<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/NCT03274947</url>
  </required_header>
  <id_info>
    <org_study_id>5111 protocol ver1</org_study_id>
    <nct_id>NCT03274947</nct_id>
  </id_info>
  <brief_title>The Utility of Cerebellar Transcranial Magnetic Stimulation in the Neurorehabilitation of Dysphagia After Stroke</brief_title>
  <official_title>An Exploration of the Application of Non-invasive Cerebellar Stimulation in the Neurorehabilitation of Dysphagia After Stroke</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Manchester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medical Research Council</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Nottingham</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Manchester</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study is designed to explore the effectiveness of non-invasive cerebellar stimulation to&#xD;
      enhance motor plasticity in the cortex after stroke. The investigators have shown that the&#xD;
      human cerebellum is strongly activated during the act of swallowing and when stimulated with&#xD;
      single TMS pulses can strongly facilitate the corticobulbar projection to the pharynx in&#xD;
      humans. More recently the investigators have identified the most relevant frequency of&#xD;
      stimulation of the cerebellum that can produce longer term excitation in the human swallowing&#xD;
      motor system. The investigators therefore believe that the potential for cerebellar&#xD;
      stimulation in improving swallowing is much greater than other methods for two reasons.&#xD;
      Firstly, previous work has shown that unlike successful recovery of hand/arm function which&#xD;
      relies on restoring activity in the stroke hemisphere, recovery of swallowing function relies&#xD;
      on increased excitability in intact projections from the non-stroke hemisphere. The&#xD;
      investigators believe that methods that can enhance these undamaged pathways have a greater&#xD;
      chance of inducing recovery in the human swallowing system in unilateral stroke. Additionally&#xD;
      cerebellar stimulation produces very high levels of corticobulbar excitation it may also have&#xD;
      the advantage of improving dysphagia in posterior fossa strokes. Second, the human cerebellum&#xD;
      is relatively easy to target and stimulate and has reduced risk of inducing unwanted effects&#xD;
      (such as seizures) which as a consequence makes cerebellar stimulation a more pragmatic&#xD;
      method for delivering therapeutic neurorehabilitation to dysphagic stroke patients compared&#xD;
      to other more complex/riskier methods.&#xD;
&#xD;
      A final factor is that the investigators have developed a &quot;virtual lesion&quot; model of&#xD;
      swallowing dysfunction in healthy volunteers which can be reversed quite successfully with&#xD;
      other neuro-stimulation protocols. The investigators can therefore use this model to test the&#xD;
      effectiveness of cerebellar stimulation protocols (ipsilateral and contralateral cerebellar&#xD;
      sites) before choosing the most effective side to apply stimulation in a proof of principle&#xD;
      trial/study in a small group of sub-acute dysphagic patients.&#xD;
&#xD;
      The hypotheses are that cerebellar TMS will:&#xD;
&#xD;
      i. Reverse the brain inhibition and behavioural dysfunction following a virtual lesion model&#xD;
      of disrupted swallowing in healthy brain (phase 1); ii. Reduce the degree of aspiration in&#xD;
      acute dysphagia after a stroke (phase 2).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Protocols:&#xD;
&#xD;
      Hypothesis 1:&#xD;
&#xD;
      Cortical excitability (in both dominant and non-dominant swallowing cortex) to TMS and&#xD;
      swallowing behaviour assessed with a swallowing reaction time task will be measured at&#xD;
      baseline. Thereafter, the virtual lesion paradigm will be applied to the dominant swallowing&#xD;
      projection followed by the cerebellar intervention (10Hz, 250 pulses). Cerebellar stimulation&#xD;
      will be applied (in a randomised fashion) on separate occasions to both the contralateral and&#xD;
      ipsilateral cerebellar hemispheres, immediately after the virtual lesion. The investigators&#xD;
      have found that placement using known reference landmarks are equivalent to using&#xD;
      neuronavigation, so the latter will not be employed. Repeat measurements of cortical&#xD;
      excitability and swallowing behaviour will then be performed and analysed against baseline&#xD;
      data and a sham cerebellar paradigm. Differences in cortical excitability and swallowing&#xD;
      responses will thus be an indication of which cerebellar region (contralesional/ipsilesional)&#xD;
      can influence excitability and reverse any behavioural changes most effectively.&#xD;
&#xD;
      Hypothesis 2:&#xD;
&#xD;
      I. Dysphagic stroke patients (n=24) recruited over a 9 month period within 14 days of stroke&#xD;
      ictus will have their swallowing assessed by videofluoroscopy before and after receiving&#xD;
      either the real or sham cerebellar stimulation (10Hz, 250 pulses) as determined from phase 1.&#xD;
      As before, placement of the coil for cerebellar stimulation will be performed using landmarks&#xD;
      already established and validated in the work from question 1. Patients will be intubated&#xD;
      with the pharyngeal EMG catheter for pre and post recordings of pharyngeal motor evoked&#xD;
      potentials (MEPs) to cortical TMS. Power calculations, based on a similar study of pharyngeal&#xD;
      stimulation indicated that the investigators would need 12 patients per group to achieve a&#xD;
      statistical power of 80% at a 5% significance level to detect changes in the primary outcome&#xD;
      measure of aspiration. In this study, the investigators will examine if the chosen site of&#xD;
      cerebellar stimulation from phase 1 can induce short-term changes in brain function&#xD;
      (pharyngeal MEPs) and swallowing function (videofluoroscopy) compared to sham interventions&#xD;
      and baseline measurement, up to 1 hour after the intervention.&#xD;
&#xD;
      II. Following stage I, once it is established that cerebellar stimulation can alter brain and&#xD;
      swallowing functions in stroke in the short-term, it will need to be appraised for clinical&#xD;
      feasibility, dose response, and longer term efficacy. Dysphagic stroke patients (n=48, 16&#xD;
      patients per group) admitted to the stroke unit and identified by videofluoroscopy will be&#xD;
      recruited over the next 21 months. Since it is not known how the cerebellar stimulation&#xD;
      method should be delivered to patients, a dose ranging treatment trial will be utilised,&#xD;
      randomising patients to one of three groups (A-C), low level stimulation, high level&#xD;
      stimulation and sham stimulation. From our previous work with pharyngeal stimulation, the&#xD;
      investigators propose that group A will receive stimulation once per day for 3 days. Group B&#xD;
      will receive stimulation twice per day for 5 days. Group C will receive sham stimulation&#xD;
      (delivered as in protocol I) twice a day for 5 days. Groups A and B will receive stimulation&#xD;
      at the optimal site (10Hz, 250 pulses) found in question 1, but all groups will also receive&#xD;
      standard speech and language therapy.&#xD;
&#xD;
      Assessments:&#xD;
&#xD;
      Swallowing before and after stimulation will be evaluated using videofluoroscopy, at 1 hour&#xD;
      for protocol I. For protocol II the investigators propose both videofluoroscopy and&#xD;
      functional scores (Functional oral ingestion scale (FOIS), the dysphagia severity rating&#xD;
      scale (DSRS) including feeding status and modified rankin scale (mRS)) at baseline and at 2&#xD;
      weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 14, 2019</start_date>
  <completion_date type="Actual">October 31, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2022</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Penetration aspiration scores on videofluoroscopy (number of swallows out of 6 that score 3 or more on the penetration aspiration scale) (Hypothesis 2 protocols 1 and 2)</measure>
    <time_frame>1 hour post intervention and 2 weeks post intervention</time_frame>
    <description>Penetration aspiration scores on videofluoroscopy (number of swallows out of 6 that score 3 or more on the penetration aspiration scale)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement of: Functional oral ingestion scale (FOIS) and or the dysphagia severity rating scale (DSRS) (Hypothesis 2 protocol 2)</measure>
    <time_frame>2 weeks post intervention</time_frame>
    <description>Improvement of: Functional oral ingestion scale (FOIS) and or the dysphagia severity rating scale (DSRS)</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Oropharyngeal Dysphagia</condition>
  <condition>Stroke</condition>
  <arm_group>
    <arm_group_label>Hypothesis 2 Protocol 2 Low dose TMS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Low level cerebellar TMS. Delivered once per day for 3 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hypothesis 2 Protocol 2 High dose TMS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>High level cerebellar TMS. Delivered twice per day for 5 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hypothesis 2 Protocol 2 Sham</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham cerebellar TMS. Delivered twice a day for 5 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hypothesis 2 Protocol 1 Cerebellar TMS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cerebellar TMS at 10Hz, 250 pulses.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hypothesis 2 Protocol 1 Sham</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham cerebellar TMS</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Cerebellar TMS</intervention_name>
    <description>Cerebellar transcranial magnetic stimulation</description>
    <arm_group_label>Hypothesis 2 Protocol 1 Cerebellar TMS</arm_group_label>
    <arm_group_label>Hypothesis 2 Protocol 2 High dose TMS</arm_group_label>
    <arm_group_label>Hypothesis 2 Protocol 2 Low dose TMS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham cerebellar TMS</intervention_name>
    <description>Sham cerebellar transcranial magnetic stimulation</description>
    <arm_group_label>Hypothesis 2 Protocol 1 Sham</arm_group_label>
    <arm_group_label>Hypothesis 2 Protocol 2 Sham</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients aged 18 years and over&#xD;
&#xD;
          -  All patients with an acute anterior or posterior cerebral circulation stroke within 6&#xD;
             weeks of symptom onset.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Advanced dementia&#xD;
&#xD;
          -  Previous history of dysphagia&#xD;
&#xD;
          -  Patients judged to be clinically unstable&#xD;
&#xD;
          -  Presence of implanted cardiac pacemaker or defibrillator&#xD;
&#xD;
          -  Any severe chronic medical condition that compromises cardiac or respiratory status&#xD;
&#xD;
          -  Patients with acute lower respiratory tract infections requiring antibiotic treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shaheen Hamdy, MBChB, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Manchester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Upper G.I laboratory, Salford Royal Hospital</name>
      <address>
        <city>Manchester</city>
        <state>Greater Manchester</state>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stroke Unit, Nottingham University Hospitals</name>
      <address>
        <city>Nottingham</city>
        <state>Notthinghamshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Smithard DG, O'Neill PA, Parks C, Morris J. Complications and outcome after acute stroke. Does dysphagia matter? Stroke. 1996 Jul;27(7):1200-4. doi: 10.1161/01.str.27.7.1200. Erratum In: Stroke 1998 Jul;29(7):1480-1.</citation>
    <PMID>8685928</PMID>
  </reference>
  <reference>
    <citation>Geeganage C, Beavan J, Ellender S, Bath PM. Interventions for dysphagia and nutritional support in acute and subacute stroke. Cochrane Database Syst Rev. 2012 Oct 17;10:CD000323. doi: 10.1002/14651858.CD000323.pub2.</citation>
    <PMID>23076886</PMID>
  </reference>
  <reference>
    <citation>Finucane TE, Bynum JP. Use of tube feeding to prevent aspiration pneumonia. Lancet. 1996 Nov 23;348(9039):1421-4. doi: 10.1016/S0140-6736(96)03369-7. No abstract available. Erratum In: Lancet 1997 Feb 1;349(9048):364.</citation>
    <PMID>8937283</PMID>
  </reference>
  <reference>
    <citation>Machado AG, Baker KB, Schuster D, Butler RS, Rezai A. Chronic electrical stimulation of the contralesional lateral cerebellar nucleus enhances recovery of motor function after cerebral ischemia in rats. Brain Res. 2009 Jul 14;1280:107-16. doi: 10.1016/j.brainres.2009.05.007. Epub 2009 May 12.</citation>
    <PMID>19445910</PMID>
  </reference>
  <reference>
    <citation>Park HJ, Furmaga H, Cooperrider J, Gale JT, Baker KB, Machado AG. Modulation of Cortical Motor Evoked Potential After Stroke During Electrical Stimulation of the Lateral Cerebellar Nucleus. Brain Stimul. 2015 Nov-Dec;8(6):1043-8. doi: 10.1016/j.brs.2015.06.020. Epub 2015 Jul 8.</citation>
    <PMID>26215752</PMID>
  </reference>
  <reference>
    <citation>Hamdy S, Rothwell JC, Brooks DJ, Bailey D, Aziz Q, Thompson DG. Identification of the cerebral loci processing human swallowing with H2(15)O PET activation. J Neurophysiol. 1999 Apr;81(4):1917-26. doi: 10.1152/jn.1999.81.4.1917.</citation>
    <PMID>10200226</PMID>
  </reference>
  <reference>
    <citation>Jayasekeran V, Rothwell J, Hamdy S. Non-invasive magnetic stimulation of the human cerebellum facilitates cortico-bulbar projections in the swallowing motor system. Neurogastroenterol Motil. 2011 Sep;23(9):831-e341. doi: 10.1111/j.1365-2982.2011.01747.x.</citation>
    <PMID>21838728</PMID>
  </reference>
  <reference>
    <citation>Vasant DH, Michou E, Mistry S, Rothwell JC, Hamdy S. High-frequency focal repetitive cerebellar stimulation induces prolonged increases in human pharyngeal motor cortex excitability. J Physiol. 2015 Nov 15;593(22):4963-77. doi: 10.1113/JP270817. Epub 2015 Sep 30.</citation>
    <PMID>26316351</PMID>
  </reference>
  <reference>
    <citation>Mistry S, Verin E, Singh S, Jefferson S, Rothwell JC, Thompson DG, Hamdy S. Unilateral suppression of pharyngeal motor cortex to repetitive transcranial magnetic stimulation reveals functional asymmetry in the hemispheric projections to human swallowing. J Physiol. 2007 Dec 1;585(Pt 2):525-38. doi: 10.1113/jphysiol.2007.144592. Epub 2007 Oct 11.</citation>
    <PMID>17932140</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>Hamdy S, Aziz Q, Rothwell JC, Singh KD, Barlow J, Hughes DG, Tallis RC, Thompson DG. The cortical topography of human swallowing musculature in health and disease. Nat Med. 1996 Nov;2(11):1217-24. doi: 10.1038/nm1196-1217.</citation>
    <PMID>8898748</PMID>
  </reference>
  <reference>
    <citation>Hamdy S, Mikulis DJ, Crawley A, Xue S, Lau H, Henry S, Diamant NE. Cortical activation during human volitional swallowing: an event-related fMRI study. Am J Physiol. 1999 Jul;277(1):G219-25. doi: 10.1152/ajpgi.1999.277.1.G219.</citation>
    <PMID>10409170</PMID>
  </reference>
  <reference>
    <citation>Hamdy S, Aziz Q, Rothwell JC, Power M, Singh KD, Nicholson DA, Tallis RC, Thompson DG. Recovery of swallowing after dysphagic stroke relates to functional reorganization in the intact motor cortex. Gastroenterology. 1998 Nov;115(5):1104-12. doi: 10.1016/s0016-5085(98)70081-2.</citation>
    <PMID>9797365</PMID>
  </reference>
  <reference>
    <citation>Hamdy S, Rothwell JC, Aziz Q, Singh KD, Thompson DG. Long-term reorganization of human motor cortex driven by short-term sensory stimulation. Nat Neurosci. 1998 May;1(1):64-8. doi: 10.1038/264.</citation>
    <PMID>10195111</PMID>
  </reference>
  <reference>
    <citation>Fraser C, Power M, Hamdy S, Rothwell J, Hobday D, Hollander I, Tyrell P, Hobson A, Williams S, Thompson D. Driving plasticity in human adult motor cortex is associated with improved motor function after brain injury. Neuron. 2002 May 30;34(5):831-40. doi: 10.1016/s0896-6273(02)00705-5.</citation>
    <PMID>12062028</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>Gow D, Rothwell J, Hobson A, Thompson D, Hamdy S. Induction of long-term plasticity in human swallowing motor cortex following repetitive cortical stimulation. Clin Neurophysiol. 2004 May;115(5):1044-51. doi: 10.1016/j.clinph.2003.12.001.</citation>
    <PMID>15066528</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>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>Jefferson S, Mistry S, Michou E, Singh S, Rothwell JC, Hamdy S. Reversal of a virtual lesion in human pharyngeal motor cortex by high frequency contralesional brain stimulation. Gastroenterology. 2009 Sep;137(3):841-9, 849.e1. doi: 10.1053/j.gastro.2009.04.056. Epub 2009 May 7.</citation>
    <PMID>19427312</PMID>
  </reference>
  <reference>
    <citation>Jayasekeran V, Singh S, Tyrrell P, Michou E, Jefferson S, Mistry S, Gamble E, Rothwell J, Thompson D, Hamdy S. Adjunctive functional pharyngeal electrical stimulation reverses swallowing disability after brain lesions. Gastroenterology. 2010 May;138(5):1737-46. doi: 10.1053/j.gastro.2010.01.052. Epub 2010 Feb 2.</citation>
    <PMID>20138037</PMID>
  </reference>
  <reference>
    <citation>Vasant DH, Mistry S, Michou E, Jefferson S, Rothwell JC, Hamdy S. Transcranial direct current stimulation reverses neurophysiological and behavioural effects of focal inhibition of human pharyngeal motor cortex on swallowing. J Physiol. 2014 Feb 15;592(4):695-709. doi: 10.1113/jphysiol.2013.263475. Epub 2013 Nov 18.</citation>
    <PMID>24247983</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>August 14, 2017</study_first_submitted>
  <study_first_submitted_qc>September 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 7, 2017</study_first_posted>
  <last_update_submitted>November 30, 2022</last_update_submitted>
  <last_update_submitted_qc>November 30, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Manchester</investigator_affiliation>
    <investigator_full_name>Prof Shaheen Hamdy PhD FRCP</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Oropharyngeal Dysphagia</keyword>
  <keyword>Stroke</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Deglutition Disorders</mesh_term>
    <mesh_term>Stroke</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No identifiable individual participant information will be shared outside the immediate research team. However, identifiable individual participant information will be made available to the Medical research council and the University of Manchester if required for the purposes of auditing the study.</ipd_description>
  </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/NCT03274947
org study id: 5111 protocol ver1
nct id: NCT03274947
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The study is designed to explore the effectiveness of non-invasive cerebellar stimulation to
      enhance motor plasticity in the cortex after stroke. The investigators have shown that the
      human cerebellum is strongly activated during the act of swallowing and when stimulated with
      single TMS pulses can strongly facilitate the corticobulbar projection to the pharynx in
      humans. More recently the investigators have identified the most relevant frequency of
      stimulation of the cerebellum that can produce longer term excitation in the human swallowing
      motor system. The investigators therefore believe that the potential for cerebellar
      stimulation in improving swallowing is much greater than other methods for two reasons.
      Firstly, previous work has shown that unlike successful recovery of hand/arm function which
      relies on restoring activity in the stroke hemisphere, recovery of swallowing function relies
      on increased excitability in intact projections from the non-stroke hemisphere. The
      investigators believe that methods that can enhance these undamaged pathways have a greater
      chance of inducing recovery in the human swallowing system in unilateral stroke. Additionally
      cerebellar stimulation produces very high levels of corticobulbar excitation it may also have
      the advantage of improving dysphagia in posterior fossa strokes. Second, the human cerebellum
      is relatively easy to target and stimulate and has reduced risk of inducing unwanted effects
      (such as seizures) which as a consequence makes cerebellar stimulation a more pragmatic
      method for delivering therapeutic neurorehabilitation to dysphagic stroke patients compared
      to other more complex/riskier methods.

      A final factor is that the investigators have developed a "virtual lesion" model of
      swallowing dysfunction in healthy volunteers which can be reversed quite successfully with
      other neuro-stimulation protocols. The investigators can therefore use this model to test the
      effectiveness of cerebellar stimulation protocols (ipsilateral and contralateral cerebellar
      sites) before choosing the most effective side to apply stimulation in a proof of principle
      trial/study in a small group of sub-acute dysphagic patients.

      The hypotheses are that cerebellar TMS will:

      i. Reverse the brain inhibition and behavioural dysfunction following a virtual lesion model
      of disrupted swallowing in healthy brain (phase 1); ii. Reduce the degree of aspiration in
      acute dysphagia after a stroke (phase 2).
Protocols:

      Hypothesis 1:

      Cortical excitability (in both dominant and non-dominant swallowing cortex) to TMS and
      swallowing behaviour assessed with a swallowing reaction time task will be measured at
      baseline. Thereafter, the virtual lesion paradigm will be applied to the dominant swallowing
      projection followed by the cerebellar intervention (10Hz, 250 pulses). Cerebellar stimulation
      will be applied (in a randomised fashion) on separate occasions to both the contralateral and
      ipsilateral cerebellar hemispheres, immediately after the virtual lesion. The investigators
      have found that placement using known reference landmarks are equivalent to using
      neuronavigation, so the latter will not be employed. Repeat measurements of cortical
      excitability and swallowing behaviour will then be performed and analysed against baseline
      data and a sham cerebellar paradigm. Differences in cortical excitability and swallowing
      responses will thus be an indication of which cerebellar region (contralesional/ipsilesional)
      can influence excitability and reverse any behavioural changes most effectively.

      Hypothesis 2:

      I. Dysphagic stroke patients (n=24) recruited over a 9 month period within 14 days of stroke
      ictus will have their swallowing assessed by videofluoroscopy before and after receiving
      either the real or sham cerebellar stimulation (10Hz, 250 pulses) as determined from phase 1.
      As before, placement of the coil for cerebellar stimulation will be performed using landmarks
      already established and validated in the work from question 1. Patients will be intubated
      with the pharyngeal EMG catheter for pre and post recordings of pharyngeal motor evoked
      potentials (MEPs) to cortical TMS. Power calculations, based on a similar study of pharyngeal
      stimulation indicated that the investigators would need 12 patients per group to achieve a
      statistical power of 80% at a 5% significance level to detect changes in the primary outcome
      measure of aspiration. In this study, the investigators will examine if the chosen site of
      cerebellar stimulation from phase 1 can induce short-term changes in brain function
      (pharyngeal MEPs) and swallowing function (videofluoroscopy) compared to sham interventions
      and baseline measurement, up to 1 hour after the intervention.

      II. Following stage I, once it is established that cerebellar stimulation can alter brain and
      swallowing functions in stroke in the short-term, it will need to be appraised for clinical
      feasibility, dose response, and longer term efficacy. Dysphagic stroke patients (n=48, 16
      patients per group) admitted to the stroke unit and identified by videofluoroscopy will be
      recruited over the next 21 months. Since it is not known how the cerebellar stimulation
      method should be delivered to patients, a dose ranging treatment trial will be utilised,
      randomising patients to one of three groups (A-C), low level stimulation, high level
      stimulation and sham stimulation. From our previous work with pharyngeal stimulation, the
      investigators propose that group A will receive stimulation once per day for 3 days. Group B
      will receive stimulation twice per day for 5 days. Group C will receive sham stimulation
      (delivered as in protocol I) twice a day for 5 days. Groups A and B will receive stimulation
      at the optimal site (10Hz, 250 pulses) found in question 1, but all groups will also receive
      standard speech and language therapy.

      Assessments:

      Swallowing before and after stimulation will be evaluated using videofluoroscopy, at 1 hour
      for protocol I. For protocol II the investigators propose both videofluoroscopy and
      functional scores (Functional oral ingestion scale (FOIS), the dysphagia severity rating
      scale (DSRS) including feeding status and modified rankin scale (mRS)) at baseline and at 2
      weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Penetration aspiration scores on videofluoroscopy (number of swallows out of 6 that score 3 or more on the penetration aspiration scale) (Hypothesis 2 protocols 1 and 2)
time frame: 1 hour post intervention and 2 weeks post intervention
description: Penetration aspiration scores on videofluoroscopy (number of swallows out of 6 that score 3 or more on the penetration aspiration scale)
measure: Improvement of: Functional oral ingestion scale (FOIS) and or the dysphagia severity rating scale (DSRS) (Hypothesis 2 protocol 2)
time frame: 2 weeks post intervention
description: Improvement of: Functional oral ingestion scale (FOIS) and or the dysphagia severity rating scale (DSRS)
arm group label: Hypothesis 2 Protocol 2 Low dose TMS
arm group type: Active Comparator
description: Low level cerebellar TMS. Delivered once per day for 3 days.
arm group label: Hypothesis 2 Protocol 2 High dose TMS
arm group type: Active Comparator
description: High level cerebellar TMS. Delivered twice per day for 5 days.
arm group label: Hypothesis 2 Protocol 2 Sham
arm group type: Sham Comparator
description: Sham cerebellar TMS. Delivered twice a day for 5 days.
arm group label: Hypothesis 2 Protocol 1 Cerebellar TMS
arm group type: Active Comparator
description: Cerebellar TMS at 10Hz, 250 pulses.
arm group label: Hypothesis 2 Protocol 1 Sham
arm group type: Sham Comparator
description: Sham cerebellar TMS
intervention type: Device
intervention name: Cerebellar TMS
description: Cerebellar transcranial magnetic stimulation
arm group label: Hypothesis 2 Protocol 1 Cerebellar TMS
arm group label: Hypothesis 2 Protocol 2 High dose TMS
arm group label: Hypothesis 2 Protocol 2 Low dose TMS
intervention type: Device
intervention name: Sham cerebellar TMS
description: Sham cerebellar transcranial magnetic stimulation
arm group label: Hypothesis 2 Protocol 1 Sham
arm group label: Hypothesis 2 Protocol 2 Sham
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Shaheen Hamdy, MBChB, PhD
role: Principal Investigator
affiliation: University of Manchester
facility: 
facility: 
country: United Kingdom
citation: Smithard DG, O'Neill PA, Parks C, Morris J. Complications and outcome after acute stroke. Does dysphagia matter? Stroke. 1996 Jul;27(7):1200-4. doi: 10.1161/01.str.27.7.1200. Erratum In: Stroke 1998 Jul;29(7):1480-1.
PMID: 8685928
citation: Geeganage C, Beavan J, Ellender S, Bath PM. Interventions for dysphagia and nutritional support in acute and subacute stroke. Cochrane Database Syst Rev. 2012 Oct 17;10:CD000323. doi: 10.1002/14651858.CD000323.pub2.
PMID: 23076886
citation: Finucane TE, Bynum JP. Use of tube feeding to prevent aspiration pneumonia. Lancet. 1996 Nov 23;348(9039):1421-4. doi: 10.1016/S0140-6736(96)03369-7. No abstract available. Erratum In: Lancet 1997 Feb 1;349(9048):364.
PMID: 8937283
citation: Machado AG, Baker KB, Schuster D, Butler RS, Rezai A. Chronic electrical stimulation of the contralesional lateral cerebellar nucleus enhances recovery of motor function after cerebral ischemia in rats. Brain Res. 2009 Jul 14;1280:107-16. doi: 10.1016/j.brainres.2009.05.007. Epub 2009 May 12.
PMID: 19445910
citation: Park HJ, Furmaga H, Cooperrider J, Gale JT, Baker KB, Machado AG. Modulation of Cortical Motor Evoked Potential After Stroke During Electrical Stimulation of the Lateral Cerebellar Nucleus. Brain Stimul. 2015 Nov-Dec;8(6):1043-8. doi: 10.1016/j.brs.2015.06.020. Epub 2015 Jul 8.
PMID: 26215752
citation: Hamdy S, Rothwell JC, Brooks DJ, Bailey D, Aziz Q, Thompson DG. Identification of the cerebral loci processing human swallowing with H2(15)O PET activation. J Neurophysiol. 1999 Apr;81(4):1917-26. doi: 10.1152/jn.1999.81.4.1917.
PMID: 10200226
citation: Jayasekeran V, Rothwell J, Hamdy S. Non-invasive magnetic stimulation of the human cerebellum facilitates cortico-bulbar projections in the swallowing motor system. Neurogastroenterol Motil. 2011 Sep;23(9):831-e341. doi: 10.1111/j.1365-2982.2011.01747.x.
PMID: 21838728
citation: Vasant DH, Michou E, Mistry S, Rothwell JC, Hamdy S. High-frequency focal repetitive cerebellar stimulation induces prolonged increases in human pharyngeal motor cortex excitability. J Physiol. 2015 Nov 15;593(22):4963-77. doi: 10.1113/JP270817. Epub 2015 Sep 30.
PMID: 26316351
citation: Mistry S, Verin E, Singh S, Jefferson S, Rothwell JC, Thompson DG, Hamdy S. Unilateral suppression of pharyngeal motor cortex to repetitive transcranial magnetic stimulation reveals functional asymmetry in the hemispheric projections to human swallowing. J Physiol. 2007 Dec 1;585(Pt 2):525-38. doi: 10.1113/jphysiol.2007.144592. Epub 2007 Oct 11.
PMID: 17932140
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: Hamdy S, Aziz Q, Rothwell JC, Singh KD, Barlow J, Hughes DG, Tallis RC, Thompson DG. The cortical topography of human swallowing musculature in health and disease. Nat Med. 1996 Nov;2(11):1217-24. doi: 10.1038/nm1196-1217.
PMID: 8898748
citation: Hamdy S, Mikulis DJ, Crawley A, Xue S, Lau H, Henry S, Diamant NE. Cortical activation during human volitional swallowing: an event-related fMRI study. Am J Physiol. 1999 Jul;277(1):G219-25. doi: 10.1152/ajpgi.1999.277.1.G219.
PMID: 10409170
citation: Hamdy S, Aziz Q, Rothwell JC, Power M, Singh KD, Nicholson DA, Tallis RC, Thompson DG. Recovery of swallowing after dysphagic stroke relates to functional reorganization in the intact motor cortex. Gastroenterology. 1998 Nov;115(5):1104-12. doi: 10.1016/s0016-5085(98)70081-2.
PMID: 9797365
citation: Hamdy S, Rothwell JC, Aziz Q, Singh KD, Thompson DG. Long-term reorganization of human motor cortex driven by short-term sensory stimulation. Nat Neurosci. 1998 May;1(1):64-8. doi: 10.1038/264.
PMID: 10195111
citation: Fraser C, Power M, Hamdy S, Rothwell J, Hobday D, Hollander I, Tyrell P, Hobson A, Williams S, Thompson D. Driving plasticity in human adult motor cortex is associated with improved motor function after brain injury. Neuron. 2002 May 30;34(5):831-40. doi: 10.1016/s0896-6273(02)00705-5.
PMID: 12062028
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: Gow D, Rothwell J, Hobson A, Thompson D, Hamdy S. Induction of long-term plasticity in human swallowing motor cortex following repetitive cortical stimulation. Clin Neurophysiol. 2004 May;115(5):1044-51. doi: 10.1016/j.clinph.2003.12.001.
PMID: 15066528
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: 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: Jefferson S, Mistry S, Michou E, Singh S, Rothwell JC, Hamdy S. Reversal of a virtual lesion in human pharyngeal motor cortex by high frequency contralesional brain stimulation. Gastroenterology. 2009 Sep;137(3):841-9, 849.e1. doi: 10.1053/j.gastro.2009.04.056. Epub 2009 May 7.
PMID: 19427312
citation: Jayasekeran V, Singh S, Tyrrell P, Michou E, Jefferson S, Mistry S, Gamble E, Rothwell J, Thompson D, Hamdy S. Adjunctive functional pharyngeal electrical stimulation reverses swallowing disability after brain lesions. Gastroenterology. 2010 May;138(5):1737-46. doi: 10.1053/j.gastro.2010.01.052. Epub 2010 Feb 2.
PMID: 20138037
citation: Vasant DH, Mistry S, Michou E, Jefferson S, Rothwell JC, Hamdy S. Transcranial direct current stimulation reverses neurophysiological and behavioural effects of focal inhibition of human pharyngeal motor cortex on swallowing. J Physiol. 2014 Feb 15;592(4):695-709. doi: 10.1113/jphysiol.2013.263475. Epub 2013 Nov 18.
PMID: 24247983
responsible party type: Principal Investigator
investigator affiliation: University of Manchester
investigator full name: Prof Shaheen Hamdy PhD FRCP
investigator title: Professor
mesh term: Deglutition Disorders
mesh term: Stroke
sharing ipd: No
ipd description: No identifiable individual participant information will be shared outside the immediate research team. However, identifiable individual participant information will be made available to the Medical research council and the University of Manchester if required for the purposes of auditing the study.