Long-Term Neuromodulatory Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Plasmatic Matrix Metalloproteinases (MMPs) Levels and Visuospatial Abilities in Mild Cognitive Impairment (MCI).

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the neurobiological mechanisms underlying the rTMS therapeutic effects are still only partially investigated. Maladaptive plasticity, glial activation, and neuroinflammation, including metalloproteases (MMPs) activation, might represent new potential targets of the neurodegenerative process and progression from MCI to AD. In this study, we aimed to evaluate the effects of bilateral rTMS over the dorsolateral prefrontal cortex (DLPFC) on plasmatic levels of MMP1, -2, -9, and -10; MMPs-related tissue inhibitors TIMP1 and TIMP2; and cognitive performances in MCI patients. Patients received high-frequency (10 Hz) rTMS (MCI-TMS, n = 9) or sham stimulation (MCI-C, n = 9) daily for four weeks, and they were monitored for six months after TMS. The plasmatic levels of MMPs and TIMPs and the cognitive and behavioral scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Beck Depression Inventory II, Beck Anxiety Inventory, and Apathy Evaluation Scale, were assessed at baseline (T0) and after 1 month (T1) and 6 months (T2) since rTMS. In the MCI-TMS group, at T2, plasmatic levels of MMP1, -9, and -10 were reduced and paralleled by increased plasmatic levels of TIMP1 and TIMP2 and improvement of visuospatial performances. In conclusion, our findings suggest that targeting DLPFC by rTMS might result in the long-term modulation of the MMPs/TIMPs system in MCI patients and the neurobiological mechanisms associated with MCI progression to dementia.

Matrix metalloproteinases, purinergic signaling, and epigenetics: hubs in the spinal neuroglial network following peripheral nerve injury.

Activation of glial cells (reactive gliosis) and the purinergic pathway, together with metalloproteinase (MMP)-induced remodeling of the neural extracellular matrix (nECM), drive maladaptive changes in the spinal cord following peripheral nerve injury (PNI). We evaluated the effects on spinal maladaptive plasticity through administration of oxidized ATP (oxATP), an antagonist of P2X receptors (P2XR), and/or GM6001, an inhibitor of MMPs, in rats following spared nerve injury (SNI) of the sciatic nerve. With morpho-molecular techniques, we demonstrated a reduction in spinal reactive gliosis and changes in the neuro-glial-nECM crosstalk via expression remodeling of P2XR, nerve growth factor (NGF) receptors (TrkA and p75), and histone deacetylase 2 (HDAC2) after treatments with oxATP/GM6001. Altogether, our data suggest that MMPs and purinergic inhibition have a modulatory impact on key proteins in the neuro-glial-nECM network, acting at different levels from intracellular signaling to epigenetic modifications.

Myasthenia gravis and telemedicine: a lesson from COVID-19 pandemic.

COVID-19 pandemic has induced an urgent reorganization of the healthcare system to ensure continuity of care for patients affected by chronic neurological diseases including myasthenia gravis (MG). Due to the fluctuating nature of the disease, early detection of disease worsening, adverse events, and possibly life-threatening complications is mandatory. This work analyzes the main unresolved issues in the management of the myasthenic patient, the possibilities offered so far by digital technologies, and proposes an online evaluation protocol based on 4 simple tests to improve MG management. Telemedicine and Digital Technology might help neurologists in the clinical decision-making process of MG management, avoiding unnecessary in presence consultations and allowing a rational use of the time and space reduced by the pandemic.

Altered sensory-motor plasticity in amyotrophic lateral sclerosis and complex regional pain type I syndrome: a shared mechanism?

Besides the prominent motor syndrome, some patients affected by amyotrophic lateral sclerosis (ALS) complain of many non-motor symptoms during the disease course, in particular chronic pain that significantly reduces the patients' quality of life. Complex regional pain syndrome (CRPS) is a rare painful condition, rarely described in ALS patients. We present the clinical case of a patient affected by spinal-onset ALS, who developed a type I CRPS (CRPS-I) at the upper limbs. To the best of our knowledge, only five cases of ALS-CRPS-I have been reported and they share some peculiar features: ALS spinal-onset with classic phenotype, rapid deterioration of quality of life, and a poor prognosis. Different mechanisms have been supposed in the pathogenesis of both CRPS and ALS, resulting in distinctive clinical presentations. Altered plasticity of brain sensory and motor areas might represent a common feature that seems to influence negatively ALS progression and prognosis.

Clinical-neurophysiological correlations in chronic inflammatory demyelinating polyradiculoneuropathy patients treated with subcutaneous immunoglobulin.

INTRODUCTION: Despite the well-described clinical efficacy of long-term subcutaneous immunoglobulin (LT-SCIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients, the neurophysiological effects of SCIg have been followed only for a short time and were not correlated with clinical parameters. METHODS: Fourteen CIDP patients were evaluated at baseline and after LT-SCIg administration for 24 to 48 months. Nerve conduction studies were performed and clinical features were assessed for: (a) overall strength, by Medical Research Council sum score; (b) sensory function, by Inflammatory Neuropathy Cause And Treatment score; (c) disability, by Rasch-built overall disability scale; (d) quality of life (QoL), by the EuroQol Visual Analog Scale. RESULTS: LT-SCIg treatment improved clinical and neurophysiological features, preserving strength and improving sensory deficits, disability, and QoL. Clinical scores correlated with the amplitude of distal motor action (dCMAP) and sensory nerve action (SNAP) potentials. DISCUSSION: LT-SCIg treatment demonstrates efficacy in maintaining and continuing clinical improvement at 24 to 48 months after start of treatment. dCMAP and SNAP amplitudes represent useful prognostic factors for functional outcome.

Astrocytes and Microglia-Mediated Immune Response in Maladaptive Plasticity is Differently Modulated by NGF in the Ventral Horn of the Spinal Cord Following Peripheral Nerve Injury.

Reactive astrocytes and activated microglia are the key players in several pathophysiologic modifications of the central nervous system. We used the spared nerve injury (SNI) of the sciatic nerve to induce glial maladaptive response in the ventral horn of lumbar spinal cord and examine its role in the remodeling of the tripartite synapse plasticity. Imaging the ventral horn revealed that SNI was associated with both an early microglial and astrocytic activation, assessed, respectively, by analysis of Iba1 and GFAP expression. Microglia, in particular, localized peculiarly surrounding the motor neurons somata. Perineuronal astrocytes, which play a key role in maintaining the homeostasis of neuronal circuitry, underwent a substantial phenotypic change following peripheral axotomy, producing reactive gliosis. The gliosis was associated with the reduction of glial aminoacid transporters (GLT1 and GlyT1) and increase of neuronal glutamate transporter EAAC1. Although the expression of GABAergic neuronal marker GAD65/67 showed no change, glutamate increase, as demonstrated by HPLC analysis, shifted the excitatory/inhibitory balance as showed by the net increase of the glutamate/GABA ratio. Moreover, endogenous NGF levels were altered in SNI animals and not restored by the intrathecal NGF administration. This treatment reverted phenotypic changes associated with reactive astrocytosis, but failed to modify microglia activation. These findings on one hand confirm the correlation between gliopathy and maladaptive plasticity of the spinal synaptic circuitry, on the other hand add new data concerning the complex peculiar behavior of different glial cells in neuronal degenerative processes, defining a special role of microglia in sustaining the inflammatory response.

Peripheral and central neurobiological effects of botulinum toxin A (BoNT/A) in neuropathic pain: a systematic review.

ABSTRACT: Botulinum toxin (BoNT), a presynaptic inhibitor of acetylcholine (Ach) release at the neuromuscular junction (NMJ), is a successful and safe drug for the treatment of several neurological disorders. However, a wide and recent literature review has demonstrated that BoNT exerts its effects not only at the "periphery" but also within the central nervous system (CNS). Studies from animal models, in fact, have shown a retrograde transport to the CNS, thus modulating synaptic function. The increasing number of articles reporting efficacy of BoNT on chronic neuropathic pain (CNP), a complex disease of the CNS, demonstrates that the central mechanisms of BoNT are far from being completely elucidated. In this new light, BoNT might interfere with the activity of spinal, brain stem, and cortical circuitry, modulating excitability and the functional organization of CNS in healthy conditions. Botulinum toxins efficacy on CNP is the result of a wide and complex action on many and diverse mechanisms at the basis of the maladaptive plasticity, the core of the pathogenesis of CNP. This systematic review aims to discuss in detail the BoNT's mechanisms and effects on peripheral and central neuroplasticity, at the basis for the clinical efficacy in CNP syndromes.

Functional Connectome Controllability in Patients with Mild Cognitive Impairment after Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex.

Background: Repetitive transcranial magnetic stimulation (rTMS) has shown therapeutic effects in neurological patients by inducing neural plasticity. In this pilot study, we analyzed the modifying effects of high-frequency (HF-)rTMS applied to the dorsolateral prefrontal cortex (DLPFC) of patients with mild cognitive impairment (MCI) using an advanced approach of functional connectome analysis based on network control theory (NCT). Methods: Using local-to-global functional parcellation, average and modal controllability (AC/MC) were estimated for DLPFC nodes of prefrontal-lateral control networks (R/LH_Cont_PFCl_3/4) from a resting-state fMRI series acquired at three time points (T0 = baseline, T1 = T0 + 4 weeks, T2 = T1 + 20 weeks) in MCI patients receiving regular daily sessions of 10 Hz HF-rTMS (n = 10, 68.00 ± 8.16 y, 4 males) or sham (n = 10, 63.80 ± 9.95 y, 5 males) stimulation, between T0 and T1. Longitudinal (group) effects on AC/MC were assessed with non-parametric statistics. Spearman correlations (ρ) of AC/MC vs. neuropsychological (RBANS) score %change (at T1, T2 vs. T0) were calculated. Results: AC median was reduced in MCI-rTMS, compared to the control group, for RH_Cont_PFCl_3/4 at T1 and T2 (vs. T0). In MCI-rTMS patients, for RH_Cont_PFCl_3, AC % change at T1 (vs. T0) was negatively correlated with semantic fluency (ρ = -0.7939, p = 0.045) and MC % change at T2 (vs. T0) was positively correlated with story memory (ρ = 0.7416, p = 0.045). Conclusions: HF-rTMS stimulation of DLFC nodes significantly affects the controllability of the functional connectome in MCI patients. Emerging correlations between AC/MC controllability and cognitive performance changes, immediately (T1 vs. T0) and six months (T2 vs. T0) after treatment, suggest NCT could help explain the HF-rTMS impact on prefrontal-lateral control network, monitoring induced neural plasticity effects in MCI patients.

Therapy of hyperhomocysteinemia in hemodialysis patients: effects of folates and N-acetylcysteine.

OBJECTIVE: Uremia represents a state where hyperhomocysteinemia is resistant to folate therapy, thus undermining intervention trials' efficacy. N-acetylcysteine (NAC), an antioxidant, in addition to folates (5-methyltetrahydrofolate, MTHF), was tested in a population of hemodialysis patients. DESIGN: The study is an open, parallel, intervention study. SETTING: Ambulatory chronic hemodialysis patients. SUBJECTS: Clinically stable chronic hemodialysis patients, on hemodialysis since more than 3 months, undergoing a folate washout. Control group on standard therapy (n = 50). INTERVENTION: One group was treated with intravenous MTHF (MTHF group, n = 48). A second group was represented by patients treated with MTHF, and, during the course of 10 hemodialysis sessions, NAC was administered intravenous (MTHF + NAC group, n = 47). MAIN OUTCOME MEASURE: Plasma homocysteine measured before and after dialysis at the first and the last treatment. RESULTS: At the end of the study, there was a significant decrease in predialysis plasma homocysteine levels in the MTHF group and MTHF + NAC group, compared with the control group, but no significant difference between the MTHF group and MTHF + NAC group. A significant decrease in postdialysis plasma homocysteine levels in MTHF + NAC group (10.27 ± 0.94 µmol/L, 95% confidence interval: 8.37-12.17) compared with the MTHF group (16.23 ± 0.83, 95% confidence interval: 14.55-17.90) was present. In the MTHF + NAC group, 64% of patients reached a postdialysis homocysteine level <12 µmol/L, compared with 19% in the MTHF group and 16% in the control group. CONCLUSIONS: NAC therapy induces a significant additional decrease in homocysteine removal during dialysis. The advantage is limited to the time of administration.

Calcium imaging of living astrocytes in the mouse spinal cord following sensory stimulation.

Astrocytic Ca(2+) dynamics have been extensively studied in ex vivo models; however, the recent development of two-photon microscopy and astrocyte-specific labeling has allowed the study of Ca(2+) signaling in living central nervous system. Ca(2+) waves in astrocytes have been described in cultured cells and slice preparations, but evidence for astrocytic activation during sensory activity is lacking. There are currently few methods to image living spinal cord: breathing and heart-beating artifacts have impeded the widespread application of this technique. We here imaged the living spinal cord by two-photon microscopy in C57BL6/J mice. Through pressurized injection, we specifically loaded spinal astrocytes using the red fluorescent dye sulforhodamine 101 (SR101) and imaged astrocytic Ca(2+) levels with Oregon-Green BAPTA-1 (OGB). Then, we studied astrocytic Ca(2+) levels at rest and after right electrical hind paw stimulation. Sensory stimulation significantly increased astrocytic Ca(2+) levels within the superficial dorsal horn of the spinal cord compared to rest. In conclusion, in vivo morphofunctional imaging of living astrocytes in spinal cord revealed that astrocytes actively participate to sensory stimulation.

Neurophysiological Hallmarks of Axonal Degeneration in CIDP Patients: A Pilot Analysis.

In this work, we aim to identify sensitive neurophysiological biomarkers of axonal degeneration in CIDP patients. A total of 16 CIDP patients, fulfilling the clinical and neurophysiological criteria for typical CIDP, treated with subcutaneous immunoglobulin (ScIg) (0.4 g/kg/week) were evaluated at baseline (before ScIg treatment) and after long-term treatment with ScIg (24 months) by clinical assessment scales, nerve conduction studies (NCS) and electromyography (EMG). Conventional and non-conventional neurophysiological parameters: motor unit potential (MUP) analysis, MUP thickness and size index (SI)] and interference pattern (IP) features were evaluated after long-term treatment (24 months) and compared with a population of 16 healthy controls (HC). An increase of distal motor latency (DML) and reduced compound motor action potential (CMAP) amplitude and area in CIDP patients suggest axonal damage of motor fibers, together with a significant increase of MUP amplitude, duration and area. Analysis of non-conventional MUP parameters shows no difference for MUP thickness; however, in CIDP patients, SI is increased and IP area and amplitude values are lower than HC. Despite clinical and neurophysiological improvement after ScIg treatment, neurophysiological analysis revealed axonal degeneration of motor fibers and motor unit remodeling. Correlation analysis shows that the axonal degeneration process is related to the diagnostic and therapeutic delay. MUP area and SI parameters can detect early signs of axonal degeneration, and their introduction in clinical practice may help to identify patients with the worst outcome.

Altered Spinal Homeostasis and Maladaptive Plasticity in GFAP Null Mice Following Peripheral Nerve Injury.

The maladaptive response of the central nervous system (CNS) following nerve injury is primarily linked to the activation of glial cells (reactive gliosis) that produce an inflammatory reaction and a wide cellular morpho-structural and functional/metabolic remodeling. Glial acidic fibrillary protein (GFAP), a major protein constituent of astrocyte intermediate filaments (IFs), is the hallmark of the reactive astrocytes, has pleiotropic functions and is significantly upregulated in the spinal cord after nerve injury. Here, we investigated the specific role of GFAP in glial reaction and maladaptive spinal cord plasticity following sciatic nerve spared nerve injury (SNI) in GFAP KO and wild-type (WT) animals. We evaluated the neuropathic behavior (thermal hyperalgesia, allodynia) and the expression of glial (vimentin, Iba1) and glutamate/GABA system markers (GLAST, GLT1, EAAC1, vGLUT, vGAT, GAD) in lumbar spinal cord sections of KO/WT animals. SNI induced neuropathic behavior in both GFAP KO and WT mice, paralleled by intense microglial reaction (Iba1 expression more pronounced in KO mice), reactive astrocytosis (vimentin increase) and expression remodeling of glial/neuronal glutamate/GABA transporters. In conclusion, it is conceivable that the lack of GFAP could be detrimental to the CNS as it lacks a critical sensor for neuroinflammation and morpho-functional-metabolic rewiring after nerve injury. Understanding the maladaptive morpho-functional changes of glial cells could represent the first step for a new glial-based targeted approach for mechanisms of disease in the CNS.

Tumor Microenvironment and Immune Escape in the Time Course of Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a malignant prognosis. GBM is characterized by high cellular heterogeneity and its progression relies on the interaction with the central nervous system, which ensures the immune-escape and tumor promotion. This interplay induces metabolic, (epi)-genetic and molecular rewiring in both domains. In the present study, we aim to characterize the time-related changes in the GBM landscape, using a syngeneic mouse model of primary GBM. GL261 glioma cells were injected in the right striatum of immuno-competent C57Bl/6 mice and animals were sacrificed after 7, 14, and 21 days (7D, 14D, 21D). The tumor development was assessed through 3D tomographic imaging and brains were processed for immunohistochemistry, immunofluorescence, and western blotting. A human transcriptomic database was inquired to support the translational value of the experimental data. Our results showed the dynamic of the tumor progression, being established as a bulk at 14D and surrounded by a dense scar of reactive astrocytes. The GBM growth was paralleled by the impairment in the microglial/macrophagic recruitment and antigen-presenting functions, while the invasive phase was characterized by changes in the extracellular matrix, as shown by the analysis of tenascin C and metalloproteinase-9. The present study emphasizes the role of the molecular changes in the microenvironment during the GBM progression, fostering the development of novel multi-targeted, time-dependent therapies in an experimental model similar to the human disease.

Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn's and Other Inflammatory Bowel Diseases.

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate interaction between the enteric nervous system and central nervous system and/or low activity of the vagus nerve, which connects the enteric and central nervous systems, could play a crucial role in their pathogenesis. Therefore, it has been suggested that appropriate neuroprosthetic stimulation of the vagus nerve could lead to the modulation of the inflammation of the gastrointestinal tract and consequent long-term control of these autoimmune diseases. In the present paper, we provide a comprehensive overview of (1) the cellular and molecular bases of the immune system, (2) the way central and enteric nervous systems interact and contribute to the immune responses, (3) the pathogenesis of the inflammatory bowel disease, and (4) the therapeutic use of vagus nerve stimulation, and in particular, the transcutaneous stimulation of the auricular branch of the vagus nerve. Then, we expose the working hypotheses for the modulation of the molecular processes that are responsible for intestinal inflammation in autoimmune diseases and the way we could develop personalized neuroprosthetic therapeutic devices and procedures in favor of the patients.

Repetitive Transcranial Magnetic Stimulation (rTMS) of Dorsolateral Prefrontal Cortex May Influence Semantic Fluency and Functional Connectivity in Fronto-Parietal Network in Mild Cognitive Impairment (MCI).

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that is increasingly used as a nonpharmacological intervention against cognitive impairment in Alzheimer's disease (AD) and other dementias. Although rTMS has been shown to modify cognitive performances and brain functional connectivity (FC) in many neurological and psychiatric diseases, there is still no evidence about the possible relationship between executive performances and resting-state brain FC following rTMS in patients with mild cognitive impairment (MCI). In this preliminary study, we aimed to evaluate the possible effects of rTMS of the bilateral dorsolateral prefrontal cortex (DLPFC) in 27 MCI patients randomly assigned to two groups: one group received high-frequency (10 Hz) rTMS (HF-rTMS) for four weeks (n = 11), and the other received sham stimulation (n = 16). Cognitive and psycho-behavior scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status, Beck Depression Inventory-II, Beck Anxiety Inventory, Apathy Evaluation Scale, and brain FC, evaluated by independent component analysis of resting state functional MRI (RS-fMRI) networks, together with the assessment of regional atrophy measures, evaluated by whole-brain voxel-based morphometry (VBM), were measured at baseline, after five weeks, and six months after rTMS stimulation. Our results showed significantly increased semantic fluency (p = 0.026) and visuo-spatial (p = 0.014) performances and increased FC within the salience network (p ≤ 0.05, cluster-level corrected) at the short-term timepoint, and increased FC within the left fronto-parietal network (p ≤ 0.05, cluster-level corrected) at the long-term timepoint, in the treated group but not in the sham group. Conversely, regional atrophy measures did not show significant longitudinal changes between the two groups across six months. Our preliminary findings suggest that targeting DLPFC by rTMS application may lead to a significant long-term increase in FC in MCI patients in a RS network associated with executive functions, and this process might counteract the progressive cortical dysfunction affecting this domain.

Reactive astrocytosis-induced perturbation of synaptic homeostasis is restored by nerve growth factor.

Reactive gliosis has been implicated in both inflammatory and neurodegenerative diseases. However, mechanisms by which astrocytic activation affects synaptic efficacy have been poorly elucidated. We have used the spared nerve injury (SNI) of the sciatic nerve to induce reactive astrocytosis in the lumbar spinal cord and investigate its potential role in disrupting the neuro-glial circuitry. Analysis of spinal cord sections revealed that SNI was associated with an increase of microglial (Iba1) and astrocytic (GFAP) markers. These changes, indicative of reactive gliosis, were paralleled by (i) a decrease of glial amino acid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. Besides the increase of Glutamate/GABA ratio, indicative of the perturbation of synaptic circuitry homeostasis, the boost of glutamate also compromised glial function in neuroprotection by up-regulating the xCT subunit of the glutamate-cystine antiport system and reducing glutathione (GSH) production. Finally, this study also shows that all these structural changes were linked to an alteration of endogenous NGF metabolism, as demonstrated by the decrease of endogenous NGF expression levels and increased activity of the NGF-degrading metalloproteinases. All the changes displayed by SNI-animals were reversed by a 7-days i.t. administration of NGF or GM6001, a generic metalloproteinase inhibitor, as compared to vehicle (ACSF)-treated animals. All together, these data strongly support the correlation between reactive astrogliosis and mechanisms underlying the perturbation of the synaptic circuitry in the SNI model of peripheral nerve injury, and the essential role of NGF in restoring both synaptic homeostasis and the neuroprotective function of glia.

Cross-talk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells.

Neuronal death has been reported to involve mitochondrial dysfunction and cell cycle reentry. In this report, we used Nerve Growth Factor (NGF)-differentiated PC12 cells to investigate mechanisms linking mitochondrial dysfunction and cell cycle activation during neuronal death induced by NGF withdrawal and/or oxidative stress. We found that loss of survival following H(2) O(2) -induced oxidative stress or NGF deprivation was preceded by a decrease in mitochondrial membrane potential (ΔΨm), increase in reactive oxygen species (ROS), and up-regulation of cyclin D1 and phosphorylation (Ser-780) of protein retinoblastoma (P-pRb), without an increase of proliferation rates. Treatment with H(2) O(2) , but not NGF deprivation, also induced the phosporylation (Ser-10) of p27(kip1) and the appearance of a cleaved P-p27(kip1) fragment of about 15 kDa. The extent of cell cycle activation appeared to be inversely correlated to the duration of toxic stimuli (pulse/continuous). H(2) O(2) -induced mitogenic responses appeared to be mediated by induction of P-MAPK and P-Akt and were blocked by p38MAPK and JNK inhibitors as well as by the CDK inhibitor flavopiridol (Flav) and by sodium selenite (Sel), a component of selenoproteins, including glutathione peroxidases. Inhibition of p38MAPK and JNK, instead, did not affect cyclin D1 changes following NGF deprivation. Finally, both Flav hydrochloride and Sel partially prevented mitochondrial dysfunction and cell death following NGF withdrawal or H(2) O(2) toxicity, but not during oxidative stress in the absence of NGF. Taken together, these data suggest that H(2) O(2) -induced oxidative stress can determine distinct patterns of mitogenic responses as a function of mitochondrial dysfunction depending on 1) intensity/duration of stress stimuli and/or 2) presence of NGF.

Neurobiological After-Effects of Low Intensity Transcranial Electric Stimulation of the Human Nervous System: From Basic Mechanisms to Metaplasticity.

Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity, however mechanisms are still far from being elucidated. We aim to review recent results from in vitro and in vivo studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from in vitro and in vivo studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.