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Silvia Rossi,
Caterina Motta,
Valeria Studer, Fabrizia Monteleone,
Valentina De Chiara,
Fabio Buttari,
Francesca Barbieri,
Giorgio Bernardi,
Luca Battistini,
Gary Cutter,
Olaf Stüve,
Marco Salvetti,
Diego Centonze
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ABSTRACT: Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation.Objective: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation.Methods: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade.Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation.Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.
Multiple Sclerosis 05/2012; · 4.26 Impact Factor
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ABSTRACT: BACKGROUND: The Expanded Disability Status Scale (EDSS) is the most widely used measure of disability in MS, however because of its limitations surrogate markers of clinical disability progression are of high interest. Transcranial magnetic stimulation (TMS) measures of demyelination and cortical excitability correlate with disability levels in MS. OBJECTIVE: Aim of this study was testing whether paired pulse (pp) TMS represents a reliable surrogate marker to measure clinical disability in MS. METHODS: ppTMS measures of intracortical synaptic transmission such as short interval intracortical inhibition (SICI), long interval intracortical inhibition (LICI), short interval intracortical facilitation (SICF) and intracortical facilitation (ICF) were collected from 74 patients affected by MS. Correlation of EDSS scores with ppTMS measures was analyzed. RESULTS: EDSS scores correlated with patient's age, disease duration, Motor Evoked Potentials latency and thresholds and SICF measures but not with age of onset, SICI, ICF and LICI. CONCLUSIONS: These findings support a possible use of SICF and MEP latency as surrogate markers of disability in MS. Further research is warranted to determine the role of SICF in the follow up of disease progression and to validate its use as an endpoint in multiple sclerosis clinical trials.
Brain Stimulation 02/2012; · 3.76 Impact Factor
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ABSTRACT: Studies in rodents show that transient receptor potential vanilloid 1 (TRPV1) channels regulate glutamate release at central and peripheral synapses. In humans, a number of nonsynonymous single-nucleotide polymorphisms (SNPs) have been described in the TRPV1 gene, and some of them significantly alter the functionality of the channel. To address the possible role of TRPV1 channels in the regulation of synaptic transmission in humans, we studied how TRPV1 genetic polymorphisms affect cortical excitability measured with transcranial magnetic stimulation (TMS). Two SNPs of the TRPV1 gene were selected and genotyped (rs222747 and rs222749) in a sample of 77 healthy subjects. In previous cell expression studies, the "G" allele of rs222747 was found to enhance the activity of the channel, whereas rs222749 had no functional effect. Allelic variants in the rs222749 region were not associated with altered cortical response to single, paired, and repetitive TMS. In contrast, subjects homozygous for the G allele in rs222747 exhibited larger short-interval intracortical facilitation (a measure of glutamate transmission) explored through paired-pulse TMS of the primary motor cortex. Recruitment curves, short-interval intracortical inhibition, intracortical facilitation, and long-interval intracortical inhibition were unchanged. LTP- and LTD-like plasticity explored through intermittent or continuous theta-burst stimulation was also similar in the "G" and "non-G" subjects. To our knowledge, our results provide the first evidence that TRPV1 channels regulate cortical excitability to paired-pulse stimulation in humans.
Journal of Neuroscience 01/2012; 32(3):873-9. · 7.11 Impact Factor
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ABSTRACT: Cerebellar repetitive transcranial magnetic stimulation may be effective in reducing peak-dose levodopa induced dyskinesia in Parkinson's disease patients. It was proposed that the antidyskinetic effect could be due to modulation of cerebello-thalamo-cortical pathways. However the neural basis for these clinical effects have not yet been demonstrated.
We investigated the effects of repeated sessions of cerebellar continuous theta burst stimulation in Parkinson's disease patients with levodopa induced dyskinesia on brain metabolism by means of positron emission tomography scan with fluorodeoxyglucose ((18)F-FDG) to characterize the specific cerebral network activated by cerebellar stimulation in these patients.
We found that five days of bilateral cerebellar continuous theta burst stimulation (cTBS) were effective in reducing levodopa induced dyskinesia. Clinical changes were paralleled by a reduction of (18)F-FDG metabolism in the cerebellum as revealed by positron emission tomography imaging. We found a global decrease in the metabolism of the bilateral cerebellar hemispheres, and a significant decrease in (18)F-FDG uptake in correspondence of bilateral dentate nucleus.
Our study demonstrates the antidyskinetic effect of cerebellar cTBS in Parkinson's disease patients with levodopa induced dyskinesia, is paralleled by modulation of the activity of the pathways connecting the cerebellar cortex with the deep cerebellar nuclei, confirming the hypothesis that the motor cerebellar circuit is involved in the generations of levodopa induced dyskinesia.
Parkinsonism & Related Disorders 09/2011; 18(1):59-62. · 3.80 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative process characterized by progressive neuronal degeneration, reduced levels of neurotransmitters, and altered forms of synaptic plasticity. In animal models of AD, amyloid-β (Aβ) and tau proteins are supposed to interfere with synaptic transmission. In the current study, we investigated the correlation between motor cortical plasticity, measured with 1 Hz repetitive transcranial magnetic stimulation (rTMS), and the levels of Aβ₁₋₄₂, total tau (t-Tau), and phosphorylated tau (p-Tau) detected in cerebrospinal fluid (CSF) of AD patients. We found that the overall rTMS after effects were milder in AD patients in comparison with controls. In AD patients the amount of rTMS-induced inhibition correlated with CSF t-Tau, but not with Aβ₁₋₄₂ CSF levels. Surprisingly, higher CSF t-Tau levels were associated to a stronger inhibition of the motor evoked potentials, implying that the expected effects of the 1 Hz rTMS protocol were more evident in patients with more pathological t-Tau CSF levels. These data could be interpreted as the consequence of CSF t-Tau mediated abnormal excitatory activity and could suggest that CSF t-Tau may impact mechanisms of cortical plasticity.
Journal of Alzheimer's disease: JAD 05/2011; 26(1):181-6. · 3.74 Impact Factor
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Michele Ribolsi,
Francesco Mori,
Valentina Magni,
Claudia Codecà,
Hajime Kusayanagi, Fabrizia Monteleone,
Ivo Alex Rubino,
Alberto Siracusano,
Giorgio Bernardi,
Diego Centonze,
Giacomo Koch
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ABSTRACT: To investigate the inter-hemispheric connections between the dorsal premotor cortex (dPM) and contralateral primary motor cortex (M1) in schizophrenia.
Sixteen medicated, nine unmedicated schizophrenia patients and 20 healthy age-matched subjects were studied by twin-coil Transcranial Magnetic Stimulation. To activate distinct facilitatory and inhibitory transcallosal pathways between dPM and the contralateral M1, the intensity of dPM stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold). Interstimulus intervals between conditioning stimulus and test stimulus were 6, 8 and 15 ms.
Schizophrenia patients had comparable efficacy of the inhibitory pathway. On the other hand, medicated patients showed less facilitation of contralateral M1 following dPM stimulation at 80% of active motor threshold, at interstimulus interval=8 ms. The individual amount of facilitation induced by dPM conditioning at 80% of active motor threshold at interstimulus interval=8 ms correlated negatively with negative symptoms.
Inter-hemispheric facilitatory dPM-M1 connectivity is selectively altered in schizophrenia.
This study produced evidence that dPM-M1 connectivity is dysfunctional and that correlates with negative symptoms. These results converge with previous studies which strongly hypothesize that inter- and intra-hemispheric connectivity disturbances may play a major role in schizophrenia.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 03/2011; 122(3):512-7. · 3.12 Impact Factor
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Francesco Mori,
Concetta Ljoka,
Elisabetta Magni,
Claudia Codecà,
Hajime Kusayanagi, Fabrizia Monteleone,
Andrea Sancesario,
Giorgio Bernardi,
Giacomo Koch,
Calogero Foti,
Diego Centonze
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ABSTRACT: Exercise therapy (ET) can be beneficial in disabled multiple sclerosis (MS) patients. Intermittent transcranial magnetic theta burst stimulation (iTBS) induces long-term excitability changes of the cerebral cortex and may ameliorate spasticity in MS. We investigated whether the combination of iTBS and a program of ET can improve motor disability in MS patients. In a double-blind, sham-controlled trial, 30 participants were randomized to three different interventions: iTBS plus ET, sham stimulation plus ET, and iTBS alone. Before and after 2 weeks of treatment, measures of spasticity through the modified Ashworth scale (MAS) and the 88 items Multiple Sclerosis Spasticity Score questionnaire (MSSS-88), fatigue through the Fatigue Severity Scale (FSS), daily living activities (ADL) through the Barthel index and health-related quality of life (HRQoL) through the 54 items Multiple Sclerosis Quality of life inventory (MSQoL-54) were collected. iTBS plus ET reduced MAS, MSSS-88, FSS scores, while in the Barthel index and MSQoL-54, physical composite scores were increased. iTBS alone caused a reduction of the MAS score, while none of the measured scales showed significant changes after sham iTBS plus ET. iTBS associated with ET is a promising tool for motor rehabilitation of MS patients.
Journal of Neurology 02/2011; 258(7):1281-7. · 3.47 Impact Factor
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ABSTRACT: Patients with multiple sclerosis may present altered patterns of connectivity between the two brain hemispheres. To date, only transcallosal connectivity between the two primary motor cortices (M1) has been investigated functionally in patients with multiple sclerosis.
The aim of this study was to investigate whether connectivity between the dorsal premotor cortex and the contralateral M1 was altered in patients with multiple sclerosis, and to see whether clinical progression is accompanied by exacerbated dorsal premotor cortex-M1 disconnectivity.
A twin-coil transcranial magnetic stimulation approach was used to investigate both excitatory and inhibitory interhemispheric connections between the left dorsal premotor cortex and the contralateral M1 in 18 multiple sclerosis patients without disability, in 18 multiple sclerosis patients with advanced disease and in 12 age-matched healthy subjects. To activate distinct inhibitory and facilitatory transcallosal pathways, the intensity of dorsal premotor cortex stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold). Results: Our sample of patients with multiple sclerosis showed altered patterns of interhemispheric dorsal premotor cortex-M1 functional connectivity even in the absence of clinical deficits. Facilitatory connections originating from dorsal premotor cortex were reduced in multiple sclerosis patients with or without disability, while inhibitory dorsal premotor cortex-M1 connections were altered only in disabled patients.
The current study demonstrates that functional excitatory connectivity originating from non-primary motor areas is compromised in multiple sclerosis patients even in the absence of clinical disability. Clinical disease progression leads to an impairment of both excitatory and inhibitory transcallosal connections.
Multiple Sclerosis 11/2010; 16(11):1308-16. · 4.26 Impact Factor
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ABSTRACT: Mechanisms of synaptic plasticity like long term depression (LTD) are altered in experimental models of Alzheimer's disease (AD). LTD-like plasticity mechanisms has not been yet fully investigated in AD patients.
Here we studied the effects of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex in a group of patients with a diagnosis of probable AD, compared to healthy age-matched controls (HS). Moreover, we tested the effects of a single dose of orally administered L-dopa, one of the key neurotransmitters in modulating synaptic plasticity mechanisms, on rTMS induced plasticity.
We found that in AD patients the 1 Hz rTMS protocol did not induce the expected inhibitory effect, while a long lasting inhibition of MEP was observed in HS. In addition, L-dopa induced a clear form of reversal of the direction of plasticity in HS that was not evident in AD.
Dopamine modulation of LTD-like plasticity is impaired when tested in AD patients.
These findings provide evidence of possible dysfunction of dopaminergic transmission in AD patients.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 11/2010; 122(4):703-7. · 3.12 Impact Factor
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Francesco Mori,
Silvia Rossi,
Giulia Sancesario,
Claudia Codec|[agrave,
Giorgia Mataluni, Fabrizia Monteleone,
Fabio Buttari,
Hajime Kusayanagi,
Maura Castelli,
Caterina Motta,
Valeria Studer,
Giorgio Bernardi,
Giacomo Koch,
Sergio Bernardini,
Diego Centonze
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ABSTRACT: Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β1−42 and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-β1–42 accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-β1–42 is reduced in the CSF of these patients. In our sample of MS patients, amyloid-β1–42 levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-β1–42 levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with θ burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-β1–42 CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between τ protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-β metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.Keywords: cognition; inflammation; LTP; τ protein; transcranial magnetic stimulation
Neuropsychopharmacology 10/2010; 36(3):559-568. · 7.99 Impact Factor
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ABSTRACT: Neuropathic pain in patients with MS is frequent and is associated with a great interference with daily life activities. In the present study, we investigated whether anodal transcranial direct current stimulation (tDCS) may be effective in reducing central chronic pain in MS patients. Patients received sham tDCS or real tDCS in a 5-day period of treatment in a randomized, double blind, sham-controlled study. Pain was measured using visual analog scale (VAS) for pain and the short form McGill questionnaire (SF-MPQ). Quality of life was measured using the Multiple Sclerosis Quality of Life-54 scale (MSQoL-54). Depressive symptoms and anxiety were also evaluated as confounding factors using the Beck Depression Inventory (BDI) and VAS for anxiety. Evaluations were performed at baseline, immediately after the end of treatment, and once a week during a 3-week follow-up period. Following anodal but not sham tDCS over the motor cortex, there was a significant pain improvement as assessed by VAS for pain and McGill questionnaire, and of overall quality of life. No depression or anxiety changes were observed. Our results show that anodal tDCS is able to reduce pain-scale scores in MS patients with central chronic pain and that this effect outlasts the period of stimulation, leading to long-lasting clinical effects. PERSPECTIVE: This article presents a new, noninvasive therapeutic approach to chronic, central neuropathic pain in multiple sclerosis, poorly responsive to current conventional medications. tDCS is known to cause long-lasting changes of neuronal excitability at the site of stimulation and in the connected areas in healthy subjects. This led us to hypothesize that pain decrease may be the result of functional plastic changes in brain structures involved in the pathogenesis of chronic neuropathic pain.
The journal of pain: official journal of the American Pain Society 12/2009; 11(5):436-42. · 3.78 Impact Factor
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ABSTRACT: In animal models, the cannabinoid system has been convincingly implicated in the regulation of long-lasting synaptic plasticity. Both long-term potentiation (LTP) and depression (LTD) phenomena can be induced in the human motor cortex by transcranial magnetic theta burst stimulation (TBS).
Here, we explored the potential involvement of the cannabinoid system in TBS-induced synaptic plasticity in humans.
We tested the effects of a cannabis-based preparation (Sativex) on continuous TBS (cTBS) and intermittent TBS (iTBS) protocols in subjects with multiple sclerosis.
We observed a shift in the polarity of synaptic plasticity induced by cTBS. In these subjects, in fact, cTBS induced the expected inhibition of motor-evoked potentials (MEPs) before Sativex exposure, whereas it caused a persisting enhancement of MEP amplitude 4 weeks after. The LTP-like phenomenon induced by iTBS was conversely unaffected by Sativex.
Our results indicate that cannabis ingredients have metaplastic effects on the motor cortex, and strongly suggest that the cannabinoid system is involved in the modulation of synaptic plasticity not only in rodents but also in humans.
Brain Stimulation 10/2009; 2(4):229-33. · 3.76 Impact Factor
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ABSTRACT: In Alzheimer's disease (AD) patients dysfunction of cholinergic neurons is considered a typical hallmark, leading to a rationale for the pharmacological treatment in use based on drugs that enhance acetylcholine neurotransmission. However, besides altered acetylcholine transmission, other neurotransmitter systems are involved in cognitive dysfunction leading to dementia. Among others, dopamine seems to be particularly involved in the regulation of cognitive processes, also having functional relationship with acetylcholine. To test whether cholinergic dysfunction can be modified by dopamine, we used short latency afferent inhibition (SLAI) as a neurophysiological tool. First, we tested the function of the cholinergic system in AD patients and in healthy subjects. Then, we tested whether a single L-dopa challenge was able to interfere with this system in both groups. We observed that SLAI was reduced in AD patients, and preserved in normal subjects. L-dopa administration was able to restore SLAI modification only in AD, having no effect in healthy subjects. We conclude that dopamine can modify SLAI in AD, thus confirming the relationship between acetylcholine and dopamine systems. Moreover, it is suggested that together with cholinergic, dopaminergic system alteration is likely to occur in AD, also. These alterations might be responsible, at least in part, for the progressive cognitive decline observed in AD patients.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2009; 34(10):2323-8. · 6.99 Impact Factor
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ABSTRACT: Acute inflammation is associated with cognitivedeficits and alterations of cortical plasticity in multiplesclerosis (MS). We tested whether early treatment withhigh-dose interferon (IFN) beta-1a, known to reduce in-flammatory activity, improves cortical function andcognitive deficits in MS.Eighty treatment-naïve relapsing-remitting MS (RRMS)patients received IFN beta-1a (44 mcg) subcutaneouslythree times per week. Cognitive performance and corti-cal plasticity were measured through the paced audito-ry serial addition test (PASAT) and intermittent thetaburst stimulation (iTBS) before and up to two years af-ter IFN beta-1a initiation. Before treatment, patients with gadolinium-enhancinglesions (Gd+) on MRI performed worse on the PASAT,and showed lower iTBS-induced plasticity, comparedwith Gd- patients. Six months after treatment initiationboth PASAT and iTBS-induced plasticity improved inGd+ and remained stable in Gd- patients. These results suggest that cognitive and synapticplasticity deficits may be rescued during high-doseIFN beta-1a treatment in newly-diagnosed RRMS pa-tients with Gd+ lesions.
Functional neurology 27(3):163-8. · 1.52 Impact Factor
