Altered GABA-ergic regulation of the motor cortex excitability in patients with post-COVID cognitive deficits (TMS study)

Three years after the global COVID-19 pandemic, it is clear that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a new disease called long-COVID or post-acute COVID-19 syndrome (PACS). Long COVID syndrome encompasses a wide range of organ dysfunction and clinical symptoms. The most frequent, persistent, and disabling symptoms are neurological, known as ‘‘neuro-long COVID”. In this article, the Italian researchers used ‘‘paired-pulse” transcranial magnetic stimulation (ppTMS) and short-latency afferent inhibition (SAI) to investigate the motor cortex excitability in a group of patients diagnosed with post-COVID syndrome and cognitive deficits. 

Most cognitive deficits in participants with neuro-long COVID are related to executive functions, such as working memory, attention, parallel processing, planning, and problem-solving.

γ –aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system. It activates receptors GABAA and GABAC, ligand-gated Cl−channels, and G protein-coupled GABAB receptors. The activation of GABAB receptors generates slow inhibitory postsynaptic potentials. Prior studies reported that SARS-CoV-2 depletes host GABA through several mechanisms: 1. The binding of SARS-CoV-2 to ACE-2 disrupts the protective function of the renin-angiotensin system and lowers GABA. 2. SARS-CoV-2 S protein contains a GABA-mimicking sequence or a short linear motif that can usurp host GABA-ergic signaling directly. 3. The SARS-CoV-2 proteins nonstructural protein 6 (NSP6), open reading frame 8 (ORF8), and open reading frame 3 (ORF3a) interact directly with host mammalian target of rapamycin complex 1 (mTORC-1), interleukin 17 (IL-17), and transmembrane protein 16F (TMEM16F), inducing premature endothelial cell senescence, a phenotype characterized by low GABA. 4. The SARS-CoV-2 protein ORF3a interacts with toll-like receptor 4, triggering the senescence of endothelial cells and lowering GABA. 5. The SARS-CoV-2 viral proteins nonstructural protein 4 (NSP4), nonstructural protein 8 (NSP8), and open reading frame 9c (ORF9c) decrease GABA by disrupting the mitochondria and triggering vascular senescence. (Afera A. et al. Neuronal and Non-Neuronal GABA in COVID-19: Relevance for Psychiatry, Reports 2022, 5(2), 22.)

The TMS is a non-invasive research tool, used to investigate cortical excitability, connectivity, and plasticity in humans. GABA receptors and glutamate regulate the neurobiochemical circuits studied by the pp TMS protocols (LICI, SICI, ICF). Intracortical facilitation (ICF) reflects glutamatergic signaling. Short-interval intracortical inhibition (SICI) reflects fast inhibitory post-synaptic potentials in corticospinal neurons mediated through GABAA receptors and short-latency afferent inhibition related to cholinergic circuits. Long-interval intracortical inhibition (LICI) depends on slow inhibitory post-synaptic potentials mediated through GABAB receptor-mediated inhibition and intracortical facilitation, related to glutamatergic regulation.  A short-latency afferent inhibition (SAI) is another TMS parameter regulated by the excitatory effect of cholinergic thalamocortical projections on the inhibitory GABA-ergic cortical network. SAI is thought to be a sensitive biomarker of neurodegenerative diseases and dementia.

The researchers emphasized that GABA depletion caused by SARS-CoV-2 may explain the neuropsychiatric symptoms observed in patients with acute COVID-19 and neuro-long-COVID, such as anxiety, depression, sleep disorders, posttraumatic stress disorder, and cognitive deficits.


About the study

The study included 18 right-handed patients diagnosed with long COVID syndrome and cognitive deficits and 16 healthy controls. Out of 18 patients with neuro-long COVID, 12 were women, and the mean age was 50 ± 11 years. During the acute phase of SARS-CoV-2 infection, the patients were not hospitalized. 

All participants were examined for the presence of persistent symptoms lasting for more than 12 weeks following the acute SARS-CoV-2 infection, such as fatigue, respiratory symptoms, palpitations, gastrointestinal tract symptoms, myalgia or joint pain, tinnitus, vertigo, visual disturbances, and fever. The participants were especially examined for persistent neurological symptoms, including paraesthesias, anosmia/ageusia, cognitive deficits, mood disturbances, headaches, hemiparesis, and insomnia.

All patients had cognitive and neuropsychological assessments. The Montreal Cognitive Assessment (MoCA) test evaluated cognitive impairments, whereas a series of psychometrically validated tests evaluated attention and executive functions. The Fatigue Severity Scale (FSS) was used to assess fatigue in daily activities.

The inhibitory and excitatory intracortical networks were evaluated by the ppTMS protocols. The resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), and short-afferent inhibition (SAI) were investigated over the motor cortex.


The results showed significantly lower median MoCA corrected scores in patients with neuro-long COVID syndrome and cognitive impairments than in healthy controls. Most of them performed sub-optimally on the neuropsychological and executive function assessment. They also displayed high levels of fatigue on the FSS.

The resting motor threshold or mean evoked motor potentials did not differ significantly between the two groups. The results of short-interval intracortical inhibition were similar in both groups. However, the results of long-interval intracortical inhibition were significantly reduced in patients diagnosed with long COVID syndrome and cognitive deterioration


According to the results of this pp-TMS study,  patients with long COVID syndrome and cognitive deterioration have significantly altered GABA-ergic regulation of the motor cortex excitability. The main finding was altered GABAB receptor-mediated inhibition in patients diagnosed with neuro-long COVID. The authors noted that abnormal GABA-ergic and glutamatergic regulation, but normal cholinergic regulation of the motor cortex excitability, may reflect more widespread changes in the regulatory crosstalk between frontal and pre-frontal cortical hubs.

In addition, these findings indicate that TMS can be a useful non-invasive electrophysiological tool for assessing cortical excitability in patients diagnosed with neuro-long COVID syndrome.

This article was published in Clinical Neurophysiology.

Journal Reference

Manganotti P et al. Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment. Clinical Neurophysiology 151 (2023) 83–91.

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