Abnormal post-exercise depression of corticomotor excitability is associated with fatigue in post-COVID-19 condition, 2026, Sebastianelli+

[SNT Gatchaman]

Abnormal post-exercise depression of corticomotor excitability is associated with fatigue in post-COVID-19 condition
Sebastianelli; Dezi; Ortelli; Ferrazzoli; Oliviero; Versace

BACKGROUND
Persistent fatigue is a disabling symptom of post-COVID-19 condition (PCC), but objective neurophysiological markers of post-exertional dysfunction remain poorly defined. Post-exercise depression (PED) of corticomotor excitability, assessed by transcranial magnetic stimulation (TMS), is an index of central fatigability, but its relationship with subjective fatigue in PCC is unclear.

METHODS
We studied 58 patients with PCC and 22 age- and sex-matched healthy controls (HCs). Participants performed a 1-min sustained maximal voluntary pinching task. Corticomotor excitability was assessed before and after exercise by motor-evoked potential (MEP) amplitude and cortical silent period (SP) duration recorded from the first dorsal interosseous muscle. Fatigue severity and perceived exertion were assessed using the Fatigue Severity Scale, Fatigue Rating Scale, and Borg CR100 scale.

RESULTS
Post-exercise modulation of corticomotor excitability differed between groups. Compared with HCs, PCC patients showed a smaller reduction in MEP amplitude. HCs showed post-exercise SP prolongation, whereas patients showed minimal change or paradoxical shortening. Lower MEP reduction and reduced SP prolongation correlated with higher fatigue and exertion.

CONCLUSIONS
PED abnormalities suggest altered regulation of corticomotor output after exertion in PCC.

SIGNIFICANCE
PED may provide an objective neurophysiological marker of altered central fatigability.

HIGHLIGHTS
• Post-exercise depression (PED) of MEPs was reduced in post-COVID-19 condition (PCC) as compared with healthy controls (HCs)

• PED-related silent period prolongation was seen in HCs but was minimal in PCC.

• Altered PED was associated with higher fatigue and exertion, supporting altered central fatigability in PCC.

Web | DOI | Clinical Neurophysiology | Paywall

 

[SNT Gatchaman]

Follow-on from —

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19 (2022)
Paola Ortelli; Davide Ferrazzoli; Luca Sebastianelli; Roberto Maestri; Sabrina Dezi; Danny Spampinato; Leopold Saltuari; Alessia Alibardi; Michael Engl; Markus Kofler; Angelo Quartarone; Giacomo Koch; Antonio Oliviero; Viviana Versace

BACKGROUND AND PURPOSE
Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS-CoV-2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions.

METHODS
Sixty-seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and ‘well-being’ were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short-interval intracortical inhibition, intracortical facilitation, long-interval intracortical inhibition and short-latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks.

RESULTS
Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and reduced mental well-being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long-interval intracortical inhibition and short-latency afferent inhibition were also impaired, indicating altered GABAB-ergic and cholinergic neurotransmission. Short-interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention.

CONCLUSIONS
Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

Web | DOI | PDF (via PMC) | European Journal of Neurology

 

[SNT Gatchaman]

Summary quotes from introduction —

Fatigue is defined as the inability to sustain or even begin physical activity, accompanied by an overwhelming feeling of exhaustion that does not improve with rest. […] In clinical settings, fatigue is usually captured as a subjective experience reported by the patient, whereas fatigability refers to measurable changes in performance that emerge during or after sustained activity. […] related but not interchangeable, and they require partly different assessment strategies.

… post-exercise depression (PED), that is, the change in cortical motor output after exertion […] After intense motor effort, healthy individuals typically show a transient decrease in motor-evoked potential (MEP) amplitude together with lengthening of the cortical silent period (SP). These post-exercise changes may persist for several minutes and are commonly accompanied by reduced maximum voluntary contraction (MVC) and increased subjective exhaustion. Altered or blunted PED has previously been reported in neurological conditions in which fatigue is a prominent symptom, including multiple sclerosis and Parkinson’s disease.

… short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI). One possible interpretation is that impaired GABAergic signaling within M1 limits the normal adaptive downregulation of cortical motor output after exertion. In this framework, PED may reflect an active inhibitory process that […] helps protect the motor system from excessive strain.

In an earlier study from our group, a large cohort of patients with PCC and prominent fatigue after mild symptomatic COVID-19 showed reduced LICI, suggesting altered GABAB-mediated inhibitory neurotransmission.

(Abstract in post #2)

We hypothesized that PCC patients would show impaired postexercise regulation of corticomotor excitability compared with HCs, reflected by lower MEP suppression and SP prolongation after the fatiguing task. We further hypothesized that higher fatigue and perceived exertion would be associated with a weaker PED response.

 

[SNT Gatchaman]

Summary quotes from methods —

Participants were eligible if they had: […] (c) a mild course of COVID-19 […] not requiring hospitalization; and (d) spontaneously reported persistent fatigue that was perceived as disabling […] lasting for at least 12 weeks after resolution of the acute SARS-CoV-2 infection.

… included 58 patients with PCC and persistent fatigue […] and had complete pre- and post-exercise TMS data available for PED assessment (mean age 48.8 ± 13.4 years; 43 women; mean education 14.3 ± 2.6 years).

Twenty-two healthy controls (HCs), matched for age, sex, and education […] None had evidence of previous SARS-CoV-2 infection. They were recruited among hospital staff undergoing weekly SARS-CoV-2 screening

We used a sustained pinching task at MVC of 1 min duration, in which PCC patients and HCs were asked to squeeze a dynamometer […] with their dominant thumb and index finger as strongly as possible. […] chosen because it provides a brief, standardized, and clinically tolerable motor task to assess fatigability while limiting excessive burden in PCC patients. The first dorsal interosseous muscle (FDI), which is involved in precision pinch, has a large and accessible cortical representation, a relatively low motor threshold, and reliable surface EMG recordings

 

[SNT Gatchaman]

Summary quotes from results —

No significant differences were found between PCC patients and HCs for demographic characteristics and for maximal force produced at the pinching task.

In contrast, Borg scale ratings, FRS, and FSS showed significant differences between groups, with higher scores in the PCC patient population.

At the individual level, Borg ratings were not significantly correlated with Max Force in PCC patients (Spearman’s ρ = 0.028, p = 0.834) or in HCs (Spearman’s ρ = 0.061, p = 0.788).

Baseline MEP amplitudes and SP durations differed significantly between PCC patients and HCs. Post-exercise modulation of cortical excitability differed significantly between patients and HCs.

Specifically, patients exhibited a significantly smaller reduction in MEP amplitude compared with HCs (median [IQR]: − 16.9 % [− 46.0 to 32.7] vs − 29.7 % [− 49.5 to − 26.6]; Mann–Whitney U = 429, p = 0.025; Cliff’s δ = − 0.32), indicating an altered modulation of corticospinal excitability following the fatiguing task).

SP duration showed a marked group separation, with controls displaying a robust post-exercise prolongation, while patients exhibited minimal change or even shortening (HCs: 26.5 % [21.7–35.7] vs patients: − 2.0 % [− 12.2 to 10.2]; Mann–Whitney U = 1092, p = 1.0 × 10⁻⁶; Cliff’s δ = 0.55).

MEP amplitude changes displayed weaker but directionally consistent positive associations with fatigue measures across the whole sample (ρ ≈ 0.18–0.29), reaching statistical significance for Borg ratings (p = 0.0096) and trending for FRS and FSS.

Visual inspection of scatterplots confirmed substantial overlap and dispersion within groups, alongside a clear linear gradient across the combined sample.

 

[SNT Gatchaman]

Summary quotes from discussion —

After the pinching task, patients showed a significantly smaller reduction in MEP amplitude compared with HCs, with some patients even showing a paradoxical increase in MEP amplitude. In healthy subjects, intense voluntary contraction is typically followed by post-exercise depression of MEP amplitude. In PCC, the lack of MEP suppression, and in some cases MEP facilitation, may reflect a failure of this adaptive downregulation.

MEP amplitude reflects however the net output of the corticomotor system and is influenced by multiple physiological levels, including pyramidal neuron excitability, intracortical inhibitory and facilitatory circuits, spinal motoneuron excitability, motor unit recruitment, afferent feedback, premotor and supplementary motor drive, basal ganglia–thalamo–cortical loops, brainstem arousal systems, and state-dependent fluctuations. Therefore, MEP amplitude reduction or paradoxical MEP facilitation after effort cannot be attributed to a single mechanism.

… the MEP findings should not be interpreted as a measure of post-exercise modulation completely independent of baseline excitability. Rather, the altered PED response occurred in the context of a pre-existing reduction in corticomotor excitability […] may itself be part of the pathophysiological substrate limiting adaptive post-exercise downregulation

Although maximal force production during the pinching task was comparable between groups, PCC patients reported significantly higher perceived effort. At the individual level, Borg ratings were not significantly associated with force production in either group. This finding supports a mismatch between objective motor output and perceived effort in PCC, which may reflect altered central processing of action cost.

Lack of PED has also been reported in fatigued patients with multiple sclerosis (Mordillo-Mateos et al., 2019, Perretti et al., 2004), in Parkinson’s disease patients with fatigue (Khedr et al., 2007), and in patients with post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (Walitt et al., 2024).

fatigability at the corticospinal level may arise from both centrally generated motor commands and sensory feedback associated with progressive muscular strain.

In our cohort, both MEP and SP modulation clearly distinguished PCC patients from HCs, however only SP modulation exhibited a consistent relationship with fatigue severity.

Longitudinal and repeated-challenge studies are needed to establish PED as a stable and sensitive biomarker, and integrated neurophysiological and neuroimaging approaches may help clarify the link between local inhibitory changes and network-level dysfunction.

 

[SugarSquared]

Interesting stuff. I wonder what the larger implications are. They mention in the discussion section that similar findings were found in ME/CFS which @SNT Gatchaman highlighted. Here is the link to the thread for the paper they reference: Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al.