Influence of Palmatine on Bone Metabolism in Ovariectomized Mice and Cytokine Secretion of Osteoblasts.

BACKGROUND/AIM: Receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG), regulate the cognate receptor RANK on osteoclast precursor cells. Herein we examined the inhibitory effects of palmatine on bone metabolism using ovariectomized (OVX) mice. MATERIALS AND METHODS: The first experimentaI set was designed to histologically and biochemically examine mice randomly divided into four groups: sham-operated, OVX, and OVX-palmatine intake groups (1 mg/kg and 10 mg/kg). The second experimental set examined the influence of palmatine on osteoblast-like cells in vitro. RESULTS: Palmatine caused significant suppression of osteoclast numbers in tissues. In palmatine-treated mice, RANKL and OPG expression decreased. In the culture supernatant of MC3T3-E1 cells, RANKL and OPG levels were significantly reduced by palmatine addition. CONCLUSION: Palmatine may attenuate osteoclast differentiation through inhibition of RANKL and OPG expression by osteoblasts. Therefore, palmatine might be a candidate anti-resorptive agent for osteoporosis therapy.

Influence of Electroacupuncture Stimulation on Nitric Monoxide Production in Vascular Endothelial Cells in Rats.

BACKGROUND/AIM: In Chinese medicine, blood stasis termed as 'Oketsu' means 'preceding state' or 'symptomatic of sickness'. Traditional Chinese medicine may improve blood flow by vasodilation or blood clotting inhibition. Although acupuncture influences the blood circulatory system, its underlying mechanisms remain unclear. Herein we evaluated changes in NO, as reflected by changes in NO2 (-), platelet aggregation, oxidative stress and endocrine responses after acupuncture stimulation in rats. MATERIALS AND METHODS: Acupuncture stimulation was administered to rats randomly divided into five groups: control, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) injection, restraint stress (RS), restraint plus acupuncture stimulation (RA), and restraint plus acupuncture with L-NAME (RLA). RESULTS: Compared to those in the RS group, levels of NO2 (-), endothelial nitric oxide synthase (NOS) protein and its mRNA significantly increased and those of hydroperoxide and soluble P-selectin significantly decreased in the RA group. CONCLUSION: Acupuncture stimulation regulates vascular endothelium NOS function and affects vascular resistance and blood characteristics through NO. Additionally, NO produced may modulate excessive reactive oxygen development and blood platelet activation.

CB1 receptor affects cortical plasticity and response to physiotherapy in multiple sclerosis.

OBJECTIVES: Therapeutic effects of physical therapy in neurologic disorders mostly rely on the promotion of use-dependent synaptic plasticity in damaged neuronal circuits. Genetic differences affecting the efficiency of synaptic plasticity mechanisms could explain why some patients do not respond adequately to the treatment. It is known that physical exercise activates the endocannabinoid system and that stimulation of cannabinoid CB1 receptors (CB1Rs) promotes synaptic plasticity in both rodents and humans. We thus tested whether CB1R genetic variants affect responsiveness to exercise therapy. METHODS: We evaluated the effect of a genetic variant of the CB1R associated with reduced receptor expression (patients with long AAT trinucleotide short tandem repeats in the CNR1 gene) on long-term potentiation (LTP)-like cortical plasticity induced by transcranial magnetic theta burst stimulation (TBS) of the motor cortex and, in parallel, on clinical response to exercise therapy in patients with multiple sclerosis. RESULTS: We found that patients with long AAT CNR1 repeats do not express TBS-induced LTP-like cortical plasticity and show poor clinical benefit after exercise therapy. CONCLUSIONS: Our results provide the first evidence that genetic differences within the CB1R may influence clinical responses to exercise therapy, and they strengthen the hypothesis that CB1Rs are involved in the regulation of synaptic plasticity and in the control of spasticity in humans. This information might be of great relevance for patient stratification and personalized rehabilitation treatment programs.

Growth factors and synaptic plasticity in relapsing-remitting multiple sclerosis.

During multiple sclerosis (MS) inflammatory attacks, and in subsequent clinical recovery phases, immune cells contribute to neuronal and oligodendroglial cell survival and tissue repair by secreting growth factors. Animal studies showed that growth factors also play a substantial role in regulating synaptic plasticity, and namely in long-term potentiation (LTP). LTP could drive clinical recovery in relapsing patients by restoring the excitability of denervated neurons. We recently reported that maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and that the platelet-derived growth factor (PDGF) may play a key role in its regulation. We also reported that a Hebbian form of LTP-like cortical plasticity, explored by paired associative stimulation (PAS), correlates with clinical recovery from a relapse in MS. Here, we explored the role of PDGF in clinical recovery and in adaptive neuroplasticity in relapsing-remitting MS (RR-MS) patients. We found a correlation between the cerebrospinal fluid (CSF) PDGF concentrations and the extent of clinical recovery after a relapse, as full recovery was more likely observed in patients with high PDGF concentrations and poor recovery in subjects with low PDGF levels. Consistently with the idea that PDGF-driven synaptic plasticity contributes to attenuate the clinical consequences of tissue damage in RR-MS, we also found a striking correlation between CSF levels of PDGF and the amplitude of LTP-like cortical plasticity explored by PAS. CSF levels of fibroblast growth factor, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor did not correlate with clinical recovery nor with measures of synaptic transmission and plasticity.

Cortical plasticity predicts recovery from relapse in multiple sclerosis.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is characterized by the occurrence of clinical relapses, followed by remitting phases of a neurological deficit. Clinical remission after a relapse can be complete, with a return to baseline function that was present before, but is sometimes only partial or absent. Remyelination and repair of the neuronal damage do contribute to recovery, but they are usually incomplete. OBJECTIVE: We tested the hypothesis that synaptic plasticity, namely long-term potentiation (LTP), may represent an additional substrate for compensating the clinical defect that results from the incomplete repair of neuronal damage. METHODS: We evaluated the correlation between a measure of LTP, named paired associative stimulation (PAS), at the time of relapse and symptom recovery, in a cohort of 22 newly-diagnosed MS patients. RESULTS: PAS-induced LTP was normal in patients with complete recovery, and reduced in patients showing incomplete or absent recovery, 12 weeks after the relapse onset. A multivariate regression model showed that PAS-induced LTP and age may contribute to predict null, partial or complete symptom recovery after a relapse. CONCLUSION: Synaptic plasticity may contribute to symptom recovery after a relapse in MS; and PAS, measured during a relapse, may be used as a predictor of recovery.

Interleukin-1ß promotes long-term potentiation in patients with multiple sclerosis.

The immune system shapes synaptic transmission and plasticity in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). These synaptic adaptations are believed to drive recovery of function after brain lesions, and also learning and memory deficits and excitotoxic neurodegeneration; whether inflammation influences synaptic plasticity in MS patients is less clear. In a cohort of 59 patients with MS, we found that continuous theta-burst transcranial magnetic stimulation did not induce the expected long-term depression (LTD)-like synaptic phenomenon, but caused persisting enhancement of brain cortical excitability. The amplitude of this long-term potentiation (LTP)-like synaptic phenomenon correlated with the concentration of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) in the cerebrospinal fluid. In MS and EAE, the brain and spinal cord are typically enriched of CD3(+) T lymphocyte infiltrates, which are, along with activated microglia and astroglia, a major cause of inflammation. Here, we found a correlation between the presence of infiltrating T lymphocytes in the hippocampus of EAE mice and synaptic plasticity alterations. We observed that T lymphocytes from EAE, but not from control mice, release IL-1ß and promote LTP appearance over LTD, thereby mimicking the facilitated LTP induction observed in the cortex of MS patients. EAE-specific T lymphocytes were able to suppress GABAergic transmission in an IL-1ß-dependent manner, providing a possible synaptic mechanism able to lower the threshold of LTP induction in MS brains. Moreover, in vivo blockade of IL-1ß signaling resulted in inflammation and synaptopathy recovery in EAE hippocampus. These data provide novel insights into the pathophysiology of MS.

Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis.

Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that platelet-derived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1) was reduced in the CSF of PP-MS patients, (2) enhanced LTP emergence in hippocampal mouse brain slices, (3) was associated with more pronounced LTP in RR-MS patients, and (4) was associated with the clinical compensation of new brain lesion formation in RR-MS. Our results show that brain plasticity reserve, in the form of LTP, is crucial to contrast clinical deterioration in MS. Enhancing PDGF signaling might represent a valuable treatment option to maintain brain reserve and to attenuate the clinical consequences of neuronal damage in the progressive phases of MS and in other neurodegenerative disorders.

Transcranial direct current stimulation ameliorates tactile sensory deficit in multiple sclerosis.

BACKGROUND: Deficit of tactile sensation in patients with MS is frequent and can be associated with interference with daily life activities. Transcranial direct current stimulation (tDCS) showed to increase tactile discrimination in healthy subjects. OBJECTIVE: In the present study, we investigated whether tDCS may be effective in ameliorating tactile sensory deficit in MS patients. METHODS: Patients received sham or real anodal tDCS of the somatosensory cortex for 5 consecutive days in a randomized, double blind, sham-controlled study. Discrimination thresholds of spatial tactile sensation were measured using the grating orientation task (GOT). As secondary outcomes we also measured subjective perception of tactile sensory deficit through a visual analog scale (VAS), quality of life and overall disability to evaluate the impact of the treatment on patients daily life. Evaluations were performed at baseline and during a 4-week follow-up period. RESULTS: Following anodal but not sham tDCS over the somatosensory cortex, there was a significant improvement of discriminatory thresholds at the GOT and increased VAS for sensation scores. Quality of life, and disability changes were not observed. CONCLUSION: Our results indicate that a five day course of anodal tDCS is able to ameliorate tactile sensory loss with long-lasting beneficial effects and could thus represent a therapeutic tool for the treatment of tactile sensory deficit in MS patients.

Short interval intracortical facilitation correlates with the degree of disability in multiple sclerosis.

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.

TRPV1 channels regulate cortical excitability in humans.

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.

Early treatment with high-dose interferon beta-1a reverses cognitive and cortical plasticity deficits in multiple sclerosis.

Acute inflammation is associated with cognitive deficits and alterations of cortical plasticity in multiple sclerosis (MS). We tested whether early treatment with high-dose interferon (IFN) beta-1a, known to reduce inflammatory activity, improves cortical function and cognitive deficits in MS. Eighty treatment-naïve relapsing-remitting MS (RRMS)patients received IFN beta-1a (44 mcg) subcutaneously three times per week. Cognitive performance and cortical plasticity were measured through the paced auditory serial addition test (PASAT) and intermittent theta burst stimulation (iTBS) before and up to two years af-ter IFN beta-1a initiation. Before treatment, patients with gadolinium-enhancing lesions (Gd+) on MRI performed worse on the PASAT,and showed lower iTBS-induced plasticity, compared with Gd- patients. Six months after treatment initiation both PASAT and iTBS-induced plasticity improved in Gd+ and remained stable in Gd- patients. These results suggest that cognitive and synaptic plasticity deficits may be rescued during high-doseIFN beta-1a treatment in newly-diagnosed RRMS patients with Gd+ lesions.

Genetic variants of the NMDA receptor influence cortical excitability and plasticity in humans.

N-methyl-d-aspartate (NMDA) receptors play crucial roles in glutamate-mediated synaptic transmission and plasticity and are involved in a variety of brain functions. Specific single nucleotide polymorphisms (SNPs) in the genes encoding NMDA receptor subunits have been associated with some neuropsychiatric disorders involving altered glutamate transmission, but how these polymorphisms impact on synaptic function in humans is unknown. Here, the role of NMDA receptors in the control of cortical excitability and plasticity was explored by comparing the response to single, paired, and repetitive transcranial magnetic stimulations of the motor cortex in 77 healthy subjects carrying specific allelic variants of the NR1 subunit gene (GRIN1 rs4880213 and rs6293) or of the NR2B subunit gene (GRIN2B rs7301328, rs3764028, and rs1805247). Our results showed that individuals homozygous for the T allele in the rs4880213 GRIN1 SNP had reduced intracortical inhibition, as expected for enhanced glutamatergic excitation in these subjects. Furthermore, individuals carrying the G allele in the rs1805247 GRIN2B SNP show greater intracortical facilitation and greater long-term potentiation-like cortical plasticity after intermittent -burst stimulation. Our results provide novel insights into the function of NMDA receptors in the human brain and might contribute to the clarification of the synaptic bases of severe neuropsychiatric disorders associated with defective glutamate transmission.

CSF tau levels influence cortical plasticity in Alzheimer's disease patients.

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-ß (Aß) 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 Aß1₋42, 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 Aß1₋42 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.

Transcranial magnetic stimulation primes the effects of exercise therapy in multiple sclerosis.

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.

Altered dopamine modulation of LTD-like plasticity in Alzheimer's disease patients.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Dopamine modulation of LTD-like plasticity is impaired when tested in AD patients. SIGNIFICANCE: These findings provide evidence of possible dysfunction of dopaminergic transmission in AD patients.

Cognitive and cortical plasticity deficits correlate with altered amyloid-ß CSF levels in multiple sclerosis.

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-ß(1-42) 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-ß(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-ß(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-ß(1-42) 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-ß(1-42) 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-ß(1-42) 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-ß metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.

Impaired inter-hemispheric facilitatory connectivity in schizophrenia.

OBJECTIVES: To investigate the inter-hemispheric connections between the dorsal premotor cortex (dPM) and contralateral primary motor cortex (M1) in schizophrenia. METHODS: 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. RESULTS: 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. CONCLUSIONS: Inter-hemispheric facilitatory dPM-M1 connectivity is selectively altered in schizophrenia. SIGNIFICANCE: 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.

Differential patterns of interhemispheric functional disconnection in mild and advanced multiple sclerosis.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. CONCLUSIONS: 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.

Effects of anodal transcranial direct current stimulation on chronic neuropathic pain in patients with multiple sclerosis.

UNLABELLED: 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.

Dopamine modulates cholinergic cortical excitability in Alzheimer's disease patients.

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.