Andrea Guerra

LONG-TERM FOLLOW-UP AND OUTCOME OF A LARGE COHORT OF PATIENTS WITH COMMON VARIABLE IMMUNODEFICIENCY

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies.

Effectiveness of Immunoglobulin Replacement Therapy on Clinical Outcome in Patients with Primary Antibody Deficiencies: Results from a Multicenter Prospective Cohort Study

A 5-years multicenter prospective study on 201 patients with common variable immunodeficiencies and 101 patients with X-linked agammaglobulinemia over a cumulative follow-up period of 1,365 patient-years was conducted to identify prognostic markers and risk factors for associated clinical co-morbidities, the effects of long-term immunoglobulin treatment and the IgG trough level to be maintained over time required to minimise infection risk. Overall, 21% of the patients with common variable immunodeficiencies and 24% of patients with X-linked agammaglobulinemia remained infection free during the study. A reduction of pneumonia episodes has been observed after initiation of Ig replacement. During the observation time, pneumonia incidence remained low and constant over time. Patients with pneumonia did not have significant lower IgG trough levels than patients without pneumonia, with the exception of patients whose IgG trough levels were persistently <400xa0mg/dL. In X-linked agammaglobulinemia, the only co-morbidity risk factor identified for pneumonia by the final multivariable model was the presence of bronchiectasis. In common variable immunodeficiencies, our data allowed us to identify a clinical phenotype characterised by a high pneumonia risk: patients with low IgG and IgA levels at diagnosis; patients who had IgA level <7xa0mg/dL and who had bronchiectasis. The effect of therapy with immunoglobulins at replacement dosage for non-infectious co-morbidities (autoimmunity, lymphocytic hyperplasia and enteropathy) remains to be established. A unique general protective trough IgG level in antibody deficiency patients will remain undefined because of the major role played by the progression of lung disease in X-linked agammaglobulinemia and in a subset of patients with common variable immunodeficiencies.

Prospective Study on CVID Patients with Adverse Reactions to Intravenous or Subcutaneous IgG Administration

IntroductionThe multicenter prospective study provides information on adverse reactions to intravenous and subcutaneous immunoglobulin treatment in a cohort of 262 patients with common variable immunodeficiency. Severe adverse reactions are a rare but unpredictable event that might occur also in patients who tolerate substitutive intravenous or subcutaneous immunoglobulin therapy for months or years.ResultsSubcutaneous therapy has been proved to be a safe option in the 13 patients who had to stop intravenous treatment and who remained out of immunoglobulin replacement for long periods of time. However, severe reactions to subcutaneous therapy occurred at the first or after several subcutaneous immunoglobulin administrations in 2 out of 13 patients.ConclusionTherefore, patients with previous severe reactions to intravenous immunoglobulin should be considered at particularly high risk for reaction to subcutaneous administration. In these cases, switching from in-hospital administration to home self-administration should be done with extreme care.

Driving Human Motor Cortical Oscillations Leads to Behaviorally Relevant Changes in Local GABAA Inhibition: A tACS-TMS Study.

Beta and gamma oscillations are the dominant oscillatory activity in the human motor cortex (M1). However, their physiological basis and precise functional significance remain poorly understood. Here, we used transcranial magnetic stimulation (TMS) to examine the physiological basis and behavioral relevance of driving beta and gamma oscillatory activity in the human M1 using transcranial alternating current stimulation (tACS). tACS was applied using a sham-controlled crossover design at individualized intensity for 20 min and TMS was performed at rest (before, during, and after tACS) and during movement preparation (before and after tACS). We demonstrated that driving gamma frequency oscillations using tACS led to a significant, duration-dependent decrease in local resting-state GABAA inhibition, as quantified by short interval intracortical inhibition. The magnitude of this effect was positively correlated with the magnitude of GABAA decrease during movement preparation, when gamma activity in motor circuitry is known to increase. In addition, gamma tACS-induced change in GABAA inhibition was closely related to performance in a motor learning task such that subjects who demonstrated a greater increase in GABAA inhibition also showed faster short-term learning. The findings presented here contribute to our understanding of the neurophysiological basis of motor rhythms and suggest that tACS may have similar physiological effects to endogenously driven local oscillatory activity. Moreover, the ability to modulate local interneuronal circuits by tACS in a behaviorally relevant manner provides a basis for tACS as a putative therapeutic intervention. SIGNIFICANCE STATEMENT Gamma oscillations have a vital role in motor control. Using a combined tACS-TMS approach, we demonstrate that driving gamma frequency oscillations modulates GABAA inhibition in the human motor cortex. Moreover, there is a clear relationship between the change in magnitude of GABAA inhibition induced by tACS and the magnitude of GABAA inhibition observed during task-related synchronization of oscillations in inhibitory interneuronal circuits, supporting the hypothesis that tACS engages endogenous oscillatory circuits. We also show that an individuals physiological response to tACS is closely related to their ability to learn a motor task. These findings contribute to our understanding of the neurophysiological basis of motor rhythms and their behavioral relevance and offer the possibility of developing tACS as a therapeutic tool.

Solutions for managing variability in non-invasive brain stimulation studies

In the last three decades, a number of non-invasive brain stimulation (NIBS) protocols, capable of assessing and modulating plasticity in the human motor cortex (M1), have been described. For almost as long, NIBS has delivered the tantalising prospect of non-invasive neuromodulation as a therapeutic intervention for neurorehabilitation, psychiatry, chronic pain and other disease states. Apart from modest effects in depression, this early promise has not been realised since the symptomatic improvements produced by NIBS are generally weak. One key factor explaining this lack of clinical translation concerns variability in response to NIBS. Several studies have demonstrated a number of physiological, technical and statistical factors accounting for intra- and inter-subject variability. However, solutions to overcome this problem are still under debate. In the present review, we have provided a detailed description of methodological and technical solutions to control known factors influencing variability. We have also suggested potential strategies to strengthen and stabilize NIBS-induced after-effects. Finally, we propose new possible outcome variables which better reflect intrinsic cortical activity, allowing a more sensitive measurement and valid interpretation of responses to NIBS.

Variability in non-invasive brain stimulation studies: Reasons and results

Non-invasive brain stimulation techniques (NIBS), such as Theta Burst Stimulation (TBS), Paired Associative Stimulation (PAS) and transcranial Direct Current Stimulation (tDCS), are widely used to probe plasticity in the human motor cortex (M1). Although TBS, PAS and tDCS differ in terms of physiological mechanisms responsible for experimentally-induced cortical plasticity, they all share the ability to elicit long-term potentiation (LTP) and depression (LTD) in M1. However, NIBS techniques are all affected by relevant variability in intra- and inter-subject responses. A growing number of factors contributing to NIBS variability have been recently identified and reported. In this review, we have readdressed the issue of variability in human NIBS studies. We have first briefly discussed the physiological mechanisms responsible for TBS, PAS and tDCS-induced cortical plasticity. Then, we have provided statistical measures of intra- and inter-subject variability, as calculated in previous studies. Finally, we have reported in detail known sources of variability by categorizing them into physiological, technical and statistical factors. Improving knowledge about sources of variability could lead to relevant advances in designing new tailored NIBS protocols in physiological and pathological conditions.

Boosting the LTP-like plasticity effect of intermittent theta-burst stimulation using gamma transcranial alternating current stimulation.

BACKGROUNDnTranscranial Alternating Current Stimulation (tACS) consists in delivering electric current to the brain using an oscillatory pattern that may entrain the rhythmic activity of cortical neurons. When delivered at gamma frequency, tACS modulates motor performance and GABA-A-ergic interneuron activity.nnnOBJECTIVEnSince interneuronal discharges play a crucial role in brain plasticity phenomena, here we co-stimulated the primary motor cortex (M1) in healthy subjects by means of tACS during intermittent theta-burst stimulation (iTBS), a transcranial magnetic stimulation paradigm known to induce long-term potentiation (LTP)-like plasticity.nnnMETHODSnWe measured and compared motor evoked potentials before and after gamma, beta and sham tACS-iTBS. While we delivered gamma-tACS, we also measured short-interval intracortical inhibition (SICI) to detect any changes in GABA-A-ergic neurotransmission.nnnRESULTSnGamma, but not beta and sham tACS, significantly boosted and prolonged the iTBS-induced after-effects. Interestingly, the extent of the gamma tACS-iTBS after-effects correlated directly with SICI changes.nnnCONCLUSIONSnOverall, our findings point to a link between gamma oscillations, interneuronal GABA-A-ergic activity and LTP-like plasticity in the human M1. Gamma tACS-iTBS co-stimulation might represent a new strategy to enhance and prolong responses to plasticity-inducing protocols, thereby lending itself to future applications in the neurorehabilitation setting.

30. Age related differences in time-varying coupling of EEG oscillations predict connectivity and excitability fluctuations in the Primary Motor Cortex: A TMS-EEG study

It has been demonstrated that in young volunteers the characteristics of the ongoing EEG activity immediately preceding a TMS of M1 influence the following MEP amplitude. In this study we explored whether there is an effect of ageing on this EEG-MEP interactions. Then by means of a TMS-EEG experiment, the pre-stimulus EEG characteristics (coherence and spectral profile) of the stimulated M1 were analysed for “high” and “low” MEPs, classified according to the 50th percentile of their amplitude distribution and thus compared in the two groups. On the stimulated hemisphere the EEG coupling was observed more often in the high compared to the low MEP trials in both groups. The coupling in the beta2 band of the stimulated M1 with the ipsilateral prefrontal cortex was able to led to significantly larger MEPs both in young and old subjects. In contrast, the coupling in the delta band of M1 with the ipsilateral parieto-occipital cortices had an effect on the MEP’s size only in young subjects. Moreover, this coupling was significantly higher in elderly brain than in young brain both for high and low MEPs. These data provide evidence for an age-related influence of time-varying synchronization of EEG rhythms in determining M1 excitability.

P215 Driving human motor cortical oscillations leads to behaviourally relevant changes in local GABA(A) Inhibition: A tACS-TMS study

Objectives Beta and gamma oscillations are the dominant oscillatory activity in the human motor cortex (M1). However, their physiological basis and precise functional significance remain poorly understood. To this end, we employed Transcranial Magnetic Stimulation (TMS) to examine the physiological basis and behavioural relevance of driving beta and gamma oscillatory activity in the human M1 using transcranial alternating current stimulation (tACS). Methods 20 healthy volunteers participated in four experimental sessions separated by at least 1xa0week. In Session 1, all subjects had a MEG scan in order to determine individual beta and gamma peak frequency for subsequent tACS sessions. In Sessions 2–4, subjects received tACS at beta frequency (∼20xa0Hz), gamma frequency (75xa0Hz) or sham stimulation. tACS was applied for 20xa0min over the left M1 and the contralateral orbit at individualised intensity. TMS measures (a single MEP, SICI and ICF) were performed at rest and during movement preparation. Results Gamma tACS led to a significant, duration-dependent decrease in local resting-state GABA(A) inhibition (pxa0=xa00.002), as quantified by SICI. The magnitude of this effect was positively correlated with the magnitude of GABA(A) decrease during movement preparation (pxa0=xa00.003), when gamma activity in motor circuitry is known to increase. In addition, gamma tACS-induced change in GABA(A) inhibition was closely related to performance in a motor learning task, such that subjects who demonstrated a greater increase in GABA(A) inhibition also showed faster short-term learning (pxa0 Discussion and conclusions Our findings show that gamma tACS is capable of modulating GABA(A) inhibition in M1 in a behaviourally relevant manner and suggest that tACS may have similar physiological effects to endogenously driven local oscillatory activity. Significance This study contributes to our understanding of the neurophysiological basis of motor rhythms and their behavioural relevance. Moreover, the ability to modulate local interneuronal circuits by tACS in a behaviourally relevant manner provides a basis for tACS as a putative therapeutic intervention.

Channel interpolation in TMS-EEG: A quantitative study towards an accurate topographical representation

The co-registration of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a successful technique for causally exploring cortical mechanisms and connections. However, various artefacts could affect TMS-EEG signals. Correct artefacted channels reconstruction is crucial to obtain accurate topographical representation and consequently accurate inverse problem solution, in order to map in a proper way the global brain responses after the stimulation of one particular brain region of interest. In this paper, we discuss the problem of artefacted channels interpolation in TMS-EEG signals. Aim of the study was to investigate two different interpolation methods evaluating their performance in two datasets: one constituted by 19 EEG channels montage (low-density spatial resolution) and the other one by 60 EEG channels montage (high-density spatial resolution). In addition, these evaluations took place in two different contexts of application: after the averaging of TMS Evoked Potentials (TEPs) in a time interval to obtain a global information in the considered range, and at fixed latencies 100 ms and 300 ms after the TMS stimulus. The results showed that the global reconstruction error was lower at fixed latencies for the high-density electrodes spatial resolution montage.