Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.

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.

Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19.

OBJECTIVE: A high proportion of patients experience fatigue and impairment of cognitive functions after coronavirus disease 2019 (COVID-19). Here we applied transcranial magnetic stimulation (TMS) to explore the activity of the main inhibitory intracortical circuits within the primary motor cortex (M1) in a sample of patients complaining of fatigue and presenting executive dysfunction after resolution of COVID-19 with neurological manifestations. METHODS: Twelve patients who recovered from typical COVID-19 pneumonia with neurological complications and complained of profound physical and mental fatigue underwent, 9 to 13 weeks from disease onset, a psychometric evaluation including a self-reported fatigue numeric-rating scale (FRS, Fatigue Rating Scale) and the Frontal Assessment Battery (FAB). Intracortical activity was evaluated by means of well-established TMS protocols including short-interval intracortical inhibition (SICI), reflecting GABAA-mediated inhibition, long-interval intracortical inhibition (LICI), a marker of GABAB receptor activity, and short-latency afferent inhibition (SAI) that indexes central cholinergic transmission. TMS data were compared to those obtained in a control group of ten healthy subjects (HS) matched by age, sex and education level. RESULTS: Post-COVID-19 patients reported marked fatigue according to FRS score (8.1 ± 1.7) and presented pathological scores at the FAB based on Italian normative data (12.2 ± 0.7). TMS revealed marked reduction of SICI, and disruption of LICI as compared to HS. SAI was also slightly diminished. CONCLUSIONS: The present study documents for the first time reduced GABAergic inhibition in the M1 in patients who recovered from COVID-19 with neurological complications and manifested fatigue and dysexecutive syndrome. SIGNIFICANCE: TMS may serve as diagnostic tool in cognitive disturbances and fatigue in post-COVID-19 patients.

Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: Insights into a challenging symptom.

More than half of patients who recover from COVID-19 experience fatigue. We studied fatigue using neuropsychological and neurophysiological investigations in post-COVID-19 patients and healthy subjects. Neuropsychological assessment included: Fatigue Severity Scale (FSS), Fatigue Rating Scale, Beck Depression Inventory, Apathy Evaluation Scale, cognitive tests, and computerized tasks. Neurophysiological examination was assessed before (PRE) and 2 min after (POST) a 1-min fatiguing isometric pinching task and included: maximum compound muscle action potential (CMAP) amplitude in first dorsal interosseous muscle (FDI) following ulnar nerve stimulation, resting motor threshold, motor evoked potential (MEP) amplitude and silent period (SP) duration in right FDI following transcranial magnetic stimulation of the left motor cortex. Maximum pinch strength was measured. Perceived exertion was assessed with the Borg-Category-Ratio scale. Patients manifested fatigue, apathy, executive deficits, impaired cognitive control, and reduction in global cognition. Perceived exertion was higher in patients. CMAP and MEP were smaller in patients both PRE and POST. CMAP did not change in either group from PRE to POST, while MEP amplitudes declined in controls POST. SP duration did not differ between groups PRE, increased in controls but decreased in patients POST. Patients' change of SP duration from PRE to POST was negatively correlated to FSS. Abnormal SP shortening and lack of MEP depression concur with a reduction in post-exhaustion corticomotor inhibition, suggesting a possible GABAB-ergic dysfunction. This impairment might be related to the neuropsychological alterations. COVID-19-associated inflammation might lead to GABAergic impairment, possibly representing the basis of fatigue and explaining apathy and executive deficits.

COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator?

COVID-19 is an ongoing viral pandemic that emerged from East Asia and quickly spread to the rest of the world. SARS-CoV-2 is the virus causing COVID-19. Acute respiratory distress syndrome (ARDS) is definitely one of the main clinically relevant consequences in patients with COVID-19. Starting from the earliest reports of the COVID-19 pandemic, two peculiar neurological manifestations (namely, hyposmia/anosmia and dysgeusia) were reported in a relevant proportion of patients infected by SARS-CoV-2. At present, the physiopathologic mechanisms accounting for the onset of these symptoms are not yet clarified. CXCL10 is a pro-inflammatory chemokine with a well-established role in the COVID-19-related cytokine storm and in subsequent development of ARDS. CXCL10 is also known to be involved in coronavirus-induced demyelination. On these bases, a role for CXCL10 as the common denominator between pulmonary and olfactory dysfunctions could be envisaged. The aim of the present report will be to hypothesize a role for CXCL10 in COVID-19 olfactory dysfunctions. Previous evidences supporting our hypothesis, with special emphasis to the role of CXCL10 in coronavirus-induced demyelination, the anatomical and physiological peculiarity of the olfactory system, and the available data supporting their link during COVID-19 infections, will be overviewed.