Long-interval Intracortical Inhibition Research Articles

Modulation of Motor Cortical Inhibition and Facilitation by Touch Sensation from the Glabrous Skin of the Human Hand.

Touch sensation from the glabrous skin of the hand is essential for precisely controlling dexterous movements, yet the neural mechanisms by which tactile inputs influence motor circuits remain largely unexplored. By pairing air-puff tactile stimulation on the hand's glabrous skin with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), we examined the effects of tactile stimuli from single or multiple fingers on corticospinal excitability and M1's intracortical circuits. Our results showed that when we targeted the hand's first dorsal interosseous (FDI) muscle with TMS, homotopic (index finger) tactile stimulation, regardless of its point (fingertip or base), reduced corticospinal excitability. Conversely, heterotopic (ring finger) tactile stimulation had no such effect. Notably, stimulating all five fingers simultaneously led to a more pronounced decrease in corticospinal excitability than stimulating individual fingers. Furthermore, tactile stimulation significantly increased intracortical facilitation (ICF) and decreased long-interval intracortical inhibition (LICI) but did not affect short-interval intracortical inhibition (SICI). Considering the significant role of the primary somatosensory cortex (S1) in tactile processing, we also examined the effects of downregulating S1 excitability via continuous theta burst stimulation (cTBS) on tactile-motor interactions. Following cTBS, the inhibitory influence of tactile inputs on corticospinal excitability was diminished. Our findings highlight the spatial specificity of tactile inputs in influencing corticospinal excitability. Moreover, we suggest that tactile inputs distinctly modulate M1's excitatory and inhibitory pathways, with S1 being crucial in facilitating tactile-motor integration.

Attentional focus differentially modulates the corticospinal and intracortical excitability during dynamic and static exercise.

Although attentional focus affects motor performance, whether corticospinal excitability and intracortical modulations differ between focus strategies depending on the exercise patterns remains unclear. In the present study, using single- and paired-pulse transcranial magnetic stimulation and peripheral nerve stimulation, we demonstrated changes in the cortical and spinal excitability under external focus (EF) and internal focus (IF) conditions with dynamic or static exercise. Participants performed the ramp-and-hold contraction task of right index finger abduction against an object (sponge or wood) with both exercises. They were asked to concentrate on the pressure on the sponge/wood induced by finger abduction under the EF condition, and on the index finger itself under the IF condition. Motor-evoked potential (MEP) and F-wave in the premotor, phasic, or tonic phase, and short- and long-interval intracortical inhibition (SICI and LICI, respectively), and intracortical facilitation (ICF) in the premotor phase were examined by recording surface electromyographic activity in the right first dorsal interosseous muscle. Increments in the MEP amplitude were larger under the EF condition than under the IF condition in the dynamic, but not static, exercise. The F-wave, SICI, and LICI did not differ between focus conditions in both exercises. In the dynamic exercise, interestingly, ICF was greater under the EF condition than under the IF condition and positively correlated with the MEP amplitude. These results indicate that corticospinal excitability and intracortical modulations to attentional focus differ depending on exercise patterns, suggesting that attentional focus differentially affects the central nervous system responsible for diverse motor behaviors.NEW & NOTEWORTHY We investigated attentional focus-dependent corticospinal and intracortical modulations in dynamic or static exercise. The corticospinal excitability was modulated differentially depending on the focus of attention during dynamic, but not static exercise. Although the reduction of intracortical GABAergic inhibition was comparable between focus conditions in both exercises, intracortical facilitation was smaller when focusing on the internal environments in the dynamic exercise, resulting in lower activation of the corticospinal tract.

Beta rebound reduces subsequent movement preparation time by modulating of GABAA inhibition.

Post-movement beta synchronization is an increase of beta power relative to baseline, which commonly used to represent the status quo of the motor system. However, its functional role to the subsequent voluntary motor output and potential electrophysiological significance remain largely unknown. Here, we examined the reaction time of a Go/No-Go task of index finger tapping which performed at the phases of power baseline and post-movement beta synchronization peak induced by index finger abduction movements at different speeds (ballistic/self-paced) in 13 healthy subjects. We found a correlation between the post-movement beta synchronization and reaction time that larger post-movement beta synchronization prolonged the reaction time during Go trials. To probe the electrophysiological significance of post-movement beta synchronization, we assessed intracortical inhibitory measures probably involving GABAB (long-interval intracortical inhibition) and GABAA (short-interval intracortical inhibition) receptors in beta baseline and post-movement beta synchronization peak induced by index finger abduction movements at different speeds. We found that short-interval intracortical inhibition but not long-interval intracortical inhibition increased in post-movement beta synchronization peak compared with that in the power baseline, and was negatively correlated with the change of post-movement beta synchronization peak value. These novel findings indicate that the post-movement beta synchronization is related to forward model updating, with high beta rebound predicting longer time for the preparation of subsequent movement by inhibitory neural pathways of GABAA.

Relationship between transcranial magnetic stimulation markers of motor control and clinical recovery in obsessive compulsive disorder/Gilles de la Tourette syndrome: a proof of concept case study.

Obsessive compulsive disorder (OCD) and Gilles de la Tourette syndrome (GTS) are neurodevelopmental disorders characterized by difficulties in controlling intrusive thoughts (obsessions) and undesired actions (tics), respectively. Both conditions have been associated with abnormal inhibition but a tangible deficit of inhibitory control abilities is controversial in GTS. Here, we examined a 25 years-old male patient with severe OCD symptoms and a mild form of GTS, where impairments in motor control were central. Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) during four experimental sessions, allowing us to assess the excitability of motor intracortical circuitry at rest as well as the degree of MEP suppression during action preparation, a phenomenon thought to regulate movement initiation. When tested for the first time, the patient presented a decent level of MEP suppression during action preparation, but he exhibited a lack of intracortical inhibition at rest, as evidenced by reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI). Interestingly, the patient's symptomatology drastically improved over the course of the sessions (reduced obsessions and tics), coinciding with feedback given on his good motor control abilities. These changes were reflected in the TMS measurements, with a significant strengthening of intracortical inhibition (SICI and LICI more pronounced than previously) and a more selective tuning of MEPs during action preparation; MEPs became even more suppressed, or selectively facilitated depending on the behavioral condition in which they we probed. This study highlights the importance of better understanding motor inhibitory mechanisms in neurodevelopmental disorders and suggests a biofeedback approach as a potential novel treatment.

GABAA Receptor Availability in Relation to Cortical Excitability in Depressed and Healthy: A Positron Emission Tomography and Transcranial Magnetic Stimulation Study

Introduction: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABA_A receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls. Methods: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [¹¹C]flumazenil positron emission tomography to assess GABA_A receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABA_A receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABA_A receptor activity, long-interval intracortical inhibition representing GABA_B receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability. Results: No significant differences in baseline GABA_A receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABA_A receptor availability and TMS outcomes. Changes in GABA_A receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT. Conclusion: We found that a change in GABA_A receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.

Effects of sleep deprivation on cortical excitability: A threshold-tracking TMS study and review of the literature

ObjectiveInsufficient sleep is linked to several health problems. Previous studies on the effects of sleep deprivation on cortical excitability using conventional transcranial magnetic stimulation (TMS) included a limited number of modalities, and few inter-stimulus intervals (ISIs) and showed conflicting results. This study aimed to investigate the effects of sleep deprivation on cortical excitability through threshold-tracking TMS, using a wide range of protocols at multiple ISIs. MethodsFifteen healthy subjects (mean age ± SD: 36 ± 3.34 years) were included. The following tests were performed before and after 24 h of sleep deprivation using semi-automated threshold-tacking TMS protocols: short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) at 11 ISIs between 1 and 30 ms, short interval intracortical facilitation (SICF) at 14 ISIs between 1 and 4.9 ms, long interval intracortical inhibition (LICI) at 6 ISIs between 50 and 300 ms, and short-latency afferent inhibition (SAI) at 12 ISIs between 16 and 30 ms. ResultsNo significant differences were observed between pre- and post-sleep deprivation measurements for SICI, ICF, SICF, or LICI at any ISIs (p < 0.05). As for SAI, we found a difference at 28 ms (p = 0.007) and 30 ms (p = 0.04) but not at other ISIs. ConclusionsSleep deprivation does not affect cortical excitability except for SAI. SignificanceThis study confirms some of the previous studies while contradicting others.

Evidence of altered corticomotor inhibition in older adults with a history of repetitive neurotrauma. A transcranial magnetic stimulation study

International concern continues regarding the association between the long-term neurophysiologic changes from repetitive neurotrauma associated with contact and collision sports. This study describes corticomotor changes in retired contact/collision sport athletes and controls, between the ages of 30 and 70 years. Retired athletes (n = 152; 49.1 ± 8.5 years) and controls (n = 72; 47.8 ± 9.5 years) were assessed using single and paired-pulse transcranial magnetic stimulation (TMS) for active motor threshold (aMT), motor evoked potential and cortical silent period duration (expressed as MEP:cSP ratio), and short- and long-interval intracortical inhibition (SICI and LICI). Motor threshold, MEP:cSP, SICI and LICI for both groups were correlated across age. Controls showed significant moderate correlations for MEP:cSP ratios at 130% (rho = 0.48, p < 0.001), 150% (rho = 0.49, p < 0.001) and 170% aMT (rho = 0.42; p < 0.001) and significant small negative correlation for SICI (rho = −0.27; p = 0.030), and moderate negative correlation for LICI (rho = −0.43; p < 0.001). Group-wise correlation analysis comparisons showed significant correlation differences between groups for 130% (p = 0.016) and 150% aMT (p = 0.009), specifically showing retired athletes were displaying increased corticomotor inhibition. While previous studies have focussed studies on older athletes (>50 years), this study is the first to characterize corticomotor differences between retired athletes and controls across the lifespan. These results, demonstrating pathophysiological differences in retired athletes across the lifespan, provide a foundation to utilise evoked potentials as a prodromal marker in supplementing neurological assessment for traumatic encephalopathy syndrome associated with contact/collision sport athletes that is currently lacking physiological biomarkers.

Excitatory-inhibitory modulation of transcranial focus ultrasound stimulation on human motor cortex.

Transcranial focus ultrasound stimulation (tFUS) is a promising non-invasive neuromodulation technology. This study aimed to evaluate the modulatory effects of tFUS on human motor cortex (M1) excitability and explore the mechanism of neurotransmitter-related intracortical circuitry and plasticity. Single pulse transcranial magnetic stimulation (TMS)-eliciting motor-evoked potentials (MEPs) were used to assessed M1 excitability in 10 subjects. Paired-pulse TMS was used to measure the effects of tFUS on GABA- and glutamate-related intracortical excitability and 1 H-MRS was used to assess the effects of repetitive tFUS on GABA and Glx (glutamine + glutamate) neurometabolic concentrations in the targeting region in nine subjects. The etFUS significantly increased M1 excitability, decreased short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI). The itFUS significantly suppressed M1 excitability, increased SICI, LICI, and decreased intracortical facilitation (ICF). Seven times of etFUS decreased the GABA concentration (6.32%), increased the Glx concentration (12.40%), and decreased the GABA/Glx ratio measured by MRS, while itFUS increased the GABA concentration (18.59%), decreased Glx concentration (0.35%), and significantly increased GABA/Glx ratio. The findings support that tFUS with different parameters can exert excitatory and inhibitory neuromodulatory effects on the human motor cortex. We provide novel insights that tFUS change cortical excitability and plasticity by regulating excitatory-inhibition balance related to the GABAergic and glutamatergic receptor function and neurotransmitter metabolic level.

Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment

ObjectiveAttention, working memory and executive processing have been reported to be consistently impaired in Neuro-Long coronavirus disease (COVID). On the hypothesis of abnormal cortical excitability, we investigated the functional state of inhibitory and excitatory cortical regulatory circuits by single “paired-pulse” transcranial magnetic stimulation (ppTMS) and Short-latency Afferent Inhibition (SAI). MethodsWe compared clinical and neurophysiological data of 18 Long COVID patients complaining of persistent cognitive impairment with 16 Healthy control (HC) subjects. Cognitive status was evaluated by means of the Montreal Cognitive Assessment (MoCA) and a neuropsychological evaluation of the executive function domain; fatigue was scored by the Fatigue Severity Scale (FSS). Resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), Short Intra-cortical Inhibition (SICI), Intra-cortical Facilitation (ICF), Long-interval Intracortical Inhibition (LICI) and Short-afferent inhibition (SAI) were investigated over the motor (M1) cortex. ResultsMoCA corrected scores were significantly different between the two groups (p = 0.023). The majority of the patients’ performed sub-optimally in the neuropsychological assessment of the executive functions. The majority (77.80%) of the patients reported high levels of perceived fatigue in the FSS. RMT, MEPs, SICI and SAI were not significantly different between the two groups. On the other hand, Long COVID patients showed a reduced amount of inhibition in LICI (p = 0.003) and a significant reduction in ICF (p < 0.001). ConclusionsNeuro-Long COVID patients performing sub-optimally in the executive functions showed a reduction of LICI related to GABAb inhibition and a reduction of ICF related to glutamatergic regulation. No alteration in cholinergic circuits was found. SignificanceThese findings can help to better understand the neurophysiological characteristics of Neuro-Long COVID, and in particular, motor cortex regulation in people with “brain fog”.

Probing the link between cortical inhibitory and excitatory processes and muscle fascicle dynamics

During movements, neural signals are translated into muscle fibre shortening, lengthening or they remain isometric. This study investigated cortical excitatory and inhibitory processes in relation to muscle fascicle dynamics during fixed-end rapid contractions. Fourteen adults performed submaximal and maximal ankle dorsiflexions. Single and paired pulse transcranial magnetic stimulation over the cortical representation projecting to the tibialis anterior (TA) was applied during rest, the activation and deactivation phase of contractions to test for short- (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Ultrasound images were taken to measure muscle fascicle dynamics of the superficial (TASF) and deep (TADP) TA compartments. The results show significantly greater maximal shortening velocities (p = 0.003, d = 0.26, CI [4.89, 18.52]) and greater maximal fascicle shortening (p = 0.003, d = 0.86, CI [0.29, 3.13]) in TASF than TADP during submaximal dorsiflexions. Significantly lower SICI levels during activation compared to deactivation (p = 0.019, d = 1.12, CI [19.82, 1.76]) and at rest (p < 0.0001) were observed. ICF was significantly greater during activation (p = 0.03) than during rest while LICI did not modulate significantly. Maximal TASF but not TADP shortening velocity correlated with SICI levels at activation (p = 0.06) and with the rate of torque development (p = 0.02). The results suggest that SICI might be related to muscle fascicle behavior and that intracortical inhibition and excitation are phase-dependently modulated.

Cortical inhibition function is associated with baseline suicidal symptoms and post-ketamine suicidal symptom reduction among patients with treatment-resistant depression and strong suicidal ideation

BackgroundWhether cortical excitation and inhibition functions differ between patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI) and healthy subjects and whether 0.5 mg/kg ketamine infusion can modulate cortical excitation and inhibition functions among patients with TRD–SI remain unclear. MethodsA total of 29 patients with TRD–SI and 35 age- and sex-matched healthy controls were assessed using paired-pulse transcranial magnetic stimulation. The patients were randomly assigned to receive either a single 0.5-mg/kg ketamine or 0.045-mg/kg midazolam infusion. Depressive and suicidal symptoms were assessed at baseline and 240 min after infusion. Intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI), all of which reflect cortical excitability and inhibition functions, were measured at the same time points. ResultsThe patients with TRD–SI had lower ICF (p < 0.001) estimates (worse cortical excitatory function) and higher SICI (p = 0.032) and LICI (p < 0.001) estimates (worse cortical inhibitory function) compared with the control group. Higher SICI estimates at baseline were associated with greater baseline suicidal symptoms. No differences were found in the SICI, ICF, and LICI estimates at 240 min after the infusion between the two groups. Low-dose ketamine did not alter the cortical excitation and inhibition functions of the patients with TRD–SI. However, decreased SICI estimates (greater cortical inhibition function) were related to the reduction of suicidal symptoms. DiscussionDysfunction of cortical excitation and inhibition may play a crucial role in the pathomechanisms of TRD and suicidal symptoms. However, we found a lack of predictive ability of the baseline cortical excitation and inhibition parameters on the antidepressant and antisuicidal effect of low-dose ketamine infusion.

Long-Interval Intracortical Inhibition and the Cortical Silent Period in Youth.

The cortical silent period (CSP) and long-interval intracortical inhibition (LICI) are putative markers of γ-aminobutyric acid receptor type B (GABAB)-mediated inhibitory neurotransmission. We aimed to assess the association between LICI and CSP in youths. We analyzed data from three previous studies of youth who underwent CSP and LICI measurements with transcranial magnetic stimulation and electromyography. We assessed CSP and LICI association using Spearman rank correlation tests and multiple linear regression analyses adjusted for demographic and clinical covariates. The sample included 16 healthy participants and 45 participants with depression. The general mean (SD) age was 15.5 (1.7), 14.3 (1.7) for healthy participants, and 15.9 (1.6) years for participants with depression. Measures were nonnormally distributed (Shapiro-Wilk, p < 0.001). CSP and LICI were not correlated at 100-millisecond (ρ = -0.2421, p = 0.06), 150-millisecond (ρ = -0.1612, p = 0.21), or 200-millisecond (ρ = -0.0507, p = 0.70) interstimulus intervals using Spearman rank correlation test. No correlations were found in the multiple regression analysis (p = 0.35). Although previous studies suggest that cortical silent period and long-interval intracortical inhibition measure GABAB receptor-mediated activity, these biomarkers were not associated in our sample of youths. Future studies should focus on the specific physiologic and pharmacodynamic properties assessed by CSP and LICI in younger populations.

Reliability of corticospinal excitability and intracortical inhibition in biceps femoris during different contraction modes.

This study aimed to determine the test-retest reliability of a range of transcranial magnetic stimulation (TMS) outcomes in the biceps femoris during isometric, eccentric and concentric contractions. Corticospinal excitability (active motor threshold 120% [AMT120%] and area under recruitment curve [AURC]), short- and long-interval intracortical inhibition (SICI and LICI) and intracortical facilitation (ICF) were assessed from the biceps femoris in 10 participants (age 26.3 ± 6.0 years; height 180.2 ± 6.6 cm, body mass 77.2 ± 8.0 kg) in three sessions. Single- and paired-pulse stimuli were delivered under low-level muscle activity (5% ± 2% of maximal isometric root mean squared surface electromyography [rmsEMG]) during isometric, concentric and eccentric contractions. Participants were provided visual feedback on their levels of rmsEMG during all contractions. Single-pulse outcomes measured during isometric contractions (AURC, AMT110%, AMT120%, AMT130%, AMT150%, AMT170%) demonstrated fair to excellent reliability (ICC range, .51 to .92; CV%, 21% to 37%), whereas SICI, LICI and ICF demonstrated good to excellent reliability (ICC range, .62 to .80; CV%, 19 to 42%). Single-pulse outcomes measured during concentric contractions demonstrated excellent reliability (ICC range, .75 to .96; CV%, 15% to 34%), whereas SICI, LICI and ICF demonstrated good to excellent reliability (ICC range, .65 to .76; CV%, 16% to 71%). Single-pulse outcomes during eccentric contractions demonstrated fair to excellent reliability (ICC range, .56 to .96; CV%, 16% to 41%), whereas SICI, LICI and ICF demonstrated good to excellent (ICC range, .67 to .86; CV%, 20% to 42%). This study found that both single- and paired-pulse TMS outcomes can be measured from the biceps femoris muscle across all contraction modes with fair to excellent reliability. However, coefficient of variation values were typically greater than the smallest worthwhile change which may make tracking physiological changes in these variables difficult without moderate to large effect sizes.

Short- and long-interval intracortical inhibition in EPM1 is related to genotype.

Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho=0.872; p < .001) and SICI (rho=0.689; p=.006). Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.

Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome

ObjectiveTranscranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI).Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. MethodsThirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. ResultsPatients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. ConclusionsEight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients. SignificanceThis study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.

Classification accuracy of blood-based and neurophysiological markers in the differential diagnosis of Alzheimer’s disease and frontotemporal lobar degeneration

BackgroundIn the last decade, non-invasive blood-based and neurophysiological biomarkers have shown great potential for the discrimination of several neurodegenerative disorders. However, in the clinical workup of patients with cognitive impairment, it will be highly unlikely that any biomarker will achieve the highest potential predictive accuracy on its own, owing to the multifactorial nature of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsIn this retrospective study, performed on 202 participants, we analysed plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau phosphorylated at amino acid 181 (p-Tau181) concentrations, as well as amyloid β42 to 40 ratio (Aβ1–42/1–40) ratio, using the ultrasensitive single-molecule array (Simoa) technique, and neurophysiological measures obtained by transcranial magnetic stimulation (TMS), including short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), and short-latency afferent inhibition (SAI). We assessed the diagnostic accuracy of combinations of both plasma and neurophysiological biomarkers in the differential diagnosis between healthy ageing, AD, and FTLD.ResultsWe observed significant differences in plasma NfL, GFAP, and p-Tau181 levels between the groups, but not for the Aβ1–42/Aβ1–40 ratio. For the evaluation of diagnostic accuracy, we adopted a two-step process which reflects the clinical judgement on clinical grounds. In the first step, the best single biomarker to classify “cases” vs “controls” was NfL (AUC 0.94, p < 0.001), whilst in the second step, the best single biomarker to classify AD vs FTLD was SAI (AUC 0.96, p < 0.001). The combination of multiple biomarkers significantly increased diagnostic accuracy. The best model for classifying “cases” vs “controls” included the predictors p-Tau181, GFAP, NfL, SICI, ICF, and SAI, resulting in an AUC of 0.99 (p < 0.001). For the second step, classifying AD from FTD, the best model included the combination of Aβ1–42/Aβ1–40 ratio, p-Tau181, SICI, ICF, and SAI, resulting in an AUC of 0.98 (p < 0.001).ConclusionsThe combined assessment of plasma and neurophysiological measures may greatly improve the differential diagnosis of AD and FTLD.

Long-interval intracortical inhibition in primary motor cortex related to working memory in middle-aged adults.

IntroductionExcitability of the primary motor cortex measured with TMS has been associated with cognitive dysfunctions in patient populations. However, only a few studies have explored this relationship in healthy adults, and even fewer have considered the role of biological sex.MethodsNinety-seven healthy middle-aged adults (53 male) completed a TMS protocol and a neuropsychological assessment. Resting Motor Threshold (RMT) and Long-Interval Intracortical Inhibition (LICI) were assessed in the left motor cortex and related to attention, episodic memory, working memory, reasoning, and global cognition composite scores to evaluate the relationship between cortical excitability and cognitive functioning.ResultsIn the whole sample, there was a significant association between LICI and cognition; specifically, higher motor inhibition was related to better working memory performance. When the sample was broken down by biological sex, LICI was only associated with working memory, reasoning, and global cognition in men. No associations were found between RMT and cognitive functions.ConclusionGreater intracortical inhibition, measured by LICI, could be a possible marker of working memory in healthy middle-aged adults, and biological sex plays a critical role in this association.

The effects of concurrent bilateral anodal tDCS of primary motor cortex and cerebellum on corticospinal excitability: a randomized, double-blind sham-controlled study

Transcranial direct current stimulation (tDCS) applied to the primary motor cortex (M1), and cerebellum (CB) can change the level of M1 corticospinal excitability (CSE). A randomized double-blinded crossover, the sham-controlled study design was used to investigate the effects of concurrent bilateral anodal tDCS of M1 and CB (concurrent bilateral a-tDCSM1+CB) on the CSE. Twenty-one healthy participants were recruited in this study. Each participant received anodal-tDCS (a-tDCS) of 2 mA, 20 min in four pseudo-randomized, counterbalanced sessions, separated by at least 7 days (7.11 days ± 0.65). These sessions were bilateral M1 stimulation (bilateral a-tDCSM1), bilateral cerebellar stimulation (bilateral a-tDCSCB), concurrent bilateral a-tDCSM1+CB, and sham stimulation (bilateral a-tDCSSham). Transcranial magnetic stimulation (TMS) was delivered over the left M1, and motor evoked potentials (MEPs) of a contralateral hand muscle were recorded before and immediately after the intervention to measure CSE changes. Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) were assessed with paired-pulse TMS protocols. Anodal-tDCS significantly increased CSE after concurrent bilateral a-tDCSM1+CB and bilateral a-tDCSCB. Interestingly, CSE was decreased after bilateral a-tDCSM1. Respective alterations in SICI, LICI, and ICF were seen, including increased SICI and decreased ICF, which indicate the involvement of glutamatergic and GABAergic systems in these effects. These results confirm that the concurrent bilateral a-tDCSM1+CB have a facilitatory effect on CSE, whereas bilateral a-tDCSM1 exert some inhibitory effects. Moreover, the effects of the 2 mA, 20 min a-tDCS on the CB were consistent with its effects on the M1.

Sleep restriction alters cortical inhibition in migraine: A transcranial magnetic stimulation study

ObjectiveMigraine is a primary headache disorder with a well-known association with insufficient sleep. However, both the underlying pathophysiology of the disease and the relationship with sleep is still unexplained. In this study, we apply transcranial magnetic stimulation to investigate possible mechanisms of insufficient sleep in migraine. MethodsWe used a randomised, blinded crossover design to examine 46 subjects with migraine during the interictal period and 29 healthy controls. Each subject underwent recordings of cortical silent period, short- and long-interval intracortical inhibition, intracortical facilitation and short-latency afferent inhibition after both two nights of habitual eight-hour sleep and two nights of restricted four-hour sleep. ResultsWe found reduced cortical silent period duration after sleep restriction in interictal migraineurs compared to controls (p = 0.046). This effect was more pronounced for non-sleep related migraine (p = 0.002) and migraine with aura (p = 0.017). The sleep restriction effect was associated with ictal symptoms of hypersensitivity such as photophobia (p = 0.017) and overall silent period was associated with premonitory dopaminergic symptoms such as yawning (p = 0.034). ConclusionsSleep restriction reduces GABAergic cortical inhibition during the interictal period in individuals with migraine. SignificanceSleep related mechanisms appear to affect the pathophysiology of migraine and may differentiate between migraine subgroups.

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

Background and purposeFatigue 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.MethodsSixty‐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.ResultsPost 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.ConclusionsPatients with fatigue and cognitive difficulties following mild COVID‐19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.