Comprehensive Observational and Longitudinal study on the Outbreak of Stroke-related Spasticity focusing on the Early Onset management with Botulinum NeuroToxin (COLOSSEO-BoNT): protocol for a real-world prospective observational study on upper limb spasticity.

INTRODUCTION: Poststroke spasticity (PSS) affects up to 40% of patients who had a stroke. Botulinum neurotoxin type A (BoNT-A) has been shown to improve spasticity, but the optimal timing of its application remains unclear. While several predictors of upper limb PSS are known, their utility in clinical practice in relation to BoNT-A treatment has yet to be fully elucidated. The COLOSSEO-BoNT study aims to investigate predictors of PSS and the effects of BoNT-A timing on spasticity-related metrics in a real-world setting. METHODS AND ANALYSIS: The recruitment will involve approximately 960 patients who have recently experienced an ischaemic stroke (within 10 days, V0) and will follow them up for 24 months. Parameters will be gathered at specific intervals: (V1) 4, (V2) 8, (V3) 12, (V4) 18 months and (V5) 24 months following enrolment. Patients will be monitored throughout their rehabilitation and outpatient clinic journeys and will be compared based on their BoNT-A treatment status-distinguishing between patients receiving treatment at different timings and those who undergo rehabilitation without treatment. Potential predictors will encompass the Fugl-Meyer assessment, the National Institute of Health Stroke Scale (NIHSS), stroke radiological characteristics, performance status, therapies and access to patient care pathways. Outcomes will evaluate muscle stiffness using the modified Ashworth scale and passive range of motion, along with measures of quality of life, pain, and functionality. ETHICS AND DISSEMINATION: This study underwent review and approval by the Ethics Committee of the Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. Regardless of the outcome, the findings will be disseminated through publication in peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT05379413.

Recurrent paraneoplastic cerebral hemorrhage in lung cancer: A case report.

Cerebral hemorrhage management in a patient requiring anticoagulant therapy is a therapeutic challenge also due to the absence of guidelines that convincingly define the best therapeutic strategy. Although the occurrence of cerebral hemorrhage in a patient with anticoagulant therapy seems to make the bleeding etiology obvious, sometimes, it is better to reflect on other possible causes and set up an adequate diagnostic workup. Herein, we describe a case of a 73-year-old male patient with atrial fibrillation, mechanical heart valve, and pacemaker that experienced an ischemic minor stroke during steady anticoagulation therapy with recurrent intracerebral haemorrhages (ICHs).

The Pathophysiology of Collateral Circulation in Acute Ischemic Stroke.

Cerebral collateral circulation is a network of blood vessels which stabilizes blood flow and maintains cerebral perfusion whenever the main arteries fail to provide an adequate blood supply, as happens in ischemic stroke. These arterial networks are able to divert blood flow to hypoperfused cerebral areas. The extent of the collateral circulation determines the volume of the salvageable tissue, the so-called "penumbra". Clinically, this is associated with greater efficacy of reperfusion therapies (thrombolysis and thrombectomy) in terms of better short- and long-term functional outcomes, lower incidence of hemorrhagic transformation and of malignant oedema, and smaller cerebral infarctions. Recent advancements in brain imaging techniques (CT and MRI) allow us to study these anastomotic networks in detail and increase the likelihood of making effective therapeutic choices. In this narrative review we will investigate the pathophysiology, the clinical aspects, and the possible diagnostic and therapeutic role of collateral circulation in acute ischemic stroke.

Lipid profiles and atrial fibrillation in ischemic stroke patients treated with thrombectomy: experience from a tertiary Italian stroke hospital.

OBJECTIVES: To assess acute lipid profiles, atrial fibrillation and other cardiovascular risk factors in patients undergoing treatments by thrombectomy (EVT) with acute ischemic stroke (AIS). METHODS: We performed a retrospective analysis of the lipid profile and vascular risk factor in 1639 consecutive patients with acute ischemic stroke between January 2016 and December 2021. To assess lipid profiles, laboratory tests, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), were obtained the day after admission. We also examined assessed the association between lipid profile, AF and EVT in multivariate logistic regression analysis. RESULTS: Median age of patients was 74 years, 54.9% were males (95% CI 52.5-57.4%), and 26.8% (95% CI, 24.7-29.0%) had AF. EVT patients (n= 370; 22.57 %; 95% CI, 20.6-24.7) showed no difference in age (median 73 years [IQR; 63-80 ] versus 74 years [ QR; 63-82+ HbA1c levels (median 5.8 [IQR; 5.4-6.2] versus 5.9 [ IQR; 5.4-6.4+TG/HDL ratio (median 2.40 [IQR; 1.65-3.48#43; versus[IQR; 1.73-3.64)] diabetes (OR 0.82; 95% CI 0.61 to 1.08), hypertension (OR 0.87; 95% CI 0.68 to 1.12) and obesity (OR 1.06; 95% CI 0.78 to 1.42) compared to non-EVT patients. Conversely, EVT patients showed lower levels of TC (160 mg/dl[ IQR;139-187] versus 173 mg/dl [ IQR;148-202] P <0.001), LDL-C (105 mg/dl [ IQR; 80-133] versus 113 mg/dl [ IQR; 88-142] ; P <0.01), TG (98 mg/dl [ IQR; 76-126] versus 107 mg/dl [ IQR; 85-139] P <0.001), non-HDL-C (117 mg/dl[ IQR; 94-145] versus 127 mg/dl [ IQR; 103-154] P <0.001), HC (8.3[ mol/l [ IQR; 6-11] versus 10 µ mol/l[ IQR; 7.3-13.5] P <0.001) than non-EVT patients. Multivariate logistic regression analysis showed an independent association of EVT with TC (OR 0.99, 95% CI 0.98-0.99), AF (OR 1.79, 95% CI 1.34-2.38), age (OR 0.98, 95% CI 0.96-0.99), and NIHSS (OR 1.17, 95% CI 0.14-1.19). CONCLUSION: Total cholesterol and all cholesterol-related measures were significantly lower in patients undergoing thrombectomy than in other stroke patients. Conversely, we found that AF was significantly high in patients with EVT, suggesting that hypercholesterolemia could be mainly linked to small-vessel occlusion stroke while large vessel occlusion (LVO) stroke could show different causes. AIS patients may have different pathogenesis and their understanding may improve enhance the discovery of specific and tailored preventive treatments.

Fatigue in patients with multiple sclerosis: from movement preparation to motor execution.

BACKGROUND: The neural mechanisms underlying fatigue in multiple sclerosis (MS) are still poorly understood. Cortico-cortical and cortico-subcortical circuitry abnormalities may play a central role in its pathogenesis. Our previous studies suggest that central fatigue may be related to an impairment of volition drive during movement preparation. OBJECTIVE: We further explored the central mechanisms of fatigue at the premovement level in MS patients during a sustained motor task. METHODS: In MS patients with (MS-F) and without (MS-NF) fatigue and age-matched healthy controls, we evaluated the motor cortex excitability and the premovement facilitation (PMF) through transcranial magnetic stimulation before and after 5min of sequenced finger-tapping movements at a fixed frequency of 2Hz. RESULTS: In MS-F patients, the number of correct sequences performed and the ability to keep a fixed movement rate during the 5-min motor task were significantly decreased in comparison to the normal controls and MS-NF patients. Also, in MS-F patients, post-exercise PMF was significantly decreased. The PMF abnormalities were highly correlated with the performance decay. CONCLUSIONS: PMF may be considered as a kind of servo-mechanism which could play a crucial role during sustained motor task in order to prevent motor performance disruption and to avoid motor exhaustion.

Increased transcranial direct current stimulation after effects during concurrent peripheral electrical nerve stimulation.

In this study we tested the hypothesis whether a lasting change in the excitability of cortical output circuits can be obtained in healthy humans by combining a peripheral nerve stimulation during a concomitant depolarization and/or hyperpolarization of motor cortex. To reach this aim we combined two different neurophysiological techniques each of them able to induce a lasting increase of cortical excitability by them self: namely median nerve repetitive electrical stimulation (rEPNS) and transcranial direct current stimulation (tDCS). Ten normal young volunteers were enrolled in the present study. All subjects underwent five different protocols of stimulation: (1, 2) tDCS alone (anodal or cathodal); (3) Sham tDCS plus rEPNS; (4, 5) anodal or cathodal tDCS plus rEPNS. The baseline MEP amplitude from abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscle, the FCR H-reflex were compared with that obtained immediately after and 10, 20, 30, 60 min after the stimulation protocol. Anodal tDCS alone induced a significant transient increase of MEP amplitude immediately after the end of stimulation while anodal tDCS + rEPNS determined MEP changes which persisted for up 60 min. Cathodal tDCS alone induced a significant reduction of MEP amplitude immediately after the end of stimulation while cathodal tDCS + rEPNS prolonged the effects for up to 60 min. Sham tDCS + rEPNS did not induce significant changes in corticospinal excitability. Anodal or cathodal tDCS + rEPNS and sham tDCS + rEPNS caused a lasting facilitation of H-reflex. These findings suggest that by providing afferent input to the motor cortex while its excitability level is increased or decreased by tDCS may be a highly effective means for inducing an enduring bi-directional plasticity. The mechanism of this protocol may be complex, involving either cortical and spinal after effects.

Protracted exercise without overt neuromuscular fatigue influences cortical excitability.

The authors' aim was to determine the cortical mechanisms that underlie the transition from effective performance to its disruption. They thus used transcranial magnetic stimulation (TMS) to study changes of corticospinal excitability after a motor exercise that did not produce overt or perceived neuromuscular fatigue. Forty-four subjects performed either 5 or 10 min of repetitive finger movements paced by tones at 2 Hz, a frequency below the spontaneous movement rate. Changes of corticospinal excitability were assessed with TMS at rest and during motor response preparation (premovement facilitation paradigm). Over time, variability of movement rate increased, while the average movement rate shifted toward self-paced rhythms, without significant changes in other kinematic parameters. Amplitudes of motor evoked potentials at rest decreased depending on task duration and TMS intensity. Moreover, 5-min exercise induced fully compensatory increases in premovement facilitation, while 10-min exercise produced partially compensatory increases with loss of temporal modulation. Our findings suggest that protracted exercise induces significant decrements in corticospinal excitability with initial impairment of the phasic motor neurons that are recruited at higher stimulus intensities. Changes in premovement facilitation likely represent compensation of premotor areas for decreased efficiency of the primary motor cortex induced by exercise.

Repetitive transcranial magnetic stimulation enhances BDNF-TrkB signaling in both brain and lymphocyte.

Repetitive transcranial magnetic stimulation (rTMS) induces neuronal long-term potentiation or depression. Although brain-derived neurotrophic factor (BDNF) and its cognate tyrosine receptor kinase B (TrkB) contribute to the effects of rTMS, their precise role and underlying mechanism remain poorly understood. Here we show that daily 5 Hz rTMS for 5 d improves BDNF-TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC-γ1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF-TrkB signaling is accompanied by an increased association between the activated TrkB and NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which correlates with heightened BDNF-TrkB signaling and intensified TrkB-NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF-TrkB-NMDAR functioning in both cortex and lymphocytes.

Is central fatigue in multiple sclerosis a disorder of movement preparation?

We tested the hypothesis that fatigue in MS is related to a dysfunction in cortical areas involved in movement preparation. Thirty-three patients with clinically definite MS (16 with fatigue MS-F, 17 without fatigue MS-NF) and a relapsing-remitting course, matched for disease severity and duration, disability scores and level of depression were enrolled. They underwent a combined assessment with magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS) and, for the electrophysiological study, were compared with 12 healthy controls. MRI was used to assess regional and total lesion-load volume (LL) on T1- and T2-weighted sequences and total brain volume on T1-weighted sequences. With TMS we tested central motor conduction time, short intracortical inhibition (SICI) and facilitation (ICF), pre-movement facilitation related to a simple reaction time paradigm and the effect of short trains of 5-Hz repetitive TMS (rTMS). No significant differences were found in total and regional LL between MS-F and MS-NF, except for a significant increase in frontal lobe LL in MS-F. Neurophysiological assessment did not disclose any difference of SICI and ICF among the three groups. The significant increase of MEP size produced by 5 Hz rTMS in controls was absent in both MS-NF and MS-F. MS-F lacked pre-movement facilitation compared with MS-NF and controls. The lack of pre-movement facilitation and the increased frontal lobe lesion load were significantly correlated to the FSS score, suggesting that central fatigue in MS is probably due to a dysfunction of cortical motor areas involved in movement preparation.

Sleep-dependent improvement in visuomotor learning: a causal role for slow waves.

STUDY OBJECTIVES: Sleep after learning often benefits memory consolidation, but the underlying mechanisms remain unclear. In previous studies, we found that learning a visuomotor task is followed by an increase in sleep slow wave activity (SWA, the electroencephalographic [EEG] power density between 0.5 and 4.5 Hz during non-rapid eye movement sleep) over the right parietal cortex. The SWA increase correlates with the postsleep improvement in visuomotor performance, suggesting that SWA may be causally responsible for the consolidation of visuomotor learning. Here, we tested this hypothesis by studying the effects of slow wave deprivation (SWD). DESIGN: After learning the task, subjects went to sleep, and acoustic stimuli were timed either to suppress slow waves (SWD) or to interfere as little as possible with spontaneous slow waves (control acoustic stimulation, CAS). SETTING: Sound-attenuated research room. PARTICIPANTS: Healthy subjects (mean age 24.6 +/- 1.0 years; n = 9 for EEG analysis, n = 12 for behavior analysis; 3 women). MEASUREMENTS AND RESULTS: Sleep time and efficiency were not affected, whereas SWA and the number of slow waves decreased in SWD relative to CAS. Relative to the night before, visuomotor performance significantly improved in the CAS condition (+5.93% +/- 0.88%) but not in the SWD condition (-0.77% +/- 1.16%), and the direct CAS vs SWD comparison showed a significant difference (P = 0.0007, n = 12, paired t test). Changes in visuomotor performance after SWD were correlated with SWA changes over right parietal cortex but not with the number of arousals identified using clinically established criteria, nor with any sign of "EEG lightening" identified using a novel automatic method based on event-related spectral perturbation analysis. CONCLUSION: These results support a causal role for sleep slow waves in sleep-dependent improvement of visuomotor performance.

The serial reaction time task revisited: a study on motor sequence learning with an arm-reaching task.

With a series of novel arm-reaching tasks, we have shown that visuomotor sequence learning encompasses the acquisition of the order of sequence elements, and the ability to combine them in a single, skilled behavior. The first component, which is mostly declarative, is reflected by changes in movement onset time (OT); the second, which occurs without subject's awareness, is measured by changes in kinematic variables, including movement time (MT). Key-press-based serial reaction time tasks (SRTT) have been used to investigate sequence learning and results interpreted as indicative of the implicit acquisition of the sequence order. One limitation to SRT studies, however, is that only one measure is used, the response time, the sum of OT and MT: this makes interpretation of which component is learnt difficult and disambiguation of implicit and explicit processes problematic. Here, we used an arm-reaching version of SRTT to propose a novel interpretation of such results. The pattern of response time changes we obtained was similar to the key-press-based tasks. However, there were significant differences between OT and MT, suggesting that both partial learning of the sequence order and skill improvement took place. Further analyses indicated that the learning of the sequence order might not occur without subjects' awareness.

Learning and consolidation of visuo-motor adaptation in Parkinson's disease.

We have previously shown in normal subjects that motor adaptation to imposed visual rotation is significantly enhanced when tested few days later. This occurs through a process of sleep-dependent memory consolidation. Here we ascertained whether patients with Parkinson's disease (PD) learn, improve, and retain new motor skills in the same way as normal subjects. We tested 16 patients in early stages of PD and 21 control subjects over two days. All subjects performed reaching movements on a digitizing tablet. Vision of the limb was precluded with an opaque screen; hand paths were shown on the screen with the targets' position. Unbeknownst to the subjects, the hand path on the screen was rotated by 30 degrees . In experiment 1, patients taking dopaminergic treatment and controls adapted to rotation with targets appearing in an unpredictable order. In experiment 2, drug-naïve patients and controls adapted to rotation in a less challenging task where target's appearance was predictable. Patients and controls made similar movements and adapted to rotation in the same way. However, when tested again over the following days, controls' performance significantly improved compared to training, while patients' performance did not. This lack of consolidation, which is present in the early stages of the disease and is independent from therapy, may be due to abnormal homeostatic processes that occur during sleep.

Cdk9/Cyclin T1 complex: a key player during the activation/differentiation process of normal lymphoid B cells.

Cdk9/Cyclin T1 complex is very important in controlling specific differentiative pathways of several cell types. Limited data are available regarding the expression of Cdk9/Cyclin T1 in hematopoietic and lymphoid tissues. Cdk9/Cyclin T1 expression seems to be related to particular stages of lymphoid differentiation/activation. In this study, we observed that the expression level of Cdk9/Cyclin T1 in vivo increases in memory B cells compared to naïve B cells, and in activated B cells, compared to non-activated ones. The expression level of the Cdk9/Cyclin T1 complex does not increase in cells induced to differentiate in vitro. In addition, we showed that Cdk9 interacts with E12 and E47, specifically activated during Germinal Center (GC) reaction. Taken together this data suggests an active role for the Cdk9/Cyclin T1 complex during lymphoid differentiation through germinal center reaction.

Cortical and brainstem LTP-like plasticity in Huntington's disease.

Recent studies have reported abnormalities in short-term plasticity in patients with Huntington's disease (HD). However, is not known whether long-term potentiation (LTP)-like plasticity is also affected in these patients. We tested cortical and brainstem LTP-like plasticity in eight symptomatic HD patients and in 10 healthy age-matched controls. To probe motor cortex LTP-like plasticity we used paired associative stimulation (PAS), a technique that combines repetitive electric stimulation of the median nerve with subsequent transcranial magnetic stimulation (TMS) of the contralateral motor cortex at 25 ms. To investigate brainstem plasticity, we induced LTP-like phenomena in the trigeminal wide dynamic range neurons (WDR) of the blink reflex circuit by pairing an high-frequency train of electrical stimuli (HFS) over the right supraorbital nerve (SO) coincident with the R2 response elicited by a preceding SO stimulus. Our results demonstrate impairment of both cortical and brainstem LTP-like plasticity in symptomatic HD patients which is similar to LTP deficits previously reported in HD animal models. These findings might well represent the neurophysiological correlates of memory deficits often present in HD.

Neural response to transcranial magnetic stimulation in adult hypothyroidism and effect of replacement treatment.

PURPOSE: Despite clinical evidences that hypothyroidism is often associated with cognitive dysfunction, affective disorders and psychosis, the effects of thyroid hormone deficiency on the adult brain have been largely unexplored. We investigated the hypothesis that hypothyroidism might affect cortical excitability and modulates inhibitory and excitatory cortical circuits by using Transcranial Magnetic Stimulation. MATERIALS AND METHODS: Cortical excitability was probed in 10 patients with overt hypothyroidism and 10 age-matched healthy controls. We tested motor thresholds and corticospinal excitability, cortical silent period and peripheral silent period, short interval intracortical inhibition, intracortical facilitation. Patients were evaluated at the time of diagnosis, as well as after 3 and 6 months replacement therapy with l-thyroxin. RESULTS: At baseline, patients showed decreased cortical excitability, with increased resting and active motor threshold and decreased steepness of the motor evoked potential recruitment curves. These changes were paralleled by longer cortical silent period and decreased short interval intracortical inhibition. After 3 months replacement therapy, all the parameters but short interval intracortical inhibition were restored to normal values. Short interval intracortical inhibition returned to normal values only after 6 months of replacement therapy. CONCLUSIONS: Thyroid hormones are needed to modulate cortical excitability and cortical inhibitory circuits in adults.

The role of the Cdk9/Cyclin T1 complex in T cell differentiation.

The Cdk9/Cyclin T1 complex is very important in controlling specific differentiative pathways of several cell types, including muscle cells and neurons. We recently demonstrated the involvement of this complex in B cell activation/differentiation. To check whether the Cdk9/Cyclin T1 complex is also involved in the T cell activation/differentiation process, we isolated different T cell populations by magnetic separation, based on their surface antigens. We observed that the expression level of Cdk9/Cyclin T1 increases in effector T cells (CD27(+)), as well as in activated T cells (CD25(+)) and memory T cells (CD45RA(-)), thus suggesting a specific upregulation of the Cdk9/Cyclin T1 complex following antigen encounter. We have previously demonstrated that in B cells, Cdk9 interacts in vivo with the E2A gene products E12/E47 (members of the basic helix-loop-helix family) which are involved in differentiation. In this article, we show that this interaction also occurs in T cells. This suggests an active role for the Cdk9/Cyclin T1 complex during lymphoid differentiation, through physical binding with E12 and E47. These preliminary results suggest that the Cdk9/Cyclin T1 complex may be important in the activation and differentiation program of lymphoid cells and that its upregulation, which is due to still unknown mechanisms, may contribute to malignant transformation.

Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial.

PURPOSE: To assess the effectiveness of slow repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for drug-resistant epilepsy. METHODS: Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a randomized, double-blind, sham-controlled, crossover study on the clinical and EEG effects of slow rTMS. The stimulus frequency was 0.3 Hz. One thousand stimuli per day were given at the resting motor threshold intensity for 5 consecutive days, with a round coil at the vertex. RESULTS: "Active" rTMS was no better than placebo for seizure reduction. However, it decreased interictal EEG epileptiform abnormalities significantly (p < 0.05) in one-third of the patients, which supports a detectable biologic effect. No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification, seizure type, EEG changes, or resting motor threshold (an index of motor cortex excitability). CONCLUSIONS: Although the antiepileptic action was not significant (p > 0.05), the individual EEG reactivity to "active" rTMS may be encouraging for the development of more-powerful, noninvasive neuromodulatory strategies.

Motor cortex abnormalities in amyotrophic lateral sclerosis with transcranial direct-current stimulation.

The aim of this study was to identify a neurophysiological marker of upper motoneuron involvement in patients with sporadic amyotrophic lateral sclerosis (ALS). For this purpose we evaluated the after-effects of transcranial direct-current stimulation (tDCS) on excitability of the motor cortex of eight ALS patients and eight healthy controls. Healthy controls showed a transient polarity-specific change in corticospinal excitability of about +/-45%, with anodal tDCS inducing facilitation and cathodal tDCS leading to inhibition, whereas no change could be induced in ALS patients after either type of tDCS. It is likely that the lack of tDCS after-effects in ALS is the result of alterations of the motoneuronal membrane or, alternatively, may represent an electrophysiological correlate of disordered glutamate neurotransmission. Further studies are warranted to confirm these results. The present findings may lead to a new, reliable electrophysiological marker of upper motoneuronal involvement in ALS.

Corticospinal excitability during motor imagery of a simple tonic finger movement in patients with writer's cramp.

Motor imagery (MI) is the mental rehearsal of a motor act without overt movement. Using transcranial magnetic stimulation (TMS), we tested the effect of MI on corticospinal excitability in patients with writer's cramp. In 10 patients with writer's cramp and 10 healthy controls, we applied focal TMS over each primary motor area and recorded motor evoked potentials (MEPs) from contralateral hand and arm muscles while participants imagined a tonic abduction of the index finger contralateral to the stimulated hemisphere. In healthy controls and patients, the MEP amplitude in the relaxed first dorsal interosseus muscle (FDI) showed a muscle-specific increase during MI; however, the increase was less pronounced in patients than in healthy controls. In addition, in patients but not in controls, the MEP amplitude also increased in hand and forearm muscles not involved in the imagined movement. This abnormal spread of facilitation was observed in the affected and unaffected upper limb. MI of simple hand movements is less efficient and less focussed in patients with writer's cramp than it is in normal subjects.