does not correlate with motor weakness, in fact can be detected in muscle clinically spared, and also with the different impairment of upper and lower motor neurons [145,146]. On the other hand, using validated questionnaires, factors associated to fatigue are motor functional status, quality of life, depression, dyspnea, and sleep patterns [139,142,149]. However, some possible correlates of fatigue in ALS have Table 3. Scales for the assessment of fatigue and sleep disturbances. ...
Introduction
The burden of non-motor symptoms is a major determinant of quality of life and outcome in amyotrophic lateral sclerosis (ALS) and has profound negative effect also on caregivers.
Areas covered
Non-motor symptoms in ALS include cognitive impairment, neurobehavioral symptoms, depression and anxiety, suicidal ideation, pain, disordered sleep, fatigue, weight loss and reduced appetite, and autonomic dysfunctions. This review summarize the measures used for the assessment of non-motor symptoms and their properties and recaps the frequency and progression of these symptoms along the course of ALS.
Expert opinion
Non-motor symptoms in ALS represent a major component of the disease and span over several domains. These symptoms require a high level of medical attention and should be checked at each visit using ad hoc questionnaires and should be proactively treated. Several instruments assessing non-motor symptoms have been used in ALS. Specific screening questionnaires for non-motor symptoms can be used for monitoring patients during telehealth visits and for remote surveillance through sensors and apps installed on smartphones. Novel trials for non-motor symptoms treatment specifically designed for ALS are necessary to increase and refine the therapeutic armamentarium. Finally, scales assessing the most frequent and burdensome non-motor symptoms should be included in clinical trials.
... There is direct physiological evidence to support why patients may experience physical fatigue, with impaired muscle contractility correlating with higher self-reported fatigue [191]. Levels of fatigue do not appear to correlate directly with motor weakness [192] or the degree of upper or lower motor neuron degeneration [193], underscoring its complex aetiology. ...
Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.
... We hypothesized that a combination between the perception of loss, loss of functionality, and the lockdown itself might have contributed together to the decrease in QoL, especially considering the reduction in direct multidisciplinary support that patients and carers have experienced at this time. Furthermore, the negative correlation between fatigue and the Physical Symptoms and Negative Emotions domains of ALSSQOL-SF concurs with other authors that highlight the experience of fatigue with worse motor function and NE (Vucic et al., 2007;Lou et al., 2010;Gibbons et al., 2013), reinforcing the importance of continuous multidisciplinary-care assessment and treatment of fatigue in ALS patients. ...
Objective
Patients with amyotrophic lateral sclerosis (ALS) experienced prolonged interruption of their rehabilitation palliative care routines due to restrictive COVID-19 pandemic public health measures. This study assesses the effects of before and after the lockdown on functionality rates and quality of life (QoL) in patients with ALS.
Methods
A longitudinal observational study was conducted. Participants were assessed three times — early January (T0), before mandatory lockdown (T1), and during lockdown (T2) — using the ALS Functional Rating Scale-revised (ALSFRS-R), Fatigue Severity Scale (FSS), and the ALS-Specific Quality of Life-Short Form (ALSSQOL-SF). The paired-sample t-test and Wilcoxon signed-rank test were used.
Results
Thirty-two patients were included with a mean age of 56.9 (SD 14.2) years and mean symptoms onset of 27.1 (SD 14.3) months. ALSFRS-R mean scores decayed significantly over time when comparing T0–T1 (0.26 ± 0.38) and T1–T2 (1.36 ± 1.43) slopes ( p < 0.001). Significant differences were observed between T1 and T2 for ALSSQOL-SF scores (115.31 ± 17.06 vs. 104.31 ± 20.65), especially in four specific domains, and FSS scores (34.06 ± 16.84 vs. 40.09 ± 17.63). Negative correlations between negative emotions and physical symptoms assessed by ALSSQOL-SF and FSS were found.
Significance of the results
Rehabilitation treatment routines in palliative care, such as physiotherapy and speech therapy, appear to mitigate the ALSFRS-R slope. Prolonged interruption of rehabilitation during the lockdown may have accelerated the functional decline in ALS patients’ motor skills with as measured after 2 months by the ALSFRS-R in the limb and bulbar subscores, but not respiratory subscore. Other short-term effects, increased fatigue and negative impact on QoL, were also verified.
... Nerve excitability has previously been used to demonstrate nodal ion-channel dysfunction in CIDP, including activity-dependent block (Cappelen-Smith et al., 2000, 2001Garg et al., 2019). Previous studies illustrated that activity-dependent changes in axonal excitability may underlie fatigue in several neuromuscular disorders (Krishnan and Kiernan, 2006;Vucic et al., 2007;Noto et al., 2013). Corroborating these findings, axonal hyperpolarization in CIDP could also lead to impaired muscle activation, and potentially explain part of the muscle fatigue in these patients. ...
... Using this "thresholdtracking" approach, the target M-wave is referred to as the "threshold response" and the current required to achieve this response is the "threshold current" (Bostock et al. 1998). Tracking changes in threshold current is a reliable and valid way to quantify activitydependent changes in the excitability of motor and sensory axons (Vagg et al. 1998;Kuwabara et al. 2002;Kiernan et al. 2004) and examine changes in axonal excitability in individuals with neuromuscular disorders (Lin et al. 2007;Vucic et al. 2007;Krishnan et al. 2008). There is evidence that axonal excitability depends on impulse load, with longer voluntary contractions (Vagg et al. 1998) and higher NMES frequencies (Bergmans 1970;Kiernan et al. 2004) producing greater decreases in axonal excitability and longer recovery times. ...
... ;Kuwabara et al. 2002;Kiernan et al. 2004) and clinically relevant(Lin et al. 2007;Vucic et al. 2007; ...
The present study was designed to (i) determine the time course of changes in motor axon excitability during and after neuromuscular electrical stimulation (NMES); and (ii) characterize the relationship between contraction fatigability, NMES frequency, and changes at the axon, neuromuscular junction, and muscle. Eight neurologically intact participants attended 3 sessions. NMES was delivered over the common peroneal nerve at 20, 40, or 60 Hz for 8 min (0.3 s “on”, 0.7 s “off”). Threshold tracking was used to measure changes in axonal excitability. Supramaximal stimuli were used to assess neuromuscular transmission and force-generating capacity of the tibialis anterior muscle. Torque decreased by 49% and 62% during 8 min of 40 and 60 Hz NMES, respectively. Maximal twitch torque decreased only during 60 Hz NMES. Motor axon excitability decreased by 14%, 27%, and 35% during 20, 40, and 60 Hz NMES, respectively. Excitability recovered to baseline immediately (20 Hz) and at 2 min (40 Hz) and 4 min (60 Hz) following NMES. Overall, decreases in axonal excitability best predicted how torque declined over 8 min of NMES. During NMES, motor axons become less excitable and motor units “drop out” of the contraction, contributing substantially to contraction fatigability and its dependence on NMES frequency.
Novelty: The excitability of motor axons decreased during NMES in a frequency-dependent manner. As excitability decreased, axons failed to reach threshold and motor units dropped out of the contraction. Overall, decreased excitability best predicted how torque declined and thus is a key contributor to fatigability during NMES.
... These neurodegenerative causes include any dysfunction of microglia, glutamate excitotoxicity, misfolded proteins, mitochondrial dysfunction, or oxidative stress (Abraham and Drory, 2012). Vucic et al. (2007) investigated the alteration of axonal excitability occurred after an induced voluntary contraction to recognize peripheral mechanisms of muscle fatigue in patients with ALS. They found that patients with ALS had a membrane hyperpolarization. ...
Muscle fatigue is a serious problem in patients with motor neuron diseases (MNDs). It commonly disturbs both daily life activity and rehabilitation tolerance. A particular concern should be taken when MNDs occur in older ages. Older patients with MNDs usually have a worse clinical presentation and a lower survival rate. This could increase the occurrence of muscle fatigue. Muscle fatigue occurs due to a dysfunction in either motor or sensory systems. Current exercise interventions performed to decrease the occurrence of muscle fatigue focused only on treating motor causes of muscle fatigue. It has been demonstrated that these interventions have a high debate in their effectiveness on decreasing the occurrence of muscle fatigue. Also, these exercise interventions ignored training the affected sensory part of muscle fatigue, however, the important role of the sensory system in driving the motor system. Thus, this review aimed to develop a novel exercise intervention by using proprioceptive training as an intervention to decrease the occurrence of muscle fatigue in patients with MNDs particularly, older ones. The physiological effects of proprioceptive training to decrease the occurrence of muscle fatigue could include two effects. The first effect includes the ability of the proprioceptive training to increase the sensitivity of muscle spindles as an attempt to normalize the firing rate of α-motoneurons, which their abnormalities have major roles in the occurrence of muscle fatigue. The second effect includes its ability to correct the abnormal movement-compensations, which develop due to the biomechanical constraints imposed on patients with MNDs.
... These changes have been linked to changes in ion channel function, particularly increased Na + and decreased axonal K + conductances, a profile which may lead to neurodegeneration and contribute to symptoms such as fasciculations and muscle cramps (de Carvalho et al., 2017;Tsugawa et al., 2018). Increased s SD has been identified in sporadic ALS (Mogyoros et al., 1998;Kanai et al., 2006;Vucic and Kiernan, 2006;Vucic et al., 2007), as well as in atypical ALS phenotypes, such as the flail arm variant (Vucic and Kiernan, 2007a), and in familial forms of ALS linked to superoxide dismutase-1 (SOD1) and c9orf72 (Vucic et al., 2008;Vucic and Kiernan, 2010;Geevasinga et al., 2015). Prolongation of s SD in ALS has been linked to upregulation of persistent Na + conductances (Kuo et al., 2005), with additional contribution from reduced fast and slow K + channel conductances producing depolarization (Vucic and Kiernan, 2006). ...
Measurement of axonal excitability provides an in vivo indication of the properties of the nerve membrane and of the ion channels expressed on these axons. Axonal excitability techniques have been utilised to investigate the pathophysiological mechanisms underlying neurological diseases. This document presents guidelines derived for such studies, based on a consensus of international experts, and highlights the potential difficulties when interpreting abnormalities in diseased axons. The present manuscript provides a state-of-the-art review of the findings of axonal excitability studies and their interpretation, in addition to suggesting guidelines for the optimal performance of excitability studies.
