A Bayesian approach to analysing cortico-cortical associative stimulation induced increases in the excitability of corticospinal projections in humans

Repeated pairing of transcranial magnetic stimulation (TMS) over left and right primary motor cortex (M1), at intensities sufficient to generate descending volleys, produces sustained increases in corticospinal excitability. In other paired associative stimulation (PAS) protocols, in which peripheral afferent stimulation is the first element, changes in corticospinal excitability achieved when the second stimulus consists of brief bursts of transcranial alternating current stimulation (tACS), are comparable to those obtained if TMS is used instead (McNickle and Carson 2015). The present aim was to determine whether associative effects are induced when the first stimulus of a cortico-cortical pair is tACS, or alternatively subthreshold TMS. Bursts of tACS (500 ms; 140 Hz; 1 mA) were associated (180 stimulus pairs) with single magnetic stimuli (120% resting motor threshold rMT) delivered over the opposite (left) M1. The tACS ended 6 ms prior to the TMS. In a separate condition, TMS (55% rMT) was delivered to right M1 6 ms before (120% rMT) TMS was applied over left M1. In a sham condition, TMS (120% rMT) was delivered to left M1 only. The limitations of null hypothesis significance testing are well documented. We therefore employed Bayes factors to assess evidence in support of experimental hypotheses—defined precisely in terms of predicted effect sizes, that these two novel variants of PAS increase corticospinal excitability. Although both interventions induced sustained (~ 20–30 min) increases in corticospinal excitability, the evidence in support of the experimental hypotheses (over specified alternatives) was generally greater for the paired TMS-TMS than the tACS-TMS conditions

Acute Effects of Strength and Skill Training on the Cortical and Spinal Circuits of Contralateral Limb

Unilateral strength and skill training increase strength and performance in the contralateral untrained limb, a phenomenon known as cross-education. Recent evidence suggests that similar neural mechanisms might be responsible for the increase in strength and skill observed in the untrained hand after unimanual training. The aims of this study were to: investigate whether a single session of unimanual strength and skill (force-tracking) training increased strength and skill in the opposite hand; measure ipsilateral (untrained) brain (via transcranial magnetic stimulation, TMS) and spinal (via the monosynaptic reflex) changes in excitability occurring after training; measure ipsilateral (untrained) pathway-specific changes in neural excitability (via TMS-conditioning of the monosynaptic reflex) occurring after training. Participants (N = 13) completed a session of unimanual strength (ballistic isometric wrist flexions) and skill (force-tracking wrist flexions) training on two separate days. Strength increased after training in the untrained hand (p = 0.025) but not in the trained hand (p = 0.611). Force-tracking performance increased in both the trained (p = 0.007) and untrained (p = 0.010) hand. Corticospinal excitability increased after force-tracking and strength training (p = 0.027), while spinal excitability was not affected (p = 0.214). TMS-conditioned monosynaptic reflex increased after force-tracking (p = 0.001) but not strength training (p = 0.689), suggesting a possible role of polysynaptic pathways in the increase of cortical excitability observed after training. The results suggest that cross-education of strength and skill at the acute stage is supported by increased excitability of the untrained motor cortex. New & Noteworthy: A single session of isometric wrist flexion strength and skill straining increased strength and skill in the untrained limb. The excitability of the untrained motor cortex increased after strength and skill training. TMS-conditioned H-reflexes increased after skill but not strength training in the untrained hand, indicating that polysynaptic pathways in the increase of cortical excitability observed after skill training

The acute effects of motor imagery and cervical transcutaneous electrical stimulation on manual dexterity and neural excitability

Transcutaneous electrical stimulation (TCES) of the spinal cord induces changes in spinal excitability. Motor imagery (MI) elicits plasticity in the motor cortex. It has been suggested that plasticity occurring in both cortical and spinal circuits might underlie the improvements in performance observed when training is combined with stimulation. We investigated the acute effects of cervical TCES and MI delivered in isolation or combined on corticospinal excitability, spinal excitability and manual performance. Participants (N = 17) completed three sessions during which they engaged in 20 min of: 1) MI, listening to an audio recording instructing to complete the purdue pegboard test (PPT) of manual performance; 2) TCES at the spinal level of C5–C6; 3) MI + TCES, listening to the MI script while receiving TCES. Before and after each condition, we measured corticospinal excitability via transcranial magnetic stimulation (TMS) at 100% and 120% motor threshold (MT), spinal excitability via single-pulse TCES and manual performance with the PPT. Manual performance was not improved by MI, TCES or MI + TCES. Corticospinal excitability assessed at 100% MT intensity increased in hand and forearm muscles after MI and MI + TCES, but not after just TCES. Conversely, corticospinal excitability assessed at 120% MT intensity was not affected by any of the conditions. The effects on spinal excitability depended on the recorded muscle: it increased after all conditions in biceps brachii (BB) and flexor carpi radialis (FCR); did not change after any conditions in the abductor pollicis brevis (APB); increased after TCES and MI + TCES, but not after just MI in the extensor carpi radialis (ECR). These findings suggest that MI and TCES increase the excitability of the central nervous system through different but complementary mechanisms, inducing changes in the excitability of spinal and cortical circuits. MI and TCES can be used in combination to modulate spinal/cortical excitability, an approach particularly relevant for people with limited residual dexterity who cannot engage in motor practice

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis syndrome

Objective: Aim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Methods: This is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries. Results: A total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems. Conclusions: The development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on NCT 05200715

Reliability of the TMS-conditioned monosynaptic reflex in the Flexor Carpi Radialis muscle

A subthreshold pulse of transcranial magnetic stimulation (TMS) on the motor cortex can modulate the amplitude of the monosynaptic reflex (H-reflex) elicited in the flexor carpi radialis (FCR) muscle, a method known as TMS-conditioning of the H-reflex. The purpose of this study was to establish the intersession reliability of this method over the course of three sessions. Eleven healthy participants received either peripheral nerve stimulation (PNS), TMS or a combination of the two. The intensity of the PNS stimuli was set to evoke a monosynaptic response (H-reflex) corresponding to 10% of the maximum motor response (Mmax), HM10%. The conditioning effect of TMS on the monosynaptic reflex was assessed by delivering subthreshold cortical pulses at different conditioning-test intervals (from -7 ms to 7 ms) from peripheral nerve stimulation. The first interval at which facilitation could be observed was deemed early facilitation (EF). Using intraclass correlation coefficients (ICCs), we found excellent reliability for Mmax amplitudes (ICC = 0.98), HM10% amplitudes (ICC = 0.85) and TMS-conditioned H-reflexes recorded at the interval following EF (EF + 2 ms) (ICC = 0.87). Good reliability (ICCs ranging from 0.67 to 0.77) was found for the other conditioning-test intervals. We conclude that TMS-conditioned H-reflexes are reliable parameters to assess the excitability of corticospinal circuits

The Effect of Sound and Stimulus Expectation on Transcranial Magnetic Stimulation-Elicited Motor Evoked Potentials.

The amplitude of motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the motor cortex is influenced by multiple factors. TMS delivery is accompanied by an abrupt clicking noise which can induce a startle response. This study investigated how masking/attenuating the sound produced by the TMS system discharging influences MEP amplitudes. In addition, the effects of increasing the time between consecutive stimuli and of making participants aware of the time at which they would be stimulated were studied. MEPs were recorded from the Flexor Carpi Radialis (FCR) muscle at rest by stimulation at motor threshold (MT), 120% MT and 140% MT intensity. Participants (N = 23) received stimulation under normal (NORMAL) conditions and while: wearing sound-attenuating earmuffs (EAR); listening to white noise (NOISE); the interval between stimuli were prolonged (LONG); stimulation timing was presented on a screen (READY). The results showed that masking (p = 0.020) and attenuating (p = 0.004) the incoming sound significantly reduced the amplitude of MEPs recorded across the intensities of stimulation. Increasing the interval between pulses had no effect on the recorded traces if a jitter was introduced (p = 1), but making participants aware of stimulation timing decreased MEP amplitudes (p = 0.049). These findings suggest that the sound produced by TMS at discharging increases MEP amplitudes and that MEP amplitudes are influenced by stimulus expectation. These confounding factors need to be considered when using TMS to assess corticospinal excitability

Safety of systemic treatments for Beh\ue7et\u2019s syndrome

Introduction: Treatment of Beh\ue7et\u2019s syndrome (BS) is aimed at controlling all symptoms of such a complex disorder, ensuring a good quality of life and preventing life-threatening complications. A better understanding of the pathogenic role of different chemokines has improved our knowledge of BS and elicited a more specific use of therapies currently available, minimizing the burden of potential side-effects related to treatment. Areas covered: This work aims to provide a detailed overview of the safety profile for current therapies available in the treatment of BS, focusing on the main side-effects, toxicity and contraindications. Expert opinion: The greatest experience in the management of BS has been achieved with the employment of monoclonal anti-tumor necrosis factor antibodies which have been advocated for BS refractory manifestations. Moreover, interleukin-1 inhibitors have proven to be effective as well as safe, despite escalation of their dosage, especially to manage the most severe and difficult-to-treat ocular manifestations. However, general treatment of BS patients remains awkward as protean clinical features may respond differently to the same treatment or even worsen. Therefore, patients\u2019 safety for therapies used in BS promotes the implementation of precision medicine, which could help targeting accurately the pathogenetic mechanisms concealed behind specific clinical phenotype

Hints for genetic and clinical differentiation of adult-onset monogenic autoinflammatory diseases

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide

Assessment of congenital neutropenia in children: common clinical sceneries and clues for management

A disparate group of rare hematological diseases characterized by impaired maturation of neutrophil granulocytes defines congenital neutropenias. Neutropenic patients are prone to recurrent infections beginning in the first months of life. Of interest is "cyclic neutropenia," an ultra-rare disorder revealed by sinusoidal variations in the neutrophil count and recurring infections every 21 days. Diagnosis of these disorders is frequently obscured by the multiple causes of recurrent fevers in children. The aim of this overview is to outline the physical assessment of children presenting with early-onset symptomatic neutropenia, identify the disease between the many medical conditions and even emergencies which should enter in differential diagnosis, hint at the potential management with granulocyte-colony stimulating factor, define the risk of evolution to hematologic malignancy, and summarize inter-professional team strategies for improving care coordination and outcomes of patients

Immunological role of IgG subclasses

The loss of tolerance to self-antigens is the unequivocal \u201cred line\u201d of autoimmunity: both development of autoreactive T and B cells and production of polyclonal autoantibodies represent seminal keys to the pathogenesis of protean autoimmune diseases. Most of these autoantibodies are immunoglobulins G (IgG), functionally distinguished in four subclasses named IgG1, IgG2, IgG3 and IgG4, due to structural differences in the hinge and heavy chain constant regions. Different studies analyzed serum levels of IgG subclasses in the course of different disorders, showing that they might have a pathogenic role by regulating interactions among immunoglobulins, Fc-gamma receptors and complement. To date, the mechanisms promoting different IgG subclasses distribution during the natural history of most autoimmune diseases remain somewhat unclear. Evidence from the medical literature shows that the serum IgG profile is peculiar for many autoimmune diseases, suggesting that different subclasses could be specific for the underlying driving autoantigens. A better knowledge of IgG subsets may probably help to elucidate their pathological task, but also to define their relevance for diagnostic purposes, patients\u2019 personalized management, and prognosis assessment