<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03228472</url>
  </required_header>
  <id_info>
    <org_study_id>IRCCS_Neuromed</org_study_id>
    <nct_id>NCT03228472</nct_id>
  </id_info>
  <brief_title>Noninvasive Brain Stimulation Training</brief_title>
  <acronym>TrainingNIBS</acronym>
  <official_title>Noninvasive Brain Stimulation Training to Help Recover Brain-related Symptoms</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Neuromed IRCCS</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Neuromed IRCCS</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Non-invasive cerebral stimulation techniques have shown potential in the treatment of&#xD;
      neurological disorders such as chronic pain, Parkinson's disease, neglect, aphasia, memory,&#xD;
      engine deficit and epilepsy In general, non-invasive cerebral stimulation techniques have&#xD;
      been shown to be able to induce changes in cortical plasticity that may last even beyond the&#xD;
      end of the stimulation period. Considering this potential, there is growing interest in the&#xD;
      application of these therapeutic techniques.&#xD;
&#xD;
      Hypotheses Based on these assumptions, the underlying hypothesis behind this project is that&#xD;
      the therapeutic use of cranial - electrical or magnetic stimulation - can aid the recovery of&#xD;
      various brain injury symptoms.&#xD;
&#xD;
      Specific objectives This study aims to provide preliminary data about the benefits of using&#xD;
      cortical stimulation to recover various brain injury symptoms. This will be made possible&#xD;
      thanks to the specific skills of a multidisciplinary team of neurologists and physiatrists,&#xD;
      healthcare professionals such as physiotherapists, occupational therapists, psychologists,&#xD;
      speech therapists and the support of a biomedical engineer. These professional figures are&#xD;
      already available at the UCK Neurosurgery of the IRCCS Neuromed directed by the proposer and&#xD;
      actively collaborate to optimize the therapeutic exercise of patients with neurological&#xD;
      damage.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction TMS is a non-invasive neuronal stimulation of surface areas of the brain that&#xD;
      since its introduction in 1985 has been frequently used in neurology as a diagnostic and&#xD;
      research tool. TMS uses magnetic fields to induce electrical currents that cross the nervous&#xD;
      tissue depolarizing neurons, and reproduced motions generated are recorded as electromyograph&#xD;
      potentials. TMS is able to explore the functionality of the cortical-spinal system, measure&#xD;
      cortical excitability, mapcortical features, and evaluate brain modulators.&#xD;
&#xD;
      Repetitive transcranial magnetic stimulation (rTMS) is frequently used in the experimental&#xD;
      field for cortical function scans and modulation of the intrinsic cortical plasticity. In&#xD;
      particular, high frequency rTMS has facilitating effects on cortico-spinal excitability and&#xD;
      the low-frequency one is usually inhibitory. rTMS is a method of extreme interest for the&#xD;
      possible therapeutic role in conditions of altered cerebral excitability, both psychiatric&#xD;
      (schizophrenia, posttraumatic stress disorder, obsessive-compulsive disorder, major&#xD;
      depression) and neurological (epilepsy , stroke, degenerative diseases). At experimental&#xD;
      level, the actual stimulation is compared with an inactive stimulus called sham, which acts&#xD;
      as a control condition.&#xD;
&#xD;
      Direct Transcranial Electric Stimulation (tDCS) requires the application of weak electrical&#xD;
      currents directly to the head for several minutes. These currents generate an electric field&#xD;
      modulating neural activity based on the application mode. tDCS alters the rate of discharge&#xD;
      of neurons. In fact, cathodic polarization applied to the motor cortex can induce a robust&#xD;
      reduction in cortical excitability, while anodic polarization increases the excitability of&#xD;
      the motor cortex. The short-term effects of tDCS are probably due to a change in neural&#xD;
      membrane polarization. Similarly to rTMS, these changes last even after the end of&#xD;
      stimulation for periods ranging from minutes to hours. Thus, tDCS can modify performance in&#xD;
      many cognitive tasks.&#xD;
&#xD;
      Non-invasive cerebral stimulation have demonstrated a potential for the treatment of&#xD;
      neurological disorders such as chronic pain, Parkinson's disease, neglect, aphasia, memory,&#xD;
      motor deficiency and epilepsy. In general, non-invasive brain stimulation techniques have&#xD;
      shown to induce changes in cortical plasticity that may last even beyond the end of the&#xD;
      stimulation period. Considering this potential, there is an increasing interest in the&#xD;
      application of these techniques in the therapeutic field.&#xD;
&#xD;
      In our study, we suggest evaluating any variations in the muscular tone of the lower limbs as&#xD;
      a result of high frequency repetitive transcranial magnetic stimulation (rTMS) in patients&#xD;
      with multiple sclerosis with relapsing-remitting pattern without evidence of medullary&#xD;
      demyelination areas. rTMS allows modulation of intracortical excitability and can therefore&#xD;
      modify the control of spinal excitability.&#xD;
&#xD;
      Sensory disorders are frequently observed within neurological disorders and are a possible&#xD;
      cause of disability. Recent studies based on non-invasive stimulation techniques have shown&#xD;
      interesting results in modulation of tactile sensory functions in healthy subjects. tDCS is&#xD;
      capable of inducing a plastic change in motor and somatosensory areas. Several studies have&#xD;
      reported anodic tDCS stimulation that can reduce both chronic and acute pain in different&#xD;
      conditions. In addition, anodic tDCS stimulation can improve the loss of tactile sensitivity&#xD;
      resulting from Multiple Sclerosis.&#xD;
&#xD;
      Most patients with Parkinson's Disease develop after several years of treatment with a number&#xD;
      of clinical complications, including dyskinesias, involuntary pathological, sometimes&#xD;
      frankly, dystonic movements. Pathological Long Term Potentiation (LTP) phenomena were&#xD;
      observed in the stigma of parkinsonian rats that developed dyskinesias following L-dopa&#xD;
      treatment. Low-frequency electric stimulation of single cells induces a reversal of enhanced&#xD;
      synaptic responses, a phenomenon known as depotentiation.&#xD;
&#xD;
      Several authors have observed that in patients with focal dystonia there is a lack of&#xD;
      intracortical inhibition of controls. A pilot study examined the effects of slow rTMS on the&#xD;
      motor cortex, highlighting normalization of intracortical inhibition and improving clinical&#xD;
      symptoms.&#xD;
&#xD;
      The role of TMS in the treatment of major drug-resistant depression has been amply defined.&#xD;
      Some early studies demonstrated that a high-frequency focal pacing of the left-sided&#xD;
      prefrontal cortex (DLPFC) induced symptom improvement, quantifiable as a reduction in the&#xD;
      score to the Hamilton Depression Rating Scale, probably via an increase in the content of&#xD;
      brain monoamines. Studies on cerebral blood flow have also shown an increase in activity in&#xD;
      the stimulated DLPFC.&#xD;
&#xD;
      It is now accepted that rTMS has the same efficacy, in the most potent drug-resistant&#xD;
      depression, of electroconvulsive therapy, with virtually null side effects.&#xD;
&#xD;
      Hypothesis Based on these assumptions, the underlying hypothesis behind this project is that&#xD;
      the therapeutic use of cranial - electrical or magnetic stimulation - can aid the recovery of&#xD;
      various brain injury symptoms.&#xD;
&#xD;
      Specific objectives This study aims to provide preliminary data about the benefits of using&#xD;
      cortical stimulation to recover various brain injury symptoms. This will be made possible&#xD;
      thanks to the specific skills of a multidisciplinary team of neurologists and physiatrists,&#xD;
      healthcare professionals such as physiotherapists, occupational therapists, psychologists,&#xD;
      speech therapists and the support of a biomedical engineer. These professional figures are&#xD;
      already available at the UCK Neurosurgery of the IRCCS Neuromed directed by the proposer and&#xD;
      actively collaborate to optimize the therapeutic exercise of patients with neurological&#xD;
      damage.&#xD;
&#xD;
      Population of the study The sample estimate was made by analogy after a literature analysis.&#xD;
      Considering the risk of abandonment quite high, our intention is to recruit at least 100&#xD;
      subjects in a population of patients with cerebral injury who are involved in the&#xD;
      neurological department of IRCCS. Neuromed in Pozzilli, featuring the symptoms described&#xD;
      below in the inclusion criteria Inclusion and exclusion criteria are specified below.&#xD;
&#xD;
      Experimental design Double-blind prospective study, between randomized, placebo-controlled&#xD;
      parallel groups.&#xD;
&#xD;
      Patients will undergo a cerebral pacing program listed below and differentiated according to&#xD;
      the type of symptom presented. All conventional therapies taken by patients will be recorded&#xD;
      by the operators. Patients will be divided into Stimulation and Sham (control) groups and&#xD;
      will be evaluated at zero time before starting treatment (T-0W) after 6 weeks to evaluate the&#xD;
      effects at the end of treatment (T-6W) and at 12 weeks (T-12W) to evaluate the maintenance of&#xD;
      long-term effects. Randomization will be balanced in accordance with age, sex and schooling.&#xD;
&#xD;
      The physiotherapy or speech therapy approach will be different between patients considering&#xD;
      the different types of brain damage and the different levels of disability, according to the&#xD;
      rehabilitation unit team for each case.&#xD;
&#xD;
      Spasticity Patients will be evaluated clinically, using a clinical scale to quantify muscle&#xD;
      tone in the various districts (Ashworth scale) and neurophysiologically by eliciting the H&#xD;
      reflection. The electrophysiological parameters detected will be: M response, H reflex and&#xD;
      its M / H ratio. Patients with spasticity to lower limbs will be enrolled in continuous&#xD;
      interferon therapy and free of cortisone for at least 30 days.&#xD;
&#xD;
      The runtime rTMS will be applied to the motor at rest (RMT) on the primary motor area for the&#xD;
      lower limb, 5 Hz (excitatory) with 20 trains of 10 sec (50 train stimuli, 1000 total stimuli)&#xD;
      with intertree intervals of 30 seconds (total 22 min. Ca) on the primary motor cortex for the&#xD;
      lower limb and we will measure the H reflex before and after the stimulation session. The&#xD;
      treatment will last 2 weeks with daily sessions.&#xD;
&#xD;
      Dyskinesia Patients with clinically diagnosed discontinuous L-Dopa treatment history will be&#xD;
      enrolled.&#xD;
&#xD;
      They will be given rTMS for 7 consecutive days with the following stimulation parameters: 1&#xD;
      Hz frequency; 90% Active Motor Threshold intensity; Train duration 899 sec (900 stimuli). At&#xD;
      the end of each individual stimulation session patients will be subjected to neurological&#xD;
      evaluation of the symptoms.&#xD;
&#xD;
      Sensory Deficits Patients with reduced tactile sensitivity to upper or lower limbs will be&#xD;
      enrolled. Patients with peripheral neuropathy, psychiatric disorders, cognitive deficits,&#xD;
      epilepsy will be excluded. TDCS stimulation will be administered for 5 consecutive days at 2&#xD;
      mA for 20 minutes. The anode will be placed 2 cm behind the C3 / C4 points of the defective&#xD;
      hemisphere. The reference electrode will be positioned over the contralateral control region.&#xD;
      Sham stimulation will have the same parameters. Clinical evaluation will be performed before&#xD;
      and after treatment, and at a distance of 1, 2 and 4 weeks.&#xD;
&#xD;
      Pain Patients with neuropathic pain in the upper or lower limbs, VAS score of at least 40,&#xD;
      will be enrolled in the absence of analgesic treatment for at least one month. Subjects with&#xD;
      peripheral neuropathic pain, headache, psychiatric disorders, cognitive deficits, epilepsy&#xD;
      will be excluded. TDCS stimulation will be administered as above. The anode will be&#xD;
      positioned 2 cm behind the CP's defective hemisphere points. The reference electrode will be&#xD;
      positioned over the contralateral control region. Clinical evaluation will be performed&#xD;
      before and after treatment, and at a distance of 1, 2 and 4 weeks.&#xD;
&#xD;
      Aphasia Patients with flu-like and non-fluent language disorders will be enrolled, evaluated&#xD;
      by clinical scales and clinical visits. TDCS stimulation will be administered for 5&#xD;
      consecutive days, followed by 2 days of pause and subsequent 5 days of 1 mA stimulation for&#xD;
      20 minutes. The anode will be located at the Broca or Wernicke area level. The cathode will&#xD;
      be placed on the homologous counterpartical area of the anode. Logopedic therapy will be&#xD;
      coupled to true tDCS stimulation and sham. Clinical evaluation will be performed before and&#xD;
      after treatment, and at a distance of 1, 2 and 4 weeks.&#xD;
&#xD;
      Dysphagia Patients with swallowing disorders will be enrolled, evaluated by clinical scales,&#xD;
      logopedic visit, Otorhinolaryngology visit. TDCS stimulation will be administered for 5&#xD;
      consecutive days at 2 mA for 20 minutes. The anode will be positioned at the level of the&#xD;
      dominant motor cortex to control the muscles of the swallowing. The reference electrode will&#xD;
      be positioned over the contralateral control region. Logopedic therapy will be coupled to&#xD;
      true tDCS stimulation and sham. Clinical evaluation will be performed before and after&#xD;
      treatment, and at a distance of 1, 2 and 4 weeks by logopedic, neurophysiological and ORL&#xD;
      assessment.&#xD;
&#xD;
      Major Depression In the study, 15 patients with major DSM-IV depression diagnosed with proven&#xD;
      drug resistance will be enrolled. Of these, five will be submitted to rTMS of the left&#xD;
      dorsolateral prefrontal cortex (DLPFC), five at rTMS of the right DLPFC and five at sham&#xD;
      stimulation. The study will be conducted in single blind. The rTMS session will last (15)&#xD;
      consecutive days. The stimulation parameters will be: 10 Hz frequency; 100% RMT intensity;&#xD;
      Train duration 10 sec (100 stimuli); Inter-train interval 1 minute; n. Total of the terrors&#xD;
      12; Duration of a session about 13 minutes. Hamilton Depression Rating Scale will be&#xD;
      administered on the first day before stimulation, and on the last day after stimulation.&#xD;
&#xD;
      Expected results The present study aims to provide preliminary data on the benefits of&#xD;
      cortical stimulation for the recovery of various brain injury symptoms.&#xD;
&#xD;
      The expected result is that neurostimulation training potentiates the recovery of the various&#xD;
      symptoms considered in the present study, resulting in brain damage.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 22, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Patients will undergo a cerebral pacing program listed below and differentiated according to the type of symptom presented. All conventional therapies taken by patients will be recorded by the operators. Patients will be divided into Stimulation and Sham (control) groups and will be evaluated at zero time before starting treatment (T-0W) after 6 weeks to evaluate the effects at the end of treatment (T-6W) and at 12 weeks (T-12W) to evaluate the maintenance of long-term effects. Randomization will be balanced in accordance with age, sex and schooling.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Barthel's Activities of Daily Living (ADL) (O'Sullivan et al 2007)</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Abilities of daily living</description>
  </primary_outcome>
  <primary_outcome>
    <measure>FIM</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Functional Independence Measurement (FIM) (Chumney et al., 2010)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>stroke</measure>
    <time_frame>up to 3 years</time_frame>
    <description>NIH Stroke Scale / Score (NIHSS)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>disability</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Expanded Disability Status Scale (EDSS) (Kurtzke, 1983)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>parkinson</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Unified Parkinson's Disease Rating Scale (Rammer et al. )</description>
  </primary_outcome>
  <primary_outcome>
    <measure>depression</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Beck Depression Inventory (BDI) (Beck, 1972)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>neuronal plasticity</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Transcranial Magnetic Stimulation (TMS) will be used to evaluate the change of neuronal plasticity in a subgroup of patients who will not present contraindications to the method. The TMS uses short-lived magnetic fields and high intensity applied at the scalp level to activate the neurons of a small region of the cerebral cortex through an electromagnetic induction. When these impulses are applied repeatedly, it is possible to induce plastic modification of cortical excitability. If these changes are induced at the level of the motor cortex, they can be measured by recording a motor evoked potential (MEP) at the muscle level represented at the stimulated region level. Any increase or decrease in AMP amplitude, which persists after the end of TMS repetitive stimulation, indicates that there have been changes in the cortical, LTP or depression (LTD).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>posture</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Stabilometric Platform</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>locomotion</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Gait Analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>deglutition</measure>
    <time_frame>up to 3 years</time_frame>
    <description>Electrophysiological and Fiberendoscopic Deglutition Study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognition</measure>
    <time_frame>up to 3 years</time_frame>
    <description>ad-hoc task</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Brain Injuries</condition>
  <arm_group>
    <arm_group_label>real stimulation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cranial - electrical or magnetic stimulation. Stimulation will be different according to clinical conditions, as specified elsewhere.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>sham stimulation</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will be treated as in the &quot;Real stimulation&quot; arm, but no electrical or magnetic stimulation will be induced.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>non invasive brain stimulation</intervention_name>
    <description>TDCS stimulation will be administered for 5 consecutive days at 2 mA for 20 minutes.&#xD;
TMS stimulation parameters will be: 10 Hz frequency; 100% RMT intensity; Train duration 10 sec (100 stimuli); Inter-train interval 1 minute; n. Total of the terrors 12; Duration of a session about 13 minutes.</description>
    <arm_group_label>real stimulation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>sham stimulation</intervention_name>
    <description>Placebo treatment</description>
    <arm_group_label>sham stimulation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        The sample estimate was made by analogy after a literature analysis. Considering the risk&#xD;
        of abandonment quite high, our intention is to recruit at least 100 subjects in a&#xD;
        population of patients with cerebral injury who are involved in the neurological department&#xD;
        of I.R.R.C.S. Neuromed by Pozzilli, featuring the symptoms described below in the inclusion&#xD;
        criteria&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          -  Males or females aged between 18 and 80;&#xD;
&#xD;
          -  Presence of: Disinfection, Multiple Sclerosis, Depression, Sensory Disorder or&#xD;
             Neuropathic Pain;&#xD;
&#xD;
          -  Female subjects can not be pregnant, can not breastfeed, have been born at least three&#xD;
             months before the beginning of the study, undertake not to schedule a pregnancy for&#xD;
             the duration of the study;&#xD;
&#xD;
          -  Patients should be able to follow protocol guidelines throughout the study;&#xD;
&#xD;
          -  Patients should be able to understand the aims and risks of the study;&#xD;
&#xD;
          -  Signature of informed consent, approved by our Ethics Committee.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Tumors or systemic infections;&#xD;
&#xD;
          -  Patients with impaired hepatic function (ALT&gt; 3 x Upper Limit Normal (ULN), Alkaline&#xD;
             Phosphatase&gt; 2 x ULN, bilirubin tot&gt; 2 x ULN if associated with any increase in ALT or&#xD;
             alkaline phosphatase); Severe or moderate renal failure;&#xD;
&#xD;
          -  Patients with TMS or tDCS (pacemaker, intracerebral metal clip, epilepsy ...)&#xD;
&#xD;
          -  Patients with other pathologies which, according to the scientific officer's opinion,&#xD;
             prevent recruitment;&#xD;
&#xD;
          -  Patients unable to even partially understand and want.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Diego Centonze, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Neuromed</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Diego Centonze, MD</last_name>
    <phone>+39 3934444159</phone>
    <email>centonze@uniroma2.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mario Stampanoni Bassi, MD</last_name>
    <phone>+39 3460181370</phone>
    <email>mario_sb@hotmail.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>IRCCS Neuromed</name>
      <address>
        <city>Pozzilli</city>
        <state>Isernia</state>
        <zip>86077</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stefania Passarelli</last_name>
      <phone>+39 0865.915217</phone>
      <email>direzionescientifica@neuromed.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Antal A, Brepohl N, Poreisz C, Boros K, Csifcsak G, Paulus W. Transcranial direct current stimulation over somatosensory cortex decreases experimentally induced acute pain perception. Clin J Pain. 2008 Jan;24(1):56-63. doi: 10.1097/AJP.0b013e318157233b.</citation>
    <PMID>18180638</PMID>
  </reference>
  <reference>
    <citation>Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985 May 11;1(8437):1106-7. doi: 10.1016/s0140-6736(85)92413-4. No abstract available.</citation>
    <PMID>2860322</PMID>
  </reference>
  <reference>
    <citation>Baxter LR Jr. Neuroimaging studies of obsessive compulsive disorder. Psychiatr Clin North Am. 1992 Dec;15(4):871-84.</citation>
    <PMID>1461802</PMID>
  </reference>
  <reference>
    <citation>Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. Transcranial magnetic stimulation induces alterations in brain monoamines. J Neural Transm (Vienna). 1997;104(2-3):191-7. doi: 10.1007/BF01273180.</citation>
    <PMID>9203081</PMID>
  </reference>
  <reference>
    <citation>Boggio PS, Zaghi S, Lopes M, Fregni F. Modulatory effects of anodal transcranial direct current stimulation on perception and pain thresholds in healthy volunteers. Eur J Neurol. 2008 Oct;15(10):1124-30. doi: 10.1111/j.1468-1331.2008.02270.x. Epub 2008 Aug 20.</citation>
    <PMID>18717717</PMID>
  </reference>
  <reference>
    <citation>Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, Cohen LG. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology. 1997 May;48(5):1398-403. doi: 10.1212/wnl.48.5.1398.</citation>
    <PMID>9153480</PMID>
  </reference>
  <reference>
    <citation>Dieckhofer A, Waberski TD, Nitsche M, Paulus W, Buchner H, Gobbele R. Transcranial direct current stimulation applied over the somatosensory cortex - differential effect on low and high frequency SEPs. Clin Neurophysiol. 2006 Oct;117(10):2221-7. doi: 10.1016/j.clinph.2006.07.136. Epub 2006 Aug 23.</citation>
    <PMID>16931142</PMID>
  </reference>
  <reference>
    <citation>Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, Castro AW, Souza DR, Riberto M, Freedman SD, Nitsche MA, Pascual-Leone A. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain. 2006 May;122(1-2):197-209. doi: 10.1016/j.pain.2006.02.023. Epub 2006 Mar 27.</citation>
    <PMID>16564618</PMID>
  </reference>
  <reference>
    <citation>Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, Natalle L, Bravo R, Rigonatti SP, Freedman SD, Nitsche MA, Pascual-Leone A, Boggio PS. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum. 2006 Dec;54(12):3988-98. doi: 10.1002/art.22195.</citation>
    <PMID>17133529</PMID>
  </reference>
  <reference>
    <citation>George MS, Wassermann EM, Williams WA, Callahan A, Ketter TA, Basser P, Hallett M, Post RM. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995 Oct 2;6(14):1853-6. doi: 10.1097/00001756-199510020-00008.</citation>
    <PMID>8547583</PMID>
  </reference>
  <reference>
    <citation>Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus M, Wassermann EM, Post RM, Murphy DL. Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study. Am J Psychiatry. 1997 Jun;154(6):867-9. doi: 10.1176/ajp.154.6.867.</citation>
    <PMID>9167520</PMID>
  </reference>
  <reference>
    <citation>Hamdy S, Rothwell JC. Gut feelings about recovery after stroke: the organization and reorganization of human swallowing motor cortex. Trends Neurosci. 1998 Jul;21(7):278-82. doi: 10.1016/s0166-2236(97)01212-5.</citation>
    <PMID>9683316</PMID>
  </reference>
  <reference>
    <citation>Hummel F, Celnik P, Giraux P, Floel A, Wu WH, Gerloff C, Cohen LG. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005 Mar;128(Pt 3):490-9. doi: 10.1093/brain/awh369. Epub 2005 Jan 5.</citation>
    <PMID>15634731</PMID>
  </reference>
  <reference>
    <citation>Hummel F, Cohen LG. Improvement of motor function with noninvasive cortical stimulation in a patient with chronic stroke. Neurorehabil Neural Repair. 2005 Mar;19(1):14-9. doi: 10.1177/1545968304272698.</citation>
    <PMID>15673839</PMID>
  </reference>
  <reference>
    <citation>Matsunaga K, Nitsche MA, Tsuji S, Rothwell JC. Effect of transcranial DC sensorimotor cortex stimulation on somatosensory evoked potentials in humans. Clin Neurophysiol. 2004 Feb;115(2):456-60. doi: 10.1016/s1388-2457(03)00362-6.</citation>
    <PMID>14744588</PMID>
  </reference>
  <reference>
    <citation>Mori F, Codeca C, Kusayanagi H, Monteleone F, Buttari F, Fiore S, Bernardi G, Koch G, Centonze D. Effects of anodal transcranial direct current stimulation on chronic neuropathic pain in patients with multiple sclerosis. J Pain. 2010 May;11(5):436-42. doi: 10.1016/j.jpain.2009.08.011. Epub 2009 Dec 16.</citation>
    <PMID>20018567</PMID>
  </reference>
  <reference>
    <citation>Mori F, Nicoletti CG, Kusayanagi H, Foti C, Restivo DA, Marciani MG, Centonze D. Transcranial direct current stimulation ameliorates tactile sensory deficit in multiple sclerosis. Brain Stimul. 2013 Jul;6(4):654-9. doi: 10.1016/j.brs.2012.10.003. Epub 2012 Oct 27.</citation>
    <PMID>23122918</PMID>
  </reference>
  <reference>
    <citation>Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994 Aug;117 ( Pt 4):847-58. doi: 10.1093/brain/117.4.847.</citation>
    <PMID>7922470</PMID>
  </reference>
  <reference>
    <citation>Pridmore S. Substitution of rapid transcranial magnetic stimulation treatments for electroconvulsive therapy treatments in a course of electroconvulsive therapy. Depress Anxiety. 2000;12(3):118-23. doi: 10.1002/1520-6394(2000)12:33.0.CO;2-G.</citation>
    <PMID>11126185</PMID>
  </reference>
  <reference>
    <citation>Que M, Schiene K, Witte OW, Zilles K. Widespread up-regulation of N-methyl-D-aspartate receptors after focal photothrombotic lesion in rat brain. Neurosci Lett. 1999 Oct 1;273(2):77-80. doi: 10.1016/s0304-3940(99)00598-4.</citation>
    <PMID>10505620</PMID>
  </reference>
  <reference>
    <citation>Ragert P, Dinse HR, Pleger B, Wilimzig C, Frombach E, Schwenkreis P, Tegenthoff M. Combination of 5 Hz repetitive transcranial magnetic stimulation (rTMS) and tactile coactivation boosts tactile discrimination in humans. Neurosci Lett. 2003 Sep 11;348(2):105-8. doi: 10.1016/s0304-3940(03)00745-6.</citation>
    <PMID>12902029</PMID>
  </reference>
  <reference>
    <citation>Ragert P, Franzkowiak S, Schwenkreis P, Tegenthoff M, Dinse HR. Improvement of tactile perception and enhancement of cortical excitability through intermittent theta burst rTMS over human primary somatosensory cortex. Exp Brain Res. 2008 Jan;184(1):1-11. doi: 10.1007/s00221-007-1073-2. Epub 2007 Aug 7. Erratum In: Exp Brain Res. 2008 Jan;184(1):141.</citation>
    <PMID>17680239</PMID>
  </reference>
  <reference>
    <citation>Ragert P, Vandermeeren Y, Camus M, Cohen LG. Improvement of spatial tactile acuity by transcranial direct current stimulation. Clin Neurophysiol. 2008 Apr;119(4):805-11. doi: 10.1016/j.clinph.2007.12.001. Epub 2008 Jan 18.</citation>
    <PMID>18203660</PMID>
  </reference>
  <reference>
    <citation>Ridding MC, Sheean G, Rothwell JC, Inzelberg R, Kujirai T. Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry. 1995 Nov;59(5):493-8. doi: 10.1136/jnnp.59.5.493.</citation>
    <PMID>8530933</PMID>
  </reference>
  <reference>
    <citation>Rogalewski A, Breitenstein C, Nitsche MA, Paulus W, Knecht S. Transcranial direct current stimulation disrupts tactile perception. Eur J Neurosci. 2004 Jul;20(1):313-6. doi: 10.1111/j.0953-816X.2004.03450.x.</citation>
    <PMID>15245504</PMID>
  </reference>
  <reference>
    <citation>Rossini PM, Calautti C, Pauri F, Baron JC. Post-stroke plastic reorganisation in the adult brain. Lancet Neurol. 2003 Aug;2(8):493-502. doi: 10.1016/s1474-4422(03)00485-x.</citation>
    <PMID>12878437</PMID>
  </reference>
  <reference>
    <citation>Siebner HR, Tormos JM, Ceballos-Baumann AO, Auer C, Catala MD, Conrad B, Pascual-Leone A. Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp. Neurology. 1999 Feb;52(3):529-37. doi: 10.1212/wnl.52.3.529.</citation>
    <PMID>10025782</PMID>
  </reference>
  <reference>
    <citation>Siebner HR, Rothwell J. Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res. 2003 Jan;148(1):1-16. doi: 10.1007/s00221-002-1234-2. Epub 2002 Nov 5.</citation>
    <PMID>12478392</PMID>
  </reference>
  <reference>
    <citation>Speer AM, Kimbrell TA, Wassermann EM, D Repella J, Willis MW, Herscovitch P, Post RM. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry. 2000 Dec 15;48(12):1133-41. doi: 10.1016/s0006-3223(00)01065-9.</citation>
    <PMID>11137053</PMID>
  </reference>
  <reference>
    <citation>Tegenthoff M, Ragert P, Pleger B, Schwenkreis P, Forster AF, Nicolas V, Dinse HR. Improvement of tactile discrimination performance and enlargement of cortical somatosensory maps after 5 Hz rTMS. PLoS Biol. 2005 Nov;3(11):e362. doi: 10.1371/journal.pbio.0030362. Epub 2005 Oct 18.</citation>
    <PMID>16218766</PMID>
  </reference>
  <reference>
    <citation>Wassermann EM, Grafman J, Berry C, Hollnagel C, Wild K, Clark K, Hallett M. Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol. 1996 Oct;101(5):412-7.</citation>
    <PMID>8913194</PMID>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>July 13, 2017</study_first_submitted>
  <study_first_submitted_qc>July 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 25, 2017</study_first_posted>
  <last_update_submitted>October 27, 2022</last_update_submitted>
  <last_update_submitted_qc>October 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Neuromed IRCCS</investigator_affiliation>
    <investigator_full_name>Mario Stampanoni Bassi</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03228472
org study id: IRCCS_Neuromed
nct id: NCT03228472
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Non-invasive cerebral stimulation techniques have shown potential in the treatment of
      neurological disorders such as chronic pain, Parkinson's disease, neglect, aphasia, memory,
      engine deficit and epilepsy In general, non-invasive cerebral stimulation techniques have
      been shown to be able to induce changes in cortical plasticity that may last even beyond the
      end of the stimulation period. Considering this potential, there is growing interest in the
      application of these therapeutic techniques.

      Hypotheses Based on these assumptions, the underlying hypothesis behind this project is that
      the therapeutic use of cranial - electrical or magnetic stimulation - can aid the recovery of
      various brain injury symptoms.

      Specific objectives This study aims to provide preliminary data about the benefits of using
      cortical stimulation to recover various brain injury symptoms. This will be made possible
      thanks to the specific skills of a multidisciplinary team of neurologists and physiatrists,
      healthcare professionals such as physiotherapists, occupational therapists, psychologists,
      speech therapists and the support of a biomedical engineer. These professional figures are
      already available at the UCK Neurosurgery of the IRCCS Neuromed directed by the proposer and
      actively collaborate to optimize the therapeutic exercise of patients with neurological
      damage.
Introduction TMS is a non-invasive neuronal stimulation of surface areas of the brain that
      since its introduction in 1985 has been frequently used in neurology as a diagnostic and
      research tool. TMS uses magnetic fields to induce electrical currents that cross the nervous
      tissue depolarizing neurons, and reproduced motions generated are recorded as electromyograph
      potentials. TMS is able to explore the functionality of the cortical-spinal system, measure
      cortical excitability, mapcortical features, and evaluate brain modulators.

      Repetitive transcranial magnetic stimulation (rTMS) is frequently used in the experimental
      field for cortical function scans and modulation of the intrinsic cortical plasticity. In
      particular, high frequency rTMS has facilitating effects on cortico-spinal excitability and
      the low-frequency one is usually inhibitory. rTMS is a method of extreme interest for the
      possible therapeutic role in conditions of altered cerebral excitability, both psychiatric
      (schizophrenia, posttraumatic stress disorder, obsessive-compulsive disorder, major
      depression) and neurological (epilepsy , stroke, degenerative diseases). At experimental
      level, the actual stimulation is compared with an inactive stimulus called sham, which acts
      as a control condition.

      Direct Transcranial Electric Stimulation (tDCS) requires the application of weak electrical
      currents directly to the head for several minutes. These currents generate an electric field
      modulating neural activity based on the application mode. tDCS alters the rate of discharge
      of neurons. In fact, cathodic polarization applied to the motor cortex can induce a robust
      reduction in cortical excitability, while anodic polarization increases the excitability of
      the motor cortex. The short-term effects of tDCS are probably due to a change in neural
      membrane polarization. Similarly to rTMS, these changes last even after the end of
      stimulation for periods ranging from minutes to hours. Thus, tDCS can modify performance in
      many cognitive tasks.

      Non-invasive cerebral stimulation have demonstrated a potential for the treatment of
      neurological disorders such as chronic pain, Parkinson's disease, neglect, aphasia, memory,
      motor deficiency and epilepsy. In general, non-invasive brain stimulation techniques have
      shown to induce changes in cortical plasticity that may last even beyond the end of the
      stimulation period. Considering this potential, there is an increasing interest in the
      application of these techniques in the therapeutic field.

      In our study, we suggest evaluating any variations in the muscular tone of the lower limbs as
      a result of high frequency repetitive transcranial magnetic stimulation (rTMS) in patients
      with multiple sclerosis with relapsing-remitting pattern without evidence of medullary
      demyelination areas. rTMS allows modulation of intracortical excitability and can therefore
      modify the control of spinal excitability.

      Sensory disorders are frequently observed within neurological disorders and are a possible
      cause of disability. Recent studies based on non-invasive stimulation techniques have shown
      interesting results in modulation of tactile sensory functions in healthy subjects. tDCS is
      capable of inducing a plastic change in motor and somatosensory areas. Several studies have
      reported anodic tDCS stimulation that can reduce both chronic and acute pain in different
      conditions. In addition, anodic tDCS stimulation can improve the loss of tactile sensitivity
      resulting from Multiple Sclerosis.

      Most patients with Parkinson's Disease develop after several years of treatment with a number
      of clinical complications, including dyskinesias, involuntary pathological, sometimes
      frankly, dystonic movements. Pathological Long Term Potentiation (LTP) phenomena were
      observed in the stigma of parkinsonian rats that developed dyskinesias following L-dopa
      treatment. Low-frequency electric stimulation of single cells induces a reversal of enhanced
      synaptic responses, a phenomenon known as depotentiation.

      Several authors have observed that in patients with focal dystonia there is a lack of
      intracortical inhibition of controls. A pilot study examined the effects of slow rTMS on the
      motor cortex, highlighting normalization of intracortical inhibition and improving clinical
      symptoms.

      The role of TMS in the treatment of major drug-resistant depression has been amply defined.
      Some early studies demonstrated that a high-frequency focal pacing of the left-sided
      prefrontal cortex (DLPFC) induced symptom improvement, quantifiable as a reduction in the
      score to the Hamilton Depression Rating Scale, probably via an increase in the content of
      brain monoamines. Studies on cerebral blood flow have also shown an increase in activity in
      the stimulated DLPFC.

      It is now accepted that rTMS has the same efficacy, in the most potent drug-resistant
      depression, of electroconvulsive therapy, with virtually null side effects.

      Hypothesis Based on these assumptions, the underlying hypothesis behind this project is that
      the therapeutic use of cranial - electrical or magnetic stimulation - can aid the recovery of
      various brain injury symptoms.

      Specific objectives This study aims to provide preliminary data about the benefits of using
      cortical stimulation to recover various brain injury symptoms. This will be made possible
      thanks to the specific skills of a multidisciplinary team of neurologists and physiatrists,
      healthcare professionals such as physiotherapists, occupational therapists, psychologists,
      speech therapists and the support of a biomedical engineer. These professional figures are
      already available at the UCK Neurosurgery of the IRCCS Neuromed directed by the proposer and
      actively collaborate to optimize the therapeutic exercise of patients with neurological
      damage.

      Population of the study The sample estimate was made by analogy after a literature analysis.
      Considering the risk of abandonment quite high, our intention is to recruit at least 100
      subjects in a population of patients with cerebral injury who are involved in the
      neurological department of IRCCS. Neuromed in Pozzilli, featuring the symptoms described
      below in the inclusion criteria Inclusion and exclusion criteria are specified below.

      Experimental design Double-blind prospective study, between randomized, placebo-controlled
      parallel groups.

      Patients will undergo a cerebral pacing program listed below and differentiated according to
      the type of symptom presented. All conventional therapies taken by patients will be recorded
      by the operators. Patients will be divided into Stimulation and Sham (control) groups and
      will be evaluated at zero time before starting treatment (T-0W) after 6 weeks to evaluate the
      effects at the end of treatment (T-6W) and at 12 weeks (T-12W) to evaluate the maintenance of
      long-term effects. Randomization will be balanced in accordance with age, sex and schooling.

      The physiotherapy or speech therapy approach will be different between patients considering
      the different types of brain damage and the different levels of disability, according to the
      rehabilitation unit team for each case.

      Spasticity Patients will be evaluated clinically, using a clinical scale to quantify muscle
      tone in the various districts (Ashworth scale) and neurophysiologically by eliciting the H
      reflection. The electrophysiological parameters detected will be: M response, H reflex and
      its M / H ratio. Patients with spasticity to lower limbs will be enrolled in continuous
      interferon therapy and free of cortisone for at least 30 days.

      The runtime rTMS will be applied to the motor at rest (RMT) on the primary motor area for the
      lower limb, 5 Hz (excitatory) with 20 trains of 10 sec (50 train stimuli, 1000 total stimuli)
      with intertree intervals of 30 seconds (total 22 min. Ca) on the primary motor cortex for the
      lower limb and we will measure the H reflex before and after the stimulation session. The
      treatment will last 2 weeks with daily sessions.

      Dyskinesia Patients with clinically diagnosed discontinuous L-Dopa treatment history will be
      enrolled.

      They will be given rTMS for 7 consecutive days with the following stimulation parameters: 1
      Hz frequency; 90% Active Motor Threshold intensity; Train duration 899 sec (900 stimuli). At
      the end of each individual stimulation session patients will be subjected to neurological
      evaluation of the symptoms.

      Sensory Deficits Patients with reduced tactile sensitivity to upper or lower limbs will be
      enrolled. Patients with peripheral neuropathy, psychiatric disorders, cognitive deficits,
      epilepsy will be excluded. TDCS stimulation will be administered for 5 consecutive days at 2
      mA for 20 minutes. The anode will be placed 2 cm behind the C3 / C4 points of the defective
      hemisphere. The reference electrode will be positioned over the contralateral control region.
      Sham stimulation will have the same parameters. Clinical evaluation will be performed before
      and after treatment, and at a distance of 1, 2 and 4 weeks.

      Pain Patients with neuropathic pain in the upper or lower limbs, VAS score of at least 40,
      will be enrolled in the absence of analgesic treatment for at least one month. Subjects with
      peripheral neuropathic pain, headache, psychiatric disorders, cognitive deficits, epilepsy
      will be excluded. TDCS stimulation will be administered as above. The anode will be
      positioned 2 cm behind the CP's defective hemisphere points. The reference electrode will be
      positioned over the contralateral control region. Clinical evaluation will be performed
      before and after treatment, and at a distance of 1, 2 and 4 weeks.

      Aphasia Patients with flu-like and non-fluent language disorders will be enrolled, evaluated
      by clinical scales and clinical visits. TDCS stimulation will be administered for 5
      consecutive days, followed by 2 days of pause and subsequent 5 days of 1 mA stimulation for
      20 minutes. The anode will be located at the Broca or Wernicke area level. The cathode will
      be placed on the homologous counterpartical area of the anode. Logopedic therapy will be
      coupled to true tDCS stimulation and sham. Clinical evaluation will be performed before and
      after treatment, and at a distance of 1, 2 and 4 weeks.

      Dysphagia Patients with swallowing disorders will be enrolled, evaluated by clinical scales,
      logopedic visit, Otorhinolaryngology visit. TDCS stimulation will be administered for 5
      consecutive days at 2 mA for 20 minutes. The anode will be positioned at the level of the
      dominant motor cortex to control the muscles of the swallowing. The reference electrode will
      be positioned over the contralateral control region. Logopedic therapy will be coupled to
      true tDCS stimulation and sham. Clinical evaluation will be performed before and after
      treatment, and at a distance of 1, 2 and 4 weeks by logopedic, neurophysiological and ORL
      assessment.

      Major Depression In the study, 15 patients with major DSM-IV depression diagnosed with proven
      drug resistance will be enrolled. Of these, five will be submitted to rTMS of the left
      dorsolateral prefrontal cortex (DLPFC), five at rTMS of the right DLPFC and five at sham
      stimulation. The study will be conducted in single blind. The rTMS session will last (15)
      consecutive days. The stimulation parameters will be: 10 Hz frequency; 100% RMT intensity;
      Train duration 10 sec (100 stimuli); Inter-train interval 1 minute; n. Total of the terrors
      12; Duration of a session about 13 minutes. Hamilton Depression Rating Scale will be
      administered on the first day before stimulation, and on the last day after stimulation.

      Expected results The present study aims to provide preliminary data on the benefits of
      cortical stimulation for the recovery of various brain injury symptoms.

      The expected result is that neurostimulation training potentiates the recovery of the various
      symptoms considered in the present study, resulting in brain damage.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will undergo a cerebral pacing program listed below and differentiated according to the type of symptom presented. All conventional therapies taken by patients will be recorded by the operators. Patients will be divided into Stimulation and Sham (control) groups and will be evaluated at zero time before starting treatment (T-0W) after 6 weeks to evaluate the effects at the end of treatment (T-6W) and at 12 weeks (T-12W) to evaluate the maintenance of long-term effects. Randomization will be balanced in accordance with age, sex and schooling.
primary purpose: Treatment
masking: None (Open Label)
measure: Barthel's Activities of Daily Living (ADL) (O'Sullivan et al 2007)
time frame: up to 3 years
description: Abilities of daily living
measure: FIM
time frame: up to 3 years
description: Functional Independence Measurement (FIM) (Chumney et al., 2010)
measure: stroke
time frame: up to 3 years
description: NIH Stroke Scale / Score (NIHSS)
measure: disability
time frame: up to 3 years
description: Expanded Disability Status Scale (EDSS) (Kurtzke, 1983)
measure: parkinson
time frame: up to 3 years
description: Unified Parkinson's Disease Rating Scale (Rammer et al. )
measure: depression
time frame: up to 3 years
description: Beck Depression Inventory (BDI) (Beck, 1972)
measure: neuronal plasticity
time frame: up to 3 years
description: Transcranial Magnetic Stimulation (TMS) will be used to evaluate the change of neuronal plasticity in a subgroup of patients who will not present contraindications to the method. The TMS uses short-lived magnetic fields and high intensity applied at the scalp level to activate the neurons of a small region of the cerebral cortex through an electromagnetic induction. When these impulses are applied repeatedly, it is possible to induce plastic modification of cortical excitability. If these changes are induced at the level of the motor cortex, they can be measured by recording a motor evoked potential (MEP) at the muscle level represented at the stimulated region level. Any increase or decrease in AMP amplitude, which persists after the end of TMS repetitive stimulation, indicates that there have been changes in the cortical, LTP or depression (LTD).
measure: posture
time frame: up to 3 years
description: Stabilometric Platform
measure: locomotion
time frame: up to 3 years
description: Gait Analysis
measure: deglutition
time frame: up to 3 years
description: Electrophysiological and Fiberendoscopic Deglutition Study
measure: Cognition
time frame: up to 3 years
description: ad-hoc task
arm group label: real stimulation
arm group type: Experimental
description: Cranial - electrical or magnetic stimulation. Stimulation will be different according to clinical conditions, as specified elsewhere.
arm group label: sham stimulation
arm group type: Placebo Comparator
description: Patients will be treated as in the "Real stimulation" arm, but no electrical or magnetic stimulation will be induced.
intervention type: Device
intervention name: non invasive brain stimulation
description: TDCS stimulation will be administered for 5 consecutive days at 2 mA for 20 minutes.
TMS stimulation parameters will be: 10 Hz frequency; 100% RMT intensity; Train duration 10 sec (100 stimuli); Inter-train interval 1 minute; n. Total of the terrors 12; Duration of a session about 13 minutes.
arm group label: real stimulation
intervention type: Device
intervention name: sham stimulation
description: Placebo treatment
arm group label: sham stimulation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Diego Centonze, MD
role: Principal Investigator
affiliation: IRCCS Neuromed
last name: Diego Centonze, MD
phone: +39 3934444159
email: centonze@uniroma2.it
last name: Mario Stampanoni Bassi, MD
phone: +39 3460181370
email: mario_sb@hotmail.it
facility: 
status: Recruiting
contact: 
country: Italy
citation: Antal A, Brepohl N, Poreisz C, Boros K, Csifcsak G, Paulus W. Transcranial direct current stimulation over somatosensory cortex decreases experimentally induced acute pain perception. Clin J Pain. 2008 Jan;24(1):56-63. doi: 10.1097/AJP.0b013e318157233b.
PMID: 18180638
citation: Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985 May 11;1(8437):1106-7. doi: 10.1016/s0140-6736(85)92413-4. No abstract available.
PMID: 2860322
citation: Baxter LR Jr. Neuroimaging studies of obsessive compulsive disorder. Psychiatr Clin North Am. 1992 Dec;15(4):871-84.
PMID: 1461802
citation: Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. Transcranial magnetic stimulation induces alterations in brain monoamines. J Neural Transm (Vienna). 1997;104(2-3):191-7. doi: 10.1007/BF01273180.
PMID: 9203081
citation: Boggio PS, Zaghi S, Lopes M, Fregni F. Modulatory effects of anodal transcranial direct current stimulation on perception and pain thresholds in healthy volunteers. Eur J Neurol. 2008 Oct;15(10):1124-30. doi: 10.1111/j.1468-1331.2008.02270.x. Epub 2008 Aug 20.
PMID: 18717717
citation: Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, Cohen LG. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology. 1997 May;48(5):1398-403. doi: 10.1212/wnl.48.5.1398.
PMID: 9153480
citation: Dieckhofer A, Waberski TD, Nitsche M, Paulus W, Buchner H, Gobbele R. Transcranial direct current stimulation applied over the somatosensory cortex - differential effect on low and high frequency SEPs. Clin Neurophysiol. 2006 Oct;117(10):2221-7. doi: 10.1016/j.clinph.2006.07.136. Epub 2006 Aug 23.
PMID: 16931142
citation: Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, Castro AW, Souza DR, Riberto M, Freedman SD, Nitsche MA, Pascual-Leone A. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain. 2006 May;122(1-2):197-209. doi: 10.1016/j.pain.2006.02.023. Epub 2006 Mar 27.
PMID: 16564618
citation: Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, Natalle L, Bravo R, Rigonatti SP, Freedman SD, Nitsche MA, Pascual-Leone A, Boggio PS. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum. 2006 Dec;54(12):3988-98. doi: 10.1002/art.22195.
PMID: 17133529
citation: George MS, Wassermann EM, Williams WA, Callahan A, Ketter TA, Basser P, Hallett M, Post RM. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995 Oct 2;6(14):1853-6. doi: 10.1097/00001756-199510020-00008.
PMID: 8547583
citation: Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus M, Wassermann EM, Post RM, Murphy DL. Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study. Am J Psychiatry. 1997 Jun;154(6):867-9. doi: 10.1176/ajp.154.6.867.
PMID: 9167520
citation: Hamdy S, Rothwell JC. Gut feelings about recovery after stroke: the organization and reorganization of human swallowing motor cortex. Trends Neurosci. 1998 Jul;21(7):278-82. doi: 10.1016/s0166-2236(97)01212-5.
PMID: 9683316
citation: Hummel F, Celnik P, Giraux P, Floel A, Wu WH, Gerloff C, Cohen LG. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005 Mar;128(Pt 3):490-9. doi: 10.1093/brain/awh369. Epub 2005 Jan 5.
PMID: 15634731
citation: Hummel F, Cohen LG. Improvement of motor function with noninvasive cortical stimulation in a patient with chronic stroke. Neurorehabil Neural Repair. 2005 Mar;19(1):14-9. doi: 10.1177/1545968304272698.
PMID: 15673839
citation: Matsunaga K, Nitsche MA, Tsuji S, Rothwell JC. Effect of transcranial DC sensorimotor cortex stimulation on somatosensory evoked potentials in humans. Clin Neurophysiol. 2004 Feb;115(2):456-60. doi: 10.1016/s1388-2457(03)00362-6.
PMID: 14744588
citation: Mori F, Codeca C, Kusayanagi H, Monteleone F, Buttari F, Fiore S, Bernardi G, Koch G, Centonze D. Effects of anodal transcranial direct current stimulation on chronic neuropathic pain in patients with multiple sclerosis. J Pain. 2010 May;11(5):436-42. doi: 10.1016/j.jpain.2009.08.011. Epub 2009 Dec 16.
PMID: 20018567
citation: Mori F, Nicoletti CG, Kusayanagi H, Foti C, Restivo DA, Marciani MG, Centonze D. Transcranial direct current stimulation ameliorates tactile sensory deficit in multiple sclerosis. Brain Stimul. 2013 Jul;6(4):654-9. doi: 10.1016/j.brs.2012.10.003. Epub 2012 Oct 27.
PMID: 23122918
citation: Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994 Aug;117 ( Pt 4):847-58. doi: 10.1093/brain/117.4.847.
PMID: 7922470
citation: Pridmore S. Substitution of rapid transcranial magnetic stimulation treatments for electroconvulsive therapy treatments in a course of electroconvulsive therapy. Depress Anxiety. 2000;12(3):118-23. doi: 10.1002/1520-6394(2000)12:33.0.CO;2-G.
PMID: 11126185
citation: Que M, Schiene K, Witte OW, Zilles K. Widespread up-regulation of N-methyl-D-aspartate receptors after focal photothrombotic lesion in rat brain. Neurosci Lett. 1999 Oct 1;273(2):77-80. doi: 10.1016/s0304-3940(99)00598-4.
PMID: 10505620
citation: Ragert P, Dinse HR, Pleger B, Wilimzig C, Frombach E, Schwenkreis P, Tegenthoff M. Combination of 5 Hz repetitive transcranial magnetic stimulation (rTMS) and tactile coactivation boosts tactile discrimination in humans. Neurosci Lett. 2003 Sep 11;348(2):105-8. doi: 10.1016/s0304-3940(03)00745-6.
PMID: 12902029
citation: Ragert P, Franzkowiak S, Schwenkreis P, Tegenthoff M, Dinse HR. Improvement of tactile perception and enhancement of cortical excitability through intermittent theta burst rTMS over human primary somatosensory cortex. Exp Brain Res. 2008 Jan;184(1):1-11. doi: 10.1007/s00221-007-1073-2. Epub 2007 Aug 7. Erratum In: Exp Brain Res. 2008 Jan;184(1):141.
PMID: 17680239
citation: Ragert P, Vandermeeren Y, Camus M, Cohen LG. Improvement of spatial tactile acuity by transcranial direct current stimulation. Clin Neurophysiol. 2008 Apr;119(4):805-11. doi: 10.1016/j.clinph.2007.12.001. Epub 2008 Jan 18.
PMID: 18203660
citation: Ridding MC, Sheean G, Rothwell JC, Inzelberg R, Kujirai T. Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry. 1995 Nov;59(5):493-8. doi: 10.1136/jnnp.59.5.493.
PMID: 8530933
citation: Rogalewski A, Breitenstein C, Nitsche MA, Paulus W, Knecht S. Transcranial direct current stimulation disrupts tactile perception. Eur J Neurosci. 2004 Jul;20(1):313-6. doi: 10.1111/j.0953-816X.2004.03450.x.
PMID: 15245504
citation: Rossini PM, Calautti C, Pauri F, Baron JC. Post-stroke plastic reorganisation in the adult brain. Lancet Neurol. 2003 Aug;2(8):493-502. doi: 10.1016/s1474-4422(03)00485-x.
PMID: 12878437
citation: Siebner HR, Tormos JM, Ceballos-Baumann AO, Auer C, Catala MD, Conrad B, Pascual-Leone A. Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp. Neurology. 1999 Feb;52(3):529-37. doi: 10.1212/wnl.52.3.529.
PMID: 10025782
citation: Siebner HR, Rothwell J. Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res. 2003 Jan;148(1):1-16. doi: 10.1007/s00221-002-1234-2. Epub 2002 Nov 5.
PMID: 12478392
citation: Speer AM, Kimbrell TA, Wassermann EM, D Repella J, Willis MW, Herscovitch P, Post RM. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry. 2000 Dec 15;48(12):1133-41. doi: 10.1016/s0006-3223(00)01065-9.
PMID: 11137053
citation: Tegenthoff M, Ragert P, Pleger B, Schwenkreis P, Forster AF, Nicolas V, Dinse HR. Improvement of tactile discrimination performance and enlargement of cortical somatosensory maps after 5 Hz rTMS. PLoS Biol. 2005 Nov;3(11):e362. doi: 10.1371/journal.pbio.0030362. Epub 2005 Oct 18.
PMID: 16218766
citation: Wassermann EM, Grafman J, Berry C, Hollnagel C, Wild K, Clark K, Hallett M. Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol. 1996 Oct;101(5):412-7.
PMID: 8913194
responsible party type: Principal Investigator
investigator affiliation: Neuromed IRCCS
investigator full name: Mario Stampanoni Bassi
investigator title: Principal Investigator
mesh term: Brain Injuries
sharing ipd: No