Functional and structural balances of homologous sensorimotor regions in multiple sclerosis fatigue.

Fatigue in multiple sclerosis (MS) is a highly disabling symptom. Among the central mechanisms behind it, an involvement of sensorimotor networks is clearly evident from structural and functional studies. We aimed at assessing whether functional/structural balances of homologous sensorimotor regions-known to be crucial for sensorimotor networks effectiveness-decrease with MS fatigue increase. Functional connectivity measures at rest and during a simple motor task (weak handgrip of either the right or left hand) were derived from primary sensorimotor areas electroencephalographic recordings in 27 mildly disabled MS patients. Structural MRI-derived inter-hemispheric asymmetries included the cortical thickness of Rolandic regions and the volume of thalami. Fatigue symptoms increased together with the functional inter-hemispheric imbalance of sensorimotor homologous areas activities at rest and during movement, in absence of any appreciable parenchymal asymmetries. This finding supports the development of compensative interventions that may revert these neuronal activity imbalances to relieve fatigue in MS.

Inter-hemispheric functional connectivity changes with corpus callosum morphology in multiple sclerosis.

Multiple sclerosis (MS) affects myelin sheaths within the central nervous system, concurring to cause brain atrophy and neurodegeneration as well as gradual functional disconnections. To explore early signs of altered connectivity in MS from a structural and functional perspective, the morphology of corpus callosum (CC) was correlated with a dynamic inter-hemispheric connectivity index. Twenty mildly disabled patients affected by a relapsing-remitting (RR) form of MS (EDSS⩽3.5) and 15 healthy subjects underwent structural MRI to measure CC thickness over 100 sections and electroencephalography to assess a spectral coherence index between primary regions devoted to hand control, at rest and during an isometric handgrip. In patients, an overall CC atrophy was associated with increased lesion load. A less efficacious inter-hemispheric coherence (IHCoh) during movement was associated with CC atrophy in sections interconnecting homologous primary motor areas (anterior mid-body). In healthy controls, less efficacious IHCoh at rest was associated with a thinner CC splenium. Our data suggest that in mildly disabled RR-MS patients a covert impairment may be detected in the correlation between the structural (CC thickness) and functional (IHCoh) measures of homologous networks, whereas these two counterparts do not yet differ individually from controls.

Movement-induced uncoupling of primary sensory and motor areas in focal task-specific hand dystonia.

INTRODUCTION: Due to growing evidence of sensorimotor integration impairment in focal task-specific hand dystonia, we aimed at describing primary sensory (S1) and primary motor (M1) cortex source activities and their functional cross-talk during a non-dystonia-inducing sensorimotor task free of biases generated by the interfering with the occurrence of dystonic movements. METHOD: Magnetoencephalographic brain signals and opponens pollicis (OP) electromyographic activities were acquired at rest and during a simple isometric contraction performed either alone or in combination with median nerve stimulation. The task was performed separately with the right and left hand by eight patients suffering from focal task-specific hand dystonia and by eight healthy volunteers. Through an ad hoc procedure Functional Source Separation (FSS), distinct sources were identified in S1 (FSS1) and M1 (FSM1) devoted to hand control. Spectral properties and functional coupling (coherence) between the two sources were assessed in alpha [8,13]Hz, beta [14,32]Hz and gamma [33,45]Hz frequency bands. RESULTS: No differences were found between spectral properties of patients and controls for either FSM1 or FSS1 cerebral sources. Functional coupling between FSM1 and FSS1 (gamma band coherence), while comparable between dystonic patients and healthy controls at rest, was selectively reduced in patients during movement. All findings were present in both hemispheres. DISCUSSION: Because previous literature has shown that gamma-band sensory-motor synchronization reflects an efficiency index of sensory-motor integration, our data demonstrate that, in dystonic patients, uncoupling replaces the functional coupling required for efficient sensory-motor control during motor exertion. The presence of bi-hemispheric abnormalities in unilateral hand dystonia supports the presence of an endophenotypic trait.

Regional personalized electrodes to select transcranial current stimulation target.

RATIONALE: Personalizing transcranial stimulations promises to enhance beneficial effects for individual patients. OBJECTIVE: To stimulate specific cortical regions by developing a procedure to bend and position custom shaped electrodes; to probe the effects on cortical excitability produced when the properly customized electrode is targeting different cortical areas. METHOD: An ad hoc neuronavigation procedure was developed to accurately shape and place the personalized electrodes on the basis of individual brain magnetic resonance images (MRI) on bilateral primary motor (M1) and somatosensory (S1) cortices. The transcranial alternating current stimulation (tACS) protocol published by Feurra et al. (2011b) was used to test the effects on cortical excitability of the personalized electrode when targeting S1 or M1. RESULTS: Neuronal excitability as evaluated by tACS was different when targeting M1 or S1, with the General Estimating Equation model indicating a clear tCS Effect (p < 0.001), and post hoc comparisons showing solely M1 20 Hz tACS to reduce M1 excitability with respect to baseline and other tACS conditions. CONCLUSIONS: The present work indicates that specific cortical regions can be targeted by tCS properly shaping and positioning the stimulating electrode. SIGNIFICANCE: Through multimodal brain investigations continuous efforts in understanding the neuronal changes related to specific neurological or psychiatric diseases become more relevant as our ability to build the compensating interventions improves. An important step forward on this path is the ability to target the specific cortical area of interest, as shown in the present pilot work.

Cortico-muscular coherence as an index of fatigue in multiple sclerosis.

BACKGROUND: Highly common in multiple sclerosis (MS), fatigue severely impacts patients' daily lives. Previous findings of altered connectivity patterns led to the hypothesis that the distortion of functional connections within the brain-muscle circuit plays a crucial pathogenic role. OBJECTIVE: The objective of this paper is to identify markers sensitive to fatigue in multiple sclerosis. METHODS: Structural (magnetic resonance imaging with assessment of thalamic volume and cortical thickness of the primary sensorimotor areas) and functional (cortico-muscular coherence (CMC) from simultaneous electroencephalo- and surface electromyographic recordings during a weak handgrip task) measures were used on 20 mildly disabled MS patients (relapsing-remitting course, Expanded Disability Status Scale score ≤ 2) who were recruited in two fatigue-dependent groups according to the Modified Fatigue Index Scale (MFIS) score. RESULTS: The two groups were similar in terms of demographic, clinical and imaging features, as well as task execution accuracy and weariness. In the absence of any fatigue-dependent brain and muscular oscillatory activity alterations, CMC worked at higher frequencies as fatigue increased, explaining 67% of MFIS variance (p=.002). CONCLUSION: Brain-muscle functional connectivity emerged as a sensitive marker of phenomena related to the origin of MS fatigue, impacting central-peripheral communication well before the appearance of any impairment in the communicating nodes.

Sensorimotor Cortex Reorganization in Alzheimer's Disease and Metal Dysfunction: A MEG Study.

Objective. To verify whether systemic biometals dysfunctions affect neurotransmission in living Alzheimer's disease (AD) patients. Methods. We performed a case-control study using magnetoencephalography to detect sensorimotor fields of AD patients, at rest and during median nerve stimulation. We analyzed position and amount of neurons synchronously activated by the stimulation in both hemispheres to investigate the capability of the primary somatosensory cortex to reorganize its circuitry disrupted by the disease. We also assessed systemic levels of copper, ceruloplasmin, non-Cp copper (i.e., copper not bound to ceruloplasmin), peroxides, transferrin, and total antioxidant capacity. Results. Patients' sensorimotor generators appeared spatially shifted, despite no change of latency and strength, while spontaneous activity sources appeared unchanged. Neuronal reorganization was greater in moderately ill patients, while delta activity increased in severe patients. Non-Cp copper was the only biological variable appearing to be associated with patient sensorimotor transmission. Conclusions. Our data strengthen the notion that non-Cp copper, not copper in general, affects neuronal activity in AD. Significance. High plasticity in the disease early stages in regions controlling more commonly used body parts strengthens the notion that physical and cognitive activities are protective factors against progression of dementia.

The myth of the 'unaffected' side after unilateral stroke: is reorganisation of the non-infarcted corticospinal system to re-establish balance the price for recovery?

BACKGROUND: Bilateral changes in the hemispheric reorganisation have been observed chronically after unilateral stroke. Our hypotheses were that activity dependent competition between the lesioned and non-lesioned corticospinal systems would result in persisting asymmetry and be associated with poor recovery. METHODS: Eleven subjects (medium 6.5 years after stroke) were compared to 9 age-matched controls. The power spectral density (PSD) of the sensorimotor electroencephalogram (SM1-EEG) and electromyogram (EMG) and corticomuscular coherence (CMC) were studied during rest and isometric contraction of right or left opponens pollicis (OP). Global recovery was assessed using NIH score. FINDINGS: There was bilateral loss of beta frequency activity in the SM1-EEGs and OP-EMGs in strokes compared to controls. There was no difference between strokes and controls in symmetry indices estimated between the two corticospinal systems for SM1-EEG, OP-EMG and CMC. Performance correlated with preservation of beta frequency power in OP-EMG in both hands. Symmetry indices for the SM1-EEG, OP-EMG and CMC correlated with recovery. INTERPRETATION: Significant changes occurred at both cortical and spinomuscular levels after stroke but to the same degree and in the same direction in both the lesioned and non-lesioned corticospinal systems. Global recovery correlated with the degree of symmetry between corticospinal systems at all three levels - cortical and spinomuscular levels and their connectivity (CMC), but not with the absolute degree of abnormality. Re-establishing balance between the corticospinal systems may be important for overall motor function, even if it is achieved at the expense of the non-lesioned system.

Inter-hemispheric coupling changes associate with motor improvements after robotic stroke rehabilitation.

PURPOSE: In the chronic phase of stroke brain plasticity plays a crucial role for further motor control improvements. This study aims to assess the brain plastic reorganizations and their association with clinical progresses induced by a robot-aided rehabilitation program in chronic stroke patients. METHODS: 7 stroke patients with an upper limb motor impairment in chronic phase underwent a multi-modal evaluation before starting and at the end of a 12-week upper-limb neurorehabilitation program. Fugl-Meyer Assessment (FMA) Scale scores and performance indices of hand movement performance (isometric pinch monitored through a visual feedback) were collected. Cerebral reorganizations were characterized by 32-channel electroencephalography (EEG) focusing on ipsilesional and contralesional resting state properties investigating both bipolar derivations overlying the middle cerebral artery territory and the primary somatosensory sources (S1) obtained through the Functional Source Separation (FSS) method. Power Spectral Density (PSD) and interhemispheric coherence (IHCoh) at rest were measured and correlated with clinical and hand control robot-induced improvements. RESULTS: After the robotic rehabilitation we found an improvement of FMAS scores and hand motor control performance and changes of brain connectivity in high frequency rhythms (24-90 Hz). In particular, the improvement of motor performance correlated with the modulation of the interhemispheric S1 coherence in the high beta band (24-33 Hz). CONCLUSIONS: Recently it has been shown that an upper limb robot-based rehabilitation improves motor performance in stroke patients. We confirm this potential and demonstrate that a robot-aided rehabilitation program induces brain reorganizations. Specifically, interhemispheric connectivity between primary somatosensory areas got closer to a 'physiological level' in parallel with the acquisition of more accurate hand control.

Role for CD30 in HIV expression.

CD30 is a member of the tumor necrosis factor (TNF)-receptor superfamily, whose ligand (CD30L) has been identified on B cells, activated macrophages and a subset of activated T cells. We show here that infection in vitro with human immunodeficiency virus (HIV) of CD4+ T-cell clones generated from HIV-seronegative individuals can enhance the expression of CD30, which often preceeds and is associated with the death of clonal T cells. Furthermore, cross-linking CD30 with an agonistic CD30-specific monoclonal antibody potentiated HIV replication induced by an insolubilized anti-CD3 antibody in T-cell lines generated from HIV-infected individuals. More importantly, paraformaldehyde-fixed CD8+ T-cell clones expressing CD30L enhanced HIV replication in anti-CD3-stimulated allogeneic or autologous HIV-infected CD4+ T-cell lines and such a potentiating effect was inhibited by an anti-CD30L antibody. The anti-CD30L antibody also exerted a suppressive effect on the spontaneous HIV replication occurring in lymph node cells, freshly derived from an HIV-seropositive patient showing CD30 expression in B cells and in a proportion of CD8+ T lymphocytes. Thus, CD30 triggering may play an important role in both HIV replication and the death of HIV-infected CD4+ T cells.

Polyinosinic acid: polycytidylic acid promotes T helper type 1-specific immune responses by stimulating macrophage production of interferon-alpha and interleukin-12.

The effects exerted on the development in vitro of Dermatophagoides pteronyssinus group I (Der p I)-specific T cell lines and T cell clones by addition of polyinosinic acid: polycytidylic acid (poly I:C) in lymphocyte bulk culture were examined. Der p I-specific T cell lines generated in presence of poly I:C exhibited reduced ability to produce interleukin (IL)-4 and IL-5 and developed into Der p I-specific CD4+ T cell clones showing a T helper (Th) type 0 or Th1, instead of Th0/Th2 cytokine profile. This effect was prevented by addition to lymphocyte bulk cultures of a mixture of antibodies specific for interferon (IFN)-alpha and IL-12, whereas the addition of anti-IFN-alpha or anti-IL-12 antibody alone was uneffective. Poly I:C also showed the ability to stimulate the production of noticeable amounts of both IFN-alpha and IL-12 by human monocytes. Taken together, these data suggest that poly I:C is a Th1-inducing agent whose activity is mediated by its ability to stimulate the production of IFN-alpha and IL-12 by monocytes.

[Simultaneous recording of nonspecific bronchial response using continuous measurement of total respiratory resistance and oxygen saturation of arterial blood]. / Uporedno pracenje nespecificnog bronhijalnog odgovora pomocu kontinuisanog merenja ukupnih disajnih otpora i saturacije arterijske krvi kiseonikom.

In 78 patients with bronchial asthma symptoms undergoing nonspecific bronchial response test with bronchoprovocation inhalation of progressively increased methacholine concentrations, total respiratory resistance (Rrs) and oxygen saturation (SaO2) of arterial blood were continually measured. An average Rrs increase was 153% when compared to the initial values and it correlated with SaO2 decrease (5.5% of the initial values). In 45 patients along with continual Rrs and SaO2 measurements, bronchoprovocation test and spirogram flow-volume curve were periodically done. Ten of these patients had no significant Rrs or FEV1 changes, but there was a considerable drop in FEF50, FEF25 and SaO2. These results, associated with dyspnea and physical pulmonary findings in the course of BPT, as well as history of patients with similar difficulties in every-day life and in work environment, point to the need of expanding diagnostic criteria for positive BPT and for patients who did not have Rrs increased double the initial values nor sufficient FEV1 20% drop. Spirometry and oximetry as complementary methods, increase Astograph sensitivity to methacholine test. Oximetry has an advantage of enabling continual SaO2 monitoring and increased patient's safety during the BPT.

[Simultaneous recording of spirometric parameters and total respiratory resistance on the Astograph in nonspecific bronchial provocation tests using methacholine]. / Uporedno pracenje spirometrijskih parametara i celokupnih disajnih otpora merenih Astografom kod nespecificnih bronhoprovokacionih testova sa metaholinom.

Parallel study results of spirometric parameters (S.P.) FEV1, FEF50, FEF25 and total respiratory resistance (Rrs) measured by Astograph in nonspecific metacholine bronchoprovocation test were analyzed in 378 patients suspected of bronchial asthma. The patients were divided into 7 groups based on Astograph and S.P. instances criteria. Of 92 patients with positive test results, 91% met the set Astograph criterium; 72% met all three S.P. criteria, 1% one criterium and 12% failed to meet any of the S.P. criteria. It was noted that the patients met more the FEF50 and FEF25 criteria (87%) than FEV1 (73%). Also, there was no significant increase in respiratory resistance for those with a predominant reaction in small airways (9%). This fact points to the need of introducing appropriate complementary Astograph methods.

Circulating autoantibodies in multiple sclerosis.

By using indirect immunofluorescence method, we analyzed the presence of antinuclear, anticardiac, microsomal, parietal-cell, smooth-muscle and mitochondrial antibodies in sera of 33 patients with definite multiple sclerosis (MS), without clinical evidence of associated autoimmune disorder, and 14 patients with other neurological disorders (OND). In MS patients, the prevalence of both organ-specific and non-organ-specific antibodies was significantly higher (p less than 0.05) than in OND patients. In both groups, the titers of circulating antibodies were low. The presence of low levels of autoantibodies in sera of MS patients might be the result of immunodysregulation in MS.