Investigating cortical excitability and inhibition in patients with schizophrenia: A TMS-EEG study.

BACKGROUND: Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls. MATERIALS AND METHODS: TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons. RESULTS: Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50-160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220-560 ms; 190-420 ms). Patients showed a reduction of both early (50-110 ms) gamma increase and later (180-230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms. CONCLUSION: Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics.

Somatosensory input in the context of transcranial magnetic stimulation coupled with electroencephalography: An evidence-based overview.

The transcranial evoked potential (TEP) is a powerful technique to investigate brain dynamics, but some methodological issues limit its interpretation. A possible contamination of the TEP by electroencephalographic (EEG) responses evoked by the somatosensory input generated by transcranial magnetic stimulation (TMS) has been postulated; nonetheless, a characterization of these responses is lacking. The aim of this work was to review current evidence about possible somatosensory evoked potentials (SEP) induced by sources of somatosensory input in the craniofacial region. Among these, only contraction of craniofacial muscle and stimulation of free cutaneous nerve endings may be able to induce EEG responses, but direct evidence is lacking due to experimental difficulties in isolating these inputs. Notably, EEG evoked activity in this context is represented by a N100/P200 complex, reflecting a saliency-related multimodal response, rather than specific activation of the primary somatosensory cortex. Strategies to minimize or remove these responses by EEG processing still yield uncertain results; therefore, data inspection is of paramount importance to judge a possible contamination of the TEP by multimodal potentials caused by somatosensory input.

Resurfacing Capitate Pyrocarbon Implant for the treatment of advanced wrist arthritis in the elderly: a retrospective study.

OBJECTIVE: Advanced forms of wrist osteoarthritis in the elderly are quite common and often under-treated, preferring a conservative management of the condition due to the age of the patient. However, in elderly people who are still active, sporty and physically demanding, surgical management of wrist osteoarthritis should be considered. Proximal Row Carpectomy associated with a Resurfacing Capitate Pyrocarbon Implant (RCPI), allows the management of a wide range of wrist arthrosis, involving both the radio-carpal and the mid-carpal joints. This treatment has been already reported as a solution in younger people affected by degenerative pathologies of the wrist, giving overall good results. Authors aimed at verifying how this technique could be useful in elderly patients, resolving the severe pain often related to this pathology and letting them recover strength and motion. PATIENTS AND METHODS: This is a retrospective analysis involving 7 cases of elderly men (mean age = 68 y.o.), suffering from severe wrist arthritis and treated with RCPI between 2016 and 2021. RESULTS: All patients reported a return to manual activities between 6 and 12 months after surgery, significantly improving pain. Two patients complained moderate pain under strain at follow-up, with residual difficulty in performing manual tasks. In all cases, an increase of strength and improvement in terms of stiffness was registered. No cases of infections or implant mobilization were reported. CONCLUSIONS: RCPI combined with proximal row carpectomy shows satisfying results in all published studies and it has been confirmed in our series as well. Indications for this procedure should be widened to elderly people, as useful alternatives to more aggressive salvage procedures, such as total prosthesis or arthrodesis.

Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature.

BACKGROUND: IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein. OBJECTIVE: To analyses the clinical characteristics of the patients reported in the literature and of an additional patient we observed in order to better delineate the phenomenological spectrum of the disease and provide indications to improve clinical recognition and facilitate diagnosis. METHODS: We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers (n.27), using PUBMED as the search engine, and in our hospital (n. 1). RESULTS: All patients shared developmental delay/regression. Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances. Correlation analysis suggested a significant positive correlation between the number of affected neurological domains and the presence of MRI abnormalities (rho = 0.45, p = 0.02), while no significant correlation emerged between the number of affected clinical domains and age at disease onset (rho = 0.18, p = 0.35) or variant type (rho = 0.30, p = 0.12). CONCLUSIONS: Our analysis highlights that the IRF2BPL mutation syndrome is highly specific to the central nervous system. Diagnostic work-up should consider the clinical picture of the IRF2BPL mutation syndrome herein delineated and the existence of conditions that share developmental delay/regression and result from acquired/genetic or unidentifiable underlying etiology.

Comparative analysis of different alternatives for sustainable short rotation woody crops in Central Italy.

Short rotation woody crops (SRWCs) can be a sustainable solution for producing biomass for bioenergy and, at the same time, mitigating CO2 emissions. Although the contribution SRWCs can give to the transition to a low-carbon energy economy, farmers are hesitant to introduce them, as they have a low added value and there are uncertain economic prospects for cultivating SRWCs. Therefore, this study aims to analyze the economic sustainability of poplar woodchip production in Central Italy. Thus, the work compares three plantations, characterized by different durations (one year, two years, and five years) and harvesting systems, to identify the solution with the optimal duration. The results show that the quinquennial harvesting system is the most advantageous according to all the indicators, whereas the biennial performs the worst.

Trapeziectomy and suspension ligamentoplasty for surgical revision of trapeziometacarpal joint arthrodesis failure: two cases.

Trapeziometacarpal joint osteoarthritis is a common degenerative disease. Arthrodesis is a widespread historical surgical technique to treat this pathology, providing pain relief and stability and strength of the thumb. Nevertheless, pantrapezial arthritis and non-union are not uncommon complications, leading in some cases to revision surgery. No gold-standard procedure has been described for revision of trapeziometacarpal arthrodesis failure. We describe two cases of failed arthrodesis treated with trapeziectomy and suspension ligamentoplasty, a well-known, biological, low-cost, successful, and easy-to-perform procedure.

Assessing Progress Towards SDGs Implementation Using Multiple Reference Point Based Multicriteria Methods: The Case Study of the European Countries.

To achieve the UN 2030 Agenda Goals, and considering their complexity and multidisciplinary, Multi-criteria analysis appears to be a suitable approach to give a true support to public decision makers in defining policy lines. This study focuses on the application of the Multiple Reference Point Weak-Strong Composite Indicators (MRP-WSCI) and its partially compensatory version (MRP-PCI), to assess, in the framework of the UN 2030 Agenda, the sustainability of the 28 members of the European Union (pre-Brexit). Countries were analyzed and compared according to their conditions and progress against the 17 Sustainable Development Goals, considering three reference years: 2007, 2012 and 2017. The analysis shows that Nordic countries reach a good level of global sustainability, with values of the indicators, W-W-W and S-W-W, between 2 and 3; while the States of east Europe, in particular Romania, Bulgaria and Greece, stay at the worst levels, having overall indicators values less than 1.5. Furthermore, the results highlight how countries in the lower group have difficulties especially in social and economic sustainability. On the other hand, states with a good overall condition record the worst results in the environmental dimension, such as the Netherlands, which shows, for the year 2017, a value for this sphere less than 2, while in the other two show a good value (over 2.5).

Spontaneous and TMS-related EEG changes as new biomarkers to measure anti-epileptic drug effects.

Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

Scaphoid waist fractures fixation with staple. Retrospective study of a not widespread procedure.

INTRODUCTION: In carpal scaphoid fractures, the surgical treatment with screw is considered the gold standard; shape memory staple however presents substantial advantages. The authors report a study on unstable fractures of the scaphoid waist (type B1, B2, B5, according to Herbert classification) treated with shape memory staple on a large sample of patients, with the aim to confirm the usefulness of this method, the quality of reduction and fixation, the functional results, the time of union and the possible complications. MATERIALS AND METHODS: A retrospective analysis of 131 patients with scaphoid waist fractures with minimum follow-up 1 year was performed. Staples were used in all cases; technical details are discussed. Outcome measures were: postoperative pain, flexion-extension wrist range, hand grip strength, radiographic consolidation, work absence. Herbert and Fisher Grading System was used to assess subjective, objective and radiographic results. RESULTS: Consolidation was achieved in all cases of primary fractures (0-30 days) within three months after surgery, and within eight months in all but two cases of delayed unions (operated within 6 months of the injury). Pain was absent at follow-up in 79% of cases, never severe or unbearable, the average flexion-extension range achieved was 112°. Handgrip strength values were comparable to those of contralateral wrist in 75% of cases. Mean time lost at work was 7.4 weeks. No algo-distrophy or malunion were observed. Discussion CONCLUSIONS: Scaphoid waist fractures' treatment with shape memory staple should be considered as an excellent alternative to screw fixation.

Premovement Suppression of Corticospinal Excitability may be a Necessary Part of Movement Preparation.

In reaction time (RT) tasks corticospinal excitability (CSE) rises just prior to movement. This is preceded by a paradoxical reduction in CSE, when the time of the imperative ("GO") stimulus is relatively predictable. Because RT tasks emphasise speed of response, it is impossible to distinguish whether reduced CSE reflects a mechanism for withholding prepared actions, or whether it is an inherent part of movement preparation. To address this question, we used transcranial magnetic stimulation (TMS) to estimate CSE changes preceding 1) RT movements; 2) movements synchronized with a predictable signal (predictive timing or PT movements); and 3) self-paced movements. Results show that CSE decreases with a similar temporal profile in all three cases, suggesting that it reflects a previously unrecognised state in the transition between rest and movement. Although TMS revealed reduced CSE in all movements, the TMS pulse itself had different effects on movement times. TMS given ~200 ms before the times to move speeded the onset of RT and self-paced movements, suggesting that their initiation depends on a form of trigger that can be conditioned by external events. On the contrary, PT movements did not show this effect, suggesting the use of a different triggering strategy prioritizing internal events.

A Flexor Digitorum Superficialis Tenodesis Technique for Surgical Treatment of Finger PIP Joint Volar Plate Chronic Avulsion.

Background: Chronic, post-traumatic, avulsion of the proximal interphalangeal (PIP) joint volar plate represents a disabling lesion. The purpose of this report is to describe a flexor digitorum superficialis (FDS) tenodesis using a mini-bone anchor inserted into the proximal phalanx, and its clinical outcome. Methods: 15 patients with chronic post-traumatic hyperextension instability of the PIP joint were treated surgically. From the first post-operative day patients were invited to start an early gradual joint active motion, wearing an extension block splint. Forty days after surgery, clinical evaluations were carried out, including: joint stability, pain and range of motion (ROM). The use of a circumferential splint was recommended for two further months, avoiding strenuous manual activities. The range of motion, time lost at work and the functional results were recorded six months after surgery. Results: At last follow up, 7 of the 13 reviewed patients presented an excellent functional recovery, with complete resolution of pain and stability with attainment of ROM comparable to the contralateral finger. The others 6 patients obtained good results, with remission of the functional impairment and pain, with either residual hyperextension or flexion contracture. There was one case of recurrence consecutively to a premature traumatic work-related activity. Conclusions: The FDS tenodesis via a bone anchor, combined with early active PIP joint protected motion, was shown in this study to be effective and reliable.

Tremor in motor neuron disease may be central rather than peripheral in origin.

BACKGROUND AND PURPOSE: Motor neuron disease (MND) refers to a spectrum of degenerative diseases affecting motor neurons. Recent clinical and post-mortem observations have revealed considerable variability in the phenotype. Rhythmic involuntary oscillations of the hands during action, resembling tremor, can occur in MND, but their pathophysiology has not yet been investigated. METHODS: A total of 120 consecutive patients with MND were screened for tremor. Twelve patients with action tremor and no other movement disorders were found. Ten took part in the study. Tremor was recorded bilaterally using surface electromyography (EMG) and triaxial accelerometer, with and without a variable weight load. Power spectra of rectified EMG and accelerometric signal were calculated. To investigate a possible cerebellar involvement, eyeblink classic conditioning was performed in five patients. RESULTS: Action tremor was present in about 10% of our population. All patients showed distal postural tremor of low amplitude and constant frequency, bilateral with a small degree of asymmetry. Two also showed simple kinetic tremor. A peak at the EMG and accelerometric recordings ranging from 4 to 12 Hz was found in all patients. Loading did not change peak frequency in either the electromyographic or accelerometric power spectra. Compared with healthy volunteers, patients had a smaller number of conditioned responses during eyeblink classic conditioning. CONCLUSIONS: Our data suggest that patients with MND can present with action tremor of a central origin, possibly due to a cerebellar dysfunction. This evidence supports the novel idea of MND as a multisystem neurodegenerative disease and that action tremor can be part of this condition.

Effects of pulse width, waveform and current direction in the cortex: A combined cTMS-EEG study.

BACKGROUND: the influence of pulse width, pulse waveform and current direction on transcranial magnetic stimulation (TMS) outcomes is of critical importance. However, their effects have only been investigated indirectly with motor-evoked potentials (MEP). By combining TMS and EEG it is possible to examine how these factors affect evoked activity from the cortex and compare that with the effects on MEP. OBJECTIVE: we used a new controllable TMS device (cTMS) to vary systematically pulse width, pulse waveform and current direction and explore their effects on global and local TMS-evoked EEG response. METHODS: In 19 healthy volunteers we measured (1) resting motor threshold (RMT) as an estimate of corticospinal excitability; (2) global mean field power (GMFP) as an estimate of global cortical excitability; and (3) local mean field power (LMFP) as an estimate of local cortical excitability. RESULTS: RMT was lower with monophasic posterior-to-anterior (PA) pulses that have a longer pulse width (p < 0.001). After adjusting for the individual motor threshold of each pulse type we found that (a) GMFP was higher with monophasic pulses (p < 0.001); (b) LMFP was higher with longer pulse width (p = 0.015); (c) early TEP polarity was modulated depending on the current direction (p = 0.01). CONCLUSIONS: Despite normalizing stimulus intensity to RMT, we found that local and global responses to TMS vary depending on pulse parameters. Since EEG responses can vary independently of the MEP, titrating parameters of TMS in relation to MEP threshold is not a useful way of ensuring that a constant set of neurons is activated within a cortical area.

Long-term treatment with low-dose medicine in chronic childhood eczema: a double-blind two-stage randomized control trial.

BACKGROUND: The efficacy of low-dose medicine (LDM) in childhood mild/moderate eczema is not known. We conducted a double-blind, two-stage, randomized, placebo-controlled clinical trial, lasting 23 months, to address this issue. METHOD: Eighty children with chronic mild/moderate eczema were randomly allocated to Group A (placebo) or Group B (treatment group; Galium-Heel®, a low-dose multicomponent medicine based upon natural substances; Guna-Interleukin 12 and Guna-Interferon-γ administered twice a day for six non-consecutive months for each stage). LDM is characterized by the use of biological molecules, such as cytokines, neuropeptides, growth factors, hormones at very low concentrations, which correspond to physiological levels within the human body. The dosage of the cytokines used in this trial (IFN-γ and IL-12) is 10 fg/ml. The SCORAD index was evaluated by the same operator: subjects with a SCORAD index below 20 were considered to have mild eczema (61/80; mean: 10.79), whereas a SCORAD index between 20-50 indicated moderate eczema (19/80; mean: 26.84). The data of 66/80 children were analyzed in stage 1 and those of 62/66 children in stage 2. The primary outcome measure was reduction of eczema severity assessed by the SCORAD index. Secondary outcomes were disease-free interval, and treatment safety and tolerability. RESULTS: The decrease in disease severity was greater in Group B than in Group A already in stage 1 (a decrease 63.9% versus 53.2%), but the difference was not significant (p = 0.16). Moreover, subjective symptoms (itching and sleep disturbances) initially decreased and then worsened in Group A, whereas itching decreased linearly and sleep disturbances decreased significantly (p=0.049) in Group B. CONCLUSIONS: Preliminary evidence suggests potential benefit, but further work is needed to validate this approach. TRIAL REGISTRATION: The trial was registered with EudraCT number 2010-018640-13 through the database of the National Clinical Trials Monitoring Centre Database (Osservatorio delle Sperimentazioni Cliniche, OsSC) of the Italian Medicines Agency.

Impaired eye blink classical conditioning distinguishes dystonic patients with and without tremor.

INTRODUCTION: Tremor is frequently associated with dystonia, but its pathophysiology is still unclear. Dysfunctions of cerebellar circuits are known to play a role in the pathophysiology of action-induced tremors, and cerebellar impairment has frequently been associated to dystonia. However, a link between dystonic tremor and cerebellar abnormalities has not been demonstrated so far. METHODS: Twenty-five patients with idiopathic isolated cervical dystonia, with and without tremor, were enrolled. We studied the excitability of inhibitory circuits in the brainstem by measuring the R2 blink reflex recovery cycle (BRC) and implicit learning mediated by the cerebellum by means of eyeblink classical conditioning (EBCC). Results were compared with those obtained in a group of age-matched healthy subjects (HS). RESULTS: Statistical analysis did not disclose any significant clinical differences among dystonic patients with and without tremor. Patients with dystonia (regardless of the presence of tremor) showed decreased inhibition of R2 blink reflex by conditioning pulses compared with HS. Patients with dystonic tremor showed a decreased number of conditioned responses in the EBCC paradigm compared to HS and dystonic patients without tremor. CONCLUSION: The present data show that cerebellar impairment segregates with the presence of tremor in patients with dystonia, suggesting that the cerebellum might have a role in the occurrence of dystonic tremor.

The Photoparoxysmal Response Reflects Abnormal Early Visuomotor Integration in the Human Motor Cortex.

BACKGROUND: Visual-paired associative stimulation (V-PAS) is a transcranial magnetic stimulation (TMS) technique able to investigate long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1) arising through early visuomotor integration. OBJECTIVE/HYPOTHESIS: Abnormal early visuomotor integration might contribute to the pathophysiology of intermittent photic stimulation (IPS)-induced photoparoxysmal response (PPR). METHODS: We applied V-PAS in 25 healthy subjects (HS), 25 PPR-positive patients, with and without idiopathic generalized epilepsy (IGE), and 8 PPR-negative patients with IGE. V-PAS consisted of primary visual area activation achieved by visual evoked potentials coupled with TMS-induced M1 activation at 100 ms interstimulus interval (ISI) (V-PAS100). Before and after V-PAS, we measured changes in motor evoked potentials (MEPs). We compared MEPs after 1 Hz repetitive TMS (rTMS) and 0.25 Hz-V-PAS100. To examine possible V-PAS-induced after-effects at other ISIs, we delivered V-PAS at 40 (V-PAS40) and 140 ms ISIs (V-PAS140). To clarify whether V-PAS100 increases parieto-/premotor-to-M1 connectivity, before and after V-PAS100, we examined MEPs evoked by paired-pulse techniques. RESULTS: V-PAS100 increased MEPs more in PPR-positive patients than in HS. PPR-negative patients had normal response to V-PAS100. 1 Hz-rTMS, 0.25 Hz-V-PAS100 and V-PAS40 elicited similar responses in HS and PPR-positive patients, whereas V-PAS140 induced stronger after-effects in PPR-positive patients than HS. After V-PAS, MEPs elicited by facilitatory paired-pulse protocols decreased similarly in HS and PPR-positive patients. Conversely, MEPs elicited by inhibitory protocols decreased in HS, whereas in PPR-positive patients, they turned from inhibition to facilitation. CONCLUSION: We suggest that abnormal early visuomotor integration contributes to the pathophysiology of PPR.