<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/NCT04490616</url>
  </required_header>
  <id_info>
    <org_study_id>2020-00434/CE 3594</org_study_id>
    <nct_id>NCT04490616</nct_id>
  </id_info>
  <brief_title>TMS Treatment of Social Cognition Skills in Mild Cognitive Impairment</brief_title>
  <official_title>EFFECTS OF rTMS TREATMENT ON SOCIAL COGNITION DYSFUNCTIONS IN MILD COGNITIVE IMPAIRMENT: AN PROSPECTIVE, DOUBLE-BINDING, RANDOMIZED, SINGLE CENTRE, EXPLORATIVE STUDY</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ospedale Regionale di Lugano</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ospedale Regionale di Lugano</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>
      Social cognitive abilities are impaired in around 17% of subjects with mild cognitive&#xD;
      impairment (MCI), and might not reflect upon functional status. Compared to healthy controls,&#xD;
      MCI showed impairments in theory of mind (ToM) and facial emotion recognition. Moreover, in&#xD;
      amnesic MCI patients, reduced ToM ability appears to be correlated with worse performances at&#xD;
      several cognitive performances. These findings, in agreement with previous evidence, confirm&#xD;
      that impaired social cognition might occur prior to dementia: typically elderly start to show&#xD;
      impairment in the complex ToM levels, which is found also in MCI patients and proceeds&#xD;
      further in AD patients. Thus, the treatment of these aspects has the potential to influence&#xD;
      the trajectory of neurodegeneration. In the last decade, it has been increasingly evident the&#xD;
      effectiveness of active stimulation of brain regions with repetitive transcranial magnetic&#xD;
      stimulation (rTMS), to improve cognitive and functional performances in patients with&#xD;
      dementia.&#xD;
&#xD;
      On the other hand, brain imaging techniques and TMS stimulations have identified two main&#xD;
      areas responsible for human social cognition- the medial prefrontal cortex (MPFC) and the&#xD;
      right temporo-parietal junction (RTPJ).&#xD;
&#xD;
      In this project, we hypothesized that an improvement of social cognition skills may be&#xD;
      obtained in MCI patients by using the rTMS on two main areas responsible for human social&#xD;
      cognition- the medial prefrontal cortex (MPFC) and the right temporoparietal junction (RTPJ).&#xD;
      Moreover, it expects that rTMS treatment may also contribute to improving cognitive abilities&#xD;
      and neuropsychiatric aspects partially modulated by the same networks stimulated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a prospective, double-binding, cross-sectional, randomized, sham-controlled, and&#xD;
      single-center project aimed to investigate the effect of rTMS treatment of social cognition&#xD;
      abilities in MCI subjects at 2 and 4 weeks, and after 8 weeks from baseline.&#xD;
&#xD;
      All patients will be recruited at Clinical Neuroscience Institute, Department of Neurology,&#xD;
      Regional Civic Hospital, Lugan; Department of Geriatric Italian Hospital Viganello; and&#xD;
      Department of Geriatric, Beata Vergine Hospital Mendrisio; Southern Switzerland, Switzerland.&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
      1. To investigate whether the application of high-frequency rTMS, for 2 or 4 weeks, to the&#xD;
      RPTJ and MPFC resulted in social cognitive improvements.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        1. To verify whether the social cognition benefits previously recorded might persist after&#xD;
           8 weeks the end of the stimulation, with a major benefit with a longer rTMS application&#xD;
           (4 weeks).&#xD;
&#xD;
        2. To investigate whether the application of high-frequency rTMS, at 2 weeks or 4 weeks, to&#xD;
           the RPTJ and MPFC contributes to improve cognitive functions as well as neuropsychiatric&#xD;
           (depression) and functional aspects.&#xD;
&#xD;
        3. To verify whether the cognitive functions, neuropsychiatric aspect, and functional&#xD;
           benefits previously recorded persist after the end of the rTMS stimulation.&#xD;
&#xD;
      Primary analysis: To investigate the behavioral effects induced by the rTMS protocol after 2&#xD;
      and 4 weeks of daily stimulation on social cognition skills, executive/attentive functions,&#xD;
      neuropsychiatric and functional aspects will be used a mixed-model ANOVA, considering the&#xD;
      group as a between-subjects factor, and time as a within-subject factor.&#xD;
&#xD;
      Secondary Analyses: To investigate the direct or mediated rTMS effect on social cognition&#xD;
      skills, a multivariate linear regression analysis will be done for each social cognition&#xD;
      measure (ToM, empathy, social perception, social behavior) changes after rTMS treatment at 2&#xD;
      and 4 weeks as the dependent factor, separately, and appropriate screening/baseline dependent&#xD;
      variables and rTMS groups as independent factors.&#xD;
&#xD;
      The evaluation and treatment of social cognition alterations in subjects with MCI can be&#xD;
      useful for two main aspects: first, the mild cognitive and behavior impairment of these&#xD;
      subjects favor a better answer at the treatment, both at the behavioral level and in terms of&#xD;
      brain structural and functional response; second, treatment of these abilities in MCI&#xD;
      population might retard the conversion to dementia. More importantly, the detection of&#xD;
      predominant social cognition alteration in early phases of cognitive decline might be&#xD;
      potentially helpful to differentiate individuals who will develop frontotemporal dementia.&#xD;
      Therefore, it is important to investigate and define a treatment protocol to limit social&#xD;
      cognition disturbances in MCI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 11, 2021</start_date>
  <completion_date type="Anticipated">August 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 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>Crossover Assignment</intervention_model>
    <intervention_model_description>In the project will be applied a two-site repetitive transcranial magnetic stimulation (rTMS) stimulation.&#xD;
MCI patients that obtained a score ≤ 10 percentiles, at least one performance/domain of social cognition assessment will be considered impaired at social cognition abilities. In the same day of cognitive-behavioral assessment, patients will be randomly assigned to one of the two groups:&#xD;
1) RR-Gr received 4 weeks of rTMS stimulation of the RTPJ and MPFC; (2) SR-Gr received of the RTPJ and MPFC sham stimulation during the first 2 weeks followed by 2 weeks of real stimulation. Each week of rTMS treatment consisted of five sessions. This paradigm has proven to be effective for improve cognitive performances in AD patients. In the sham condition, a sham coil will be used.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Comparison of Deceptive Box Task score</measure>
    <time_frame>Week 2</time_frame>
    <description>(5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Look-prediction/say-prediction test score</measure>
    <time_frame>Week 2</time_frame>
    <description>(5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Empathy Quotient score</measure>
    <time_frame>Week 2</time_frame>
    <description>(60 items). Minimum value=0, maximum value=80. A higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Ekman 60 test score</measure>
    <time_frame>Week 2</time_frame>
    <description>(60 b/w pictures). Minimum value=0, maximum value=60. Higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Frontal Behavioral Inventory score</measure>
    <time_frame>Week 2</time_frame>
    <description>(24 items). Minimum value=0, maximum value=69. Higher score means a worse outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Deceptive Box Task score</measure>
    <time_frame>Week 4</time_frame>
    <description>(5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Look-prediction/say-prediction test</measure>
    <time_frame>Week 4</time_frame>
    <description>(5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Empathy Quotient score</measure>
    <time_frame>Week 4</time_frame>
    <description>(60 items). Minimum value=0, maximum value=80. A higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Ekman 60 test score</measure>
    <time_frame>Week 4</time_frame>
    <description>(60 b/w pictures). Minimum value=0, maximum value=60. Higher score means a better outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of Frontal Behavioral Inventory score</measure>
    <time_frame>Week 4</time_frame>
    <description>(24 items). Minimum value=0, maximum value=69. Higher score means a worse outcome.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in Deceptive Box Task Test.</measure>
    <time_frame>Week 12</time_frame>
    <description>(5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in Look/say Test</measure>
    <time_frame>Week 12</time_frame>
    <description>(5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in Empathy Quotient scale</measure>
    <time_frame>Week 12</time_frame>
    <description>(60 items). Minimum value=0, maximum value=80. A higher score means a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in Ekman 60 Test</measure>
    <time_frame>Week 12</time_frame>
    <description>(60 b/w pictures). Minimum value=0, maximum value=60. Higher score means a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in Frontal Behavioral Inventory</measure>
    <time_frame>Week 12</time_frame>
    <description>(24 items). Minimum value=0, maximum value=69. Higher score means a worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison Montreal Cognitive Assessment</measure>
    <time_frame>through study completion, an average of 12 weeks</time_frame>
    <description>(30 items). Minimum value=0, maximum value=30. Higher score means a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of Geriatric Depression Scale score</measure>
    <time_frame>through study completion, an average of 12 weeks</time_frame>
    <description>(30 items). Minimum value=0, maximum value=30. Higher score means a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of Euroquol-5 dimensions score</measure>
    <time_frame>athrough study completion, an average of 12 weeks</time_frame>
    <description>(visual analogue scale with 100-point scale). Minimum value=0, maximum value=100. Higher score means a better outcome.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">32</enrollment>
  <condition>Mild Cognitive Impairment</condition>
  <arm_group>
    <arm_group_label>RR-GR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>MCI patients with social cognition deficits will receive 4 weeks of rTMS stimulation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SR-GR</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>MCI patients with social cognition deficits will receive 2 weeks of placebo treatment, followed by 2 weeks of real rTMS stimulation</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>rTMS treatment</intervention_name>
    <description>A two-site rTMS stimulation delivered by a Magstim unit featuring a double 70 mm cooled coil will be applied.&#xD;
MCI patients will be randomly assigned to one of the two study groups:&#xD;
RR-Gr will receive 4 weeks of rTMS stimulation of the right temporo-parietal junction (RTPJ) and medial prefrontal cortex (MPFC);&#xD;
PL-Gr will receive sham stimulation of the RTPJ and MPFC during the first 2 weeks followed by 2 weeks of real stimulation. Each week of rTMS treatment will consist of five sessions (50 min, one per day).&#xD;
For each area target, a total of 2000 pulses at 20Hz, 3-s train duration, and 28-s inter-train interval at 100% motor threshold (MT) will be delivered per session. A fixed intensity of MT will ensure a more consistent spatial spread of TMS effects in subjects' brains not influenced by differences in individual MT. In the sham condition, a sham coil will be used.&#xD;
Each session lasted for about 60 min including time for set up and 50 min of stimulation.</description>
    <arm_group_label>RR-GR</arm_group_label>
    <arm_group_label>SR-GR</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects aged 50 to 85 years old, inclusive, at the time of informed consent;&#xD;
&#xD;
          -  Must have at least 5 years of education or work experience to exclude mental deficits&#xD;
             other than MCI;&#xD;
&#xD;
          -  Must meet Petersen's criteria for mild cognitive impairment, and must have:&#xD;
&#xD;
          -  Clinical dementia rating global score of 0.5;&#xD;
&#xD;
          -  Mini-Mental State Examination score between 24 and 30;&#xD;
&#xD;
          -  Must have a score ≥ 26.5 at Token test to ensure that subjects have the ability to&#xD;
             understand the instructions and procedures;&#xD;
&#xD;
          -  Must have a score &lt; 29 at Beck Depression Inventory to exclude major depression that&#xD;
             could compromise the patient's ability to engage in the study;&#xD;
&#xD;
          -  Apart from a clinical diagnosis of MCI, the subject must be in good health;&#xD;
&#xD;
          -  Must be on stable dose of antidepressant (if applicable) for at least 2 months prior&#xD;
             to the enrolment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any uncontrolled medical or neurological/neurodegenerative condition (other than MCI);&#xD;
&#xD;
          -  Clinical significant unstable psychiatric illness requiring treatment with&#xD;
             neuroleptic;&#xD;
&#xD;
          -  Transient ischemic attack, stroke, or any unexplained loss of consciousness or severe&#xD;
             ongoing stressor within 1 year prior to screening;&#xD;
&#xD;
          -  History of seizure within10 years prior to screening;&#xD;
&#xD;
          -  Recent history of alcohol or substance abuse or use of cannabinoids;&#xD;
&#xD;
          -  Any other medical conditions that are not stable or controlled, or could affect the&#xD;
             subject's safety or interfere with the study assessments and treatment;&#xD;
&#xD;
          -  Contraindication to having TMS treatment;&#xD;
&#xD;
          -  Inability to understand the purpose of the study or to comply with study requirements.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Leonardo Sacco, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>+41 091 811 6921</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Leonardo Sacco, Dr</last_name>
    <phone>+41 091 811 6921</phone>
    <email>leonardo.sacco@eoc.ch</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Gianna C. Riccitelli, Dr</last_name>
    <phone>+41 091 811 6921</phone>
    <email>gianna.riccitelli@eoc.ch</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Neurocentro della Svizzera italiana,Ospedale Regionale di Lugano</name>
      <address>
        <city>Lugano</city>
        <state>Ticino</state>
        <zip>6903</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gianna C Riccitelli, PhD</last_name>
      <phone>091 811 6398</phone>
      <email>gianna.riccitelli@eoc.ch</email>
    </contact>
    <contact_backup>
      <last_name>Leonardo Sacco, MD</last_name>
      <phone>091 811 6921</phone>
      <email>leonardo.sacco@eoc.ch</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <reference>
    <citation>Freedman M, Binns MA, Black SE, Murphy C, Stuss DT. Theory of mind and recognition of facial emotion in dementia: challenge to current concepts. Alzheimer Dis Assoc Disord. 2013 Jan-Mar;27(1):56-61. doi: 10.1097/WAD.0b013e31824ea5db.</citation>
    <PMID>22407224</PMID>
  </reference>
  <results_reference>
    <citation>Adolphs R. The social brain: neural basis of social knowledge. Annu Rev Psychol. 2009;60:693-716. doi: 10.1146/annurev.psych.60.110707.163514.</citation>
    <PMID>18771388</PMID>
  </results_reference>
  <results_reference>
    <citation>Wondra JD, Ellsworth PC. An appraisal theory of empathy and other vicarious emotional experiences. Psychol Rev. 2015 Jul;122(3):411-28. doi: 10.1037/a0039252. Epub 2015 May 11.</citation>
    <PMID>25961468</PMID>
  </results_reference>
  <results_reference>
    <citation>Apperly IA, Samson D, Chiavarino C, Humphreys GW. Frontal and temporo-parietal lobe contributions to theory of mind: neuropsychological evidence from a false-belief task with reduced language and executive demands. J Cogn Neurosci. 2004 Dec;16(10):1773-84. doi: 10.1162/0898929042947928.</citation>
    <PMID>15701227</PMID>
  </results_reference>
  <results_reference>
    <citation>Wood JN, Knutson KM, Grafman J. Psychological structure and neural correlates of event knowledge. Cereb Cortex. 2005 Aug;15(8):1155-61. doi: 10.1093/cercor/bhh215. Epub 2004 Nov 24.</citation>
    <PMID>15563720</PMID>
  </results_reference>
  <results_reference>
    <citation>Van Overwalle F. Social cognition and the brain: a meta-analysis. Hum Brain Mapp. 2009 Mar;30(3):829-58. doi: 10.1002/hbm.20547.</citation>
    <PMID>18381770</PMID>
  </results_reference>
  <results_reference>
    <citation>Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006 Apr;7(4):268-77. doi: 10.1038/nrn1884.</citation>
    <PMID>16552413</PMID>
  </results_reference>
  <results_reference>
    <citation>Cabeza R, Ciaramelli E, Moscovitch M. Cognitive contributions of the ventral parietal cortex: an integrative theoretical account. Trends Cogn Sci. 2012 Jun;16(6):338-52. doi: 10.1016/j.tics.2012.04.008. Epub 2012 May 19.</citation>
    <PMID>22609315</PMID>
  </results_reference>
  <results_reference>
    <citation>Dodich A, Cerami C, Crespi C, Canessa N, Lettieri G, Iannaccone S, Marcone A, Cappa SF, Cacioppo JT. Differential Impairment of Cognitive and Affective Mentalizing Abilities in Neurodegenerative Dementias: Evidence from Behavioral Variant of Frontotemporal Dementia, Alzheimer's Disease, and Mild Cognitive Impairment. J Alzheimers Dis. 2016;50(4):1011-22. doi: 10.3233/JAD-150605.</citation>
    <PMID>26836153</PMID>
  </results_reference>
  <results_reference>
    <citation>Padala PR, Padala KP, Lensing SY, Jackson AN, Hunter CR, Parkes CM, Dennis RA, Bopp MM, Caceda R, Mennemeier MS, Roberson PK, Sullivan DH. Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study. Psychiatry Res. 2018 Mar;261:312-318. doi: 10.1016/j.psychres.2017.12.063. Epub 2018 Jan 5.</citation>
    <PMID>29331848</PMID>
  </results_reference>
  <results_reference>
    <citation>Ferrari C, Vecchi T, Todorov A, Cattaneo Z. Interfering with activity in the dorsomedial prefrontal cortex via TMS affects social impressions updating. Cogn Affect Behav Neurosci. 2016 Aug;16(4):626-34. doi: 10.3758/s13415-016-0419-2.</citation>
    <PMID>27012713</PMID>
  </results_reference>
  <results_reference>
    <citation>Cotelli M, Manenti R, Cappa SF, Zanetti O, Miniussi C. Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline. Eur J Neurol. 2008 Dec;15(12):1286-92. doi: 10.1111/j.1468-1331.2008.02202.x.</citation>
    <PMID>19049544</PMID>
  </results_reference>
  <results_reference>
    <citation>Cotelli M, Calabria M, Zanetti O. Cognitive rehabilitation in Alzheimer's Disease. Aging Clin Exp Res. 2006 Apr;18(2):141-3. doi: 10.1007/BF03327429.</citation>
    <PMID>16702783</PMID>
  </results_reference>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>July 10, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 29, 2020</study_first_posted>
  <last_update_submitted>September 21, 2022</last_update_submitted>
  <last_update_submitted_qc>September 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ospedale Regionale di Lugano</investigator_affiliation>
    <investigator_full_name>Leonardo Sacco</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>ripetitive transcranial magnetic stimulation treatment</keyword>
  <keyword>social cognition</keyword>
  <keyword>theory of mind</keyword>
  <keyword>empathy</keyword>
  <keyword>social perception</keyword>
  <keyword>social behavior</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cognitive Dysfunction</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/NCT04490616
org study id: 2020-00434/CE 3594
nct id: NCT04490616
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Social cognitive abilities are impaired in around 17% of subjects with mild cognitive
      impairment (MCI), and might not reflect upon functional status. Compared to healthy controls,
      MCI showed impairments in theory of mind (ToM) and facial emotion recognition. Moreover, in
      amnesic MCI patients, reduced ToM ability appears to be correlated with worse performances at
      several cognitive performances. These findings, in agreement with previous evidence, confirm
      that impaired social cognition might occur prior to dementia: typically elderly start to show
      impairment in the complex ToM levels, which is found also in MCI patients and proceeds
      further in AD patients. Thus, the treatment of these aspects has the potential to influence
      the trajectory of neurodegeneration. In the last decade, it has been increasingly evident the
      effectiveness of active stimulation of brain regions with repetitive transcranial magnetic
      stimulation (rTMS), to improve cognitive and functional performances in patients with
      dementia.

      On the other hand, brain imaging techniques and TMS stimulations have identified two main
      areas responsible for human social cognition- the medial prefrontal cortex (MPFC) and the
      right temporo-parietal junction (RTPJ).

      In this project, we hypothesized that an improvement of social cognition skills may be
      obtained in MCI patients by using the rTMS on two main areas responsible for human social
      cognition- the medial prefrontal cortex (MPFC) and the right temporoparietal junction (RTPJ).
      Moreover, it expects that rTMS treatment may also contribute to improving cognitive abilities
      and neuropsychiatric aspects partially modulated by the same networks stimulated.
This is a prospective, double-binding, cross-sectional, randomized, sham-controlled, and
      single-center project aimed to investigate the effect of rTMS treatment of social cognition
      abilities in MCI subjects at 2 and 4 weeks, and after 8 weeks from baseline.

      All patients will be recruited at Clinical Neuroscience Institute, Department of Neurology,
      Regional Civic Hospital, Lugan; Department of Geriatric Italian Hospital Viganello; and
      Department of Geriatric, Beata Vergine Hospital Mendrisio; Southern Switzerland, Switzerland.

      Primary objective:

      1. To investigate whether the application of high-frequency rTMS, for 2 or 4 weeks, to the
      RPTJ and MPFC resulted in social cognitive improvements.

      Secondary objectives:

        1. To verify whether the social cognition benefits previously recorded might persist after
           8 weeks the end of the stimulation, with a major benefit with a longer rTMS application
           (4 weeks).

        2. To investigate whether the application of high-frequency rTMS, at 2 weeks or 4 weeks, to
           the RPTJ and MPFC contributes to improve cognitive functions as well as neuropsychiatric
           (depression) and functional aspects.

        3. To verify whether the cognitive functions, neuropsychiatric aspect, and functional
           benefits previously recorded persist after the end of the rTMS stimulation.

      Primary analysis: To investigate the behavioral effects induced by the rTMS protocol after 2
      and 4 weeks of daily stimulation on social cognition skills, executive/attentive functions,
      neuropsychiatric and functional aspects will be used a mixed-model ANOVA, considering the
      group as a between-subjects factor, and time as a within-subject factor.

      Secondary Analyses: To investigate the direct or mediated rTMS effect on social cognition
      skills, a multivariate linear regression analysis will be done for each social cognition
      measure (ToM, empathy, social perception, social behavior) changes after rTMS treatment at 2
      and 4 weeks as the dependent factor, separately, and appropriate screening/baseline dependent
      variables and rTMS groups as independent factors.

      The evaluation and treatment of social cognition alterations in subjects with MCI can be
      useful for two main aspects: first, the mild cognitive and behavior impairment of these
      subjects favor a better answer at the treatment, both at the behavioral level and in terms of
      brain structural and functional response; second, treatment of these abilities in MCI
      population might retard the conversion to dementia. More importantly, the detection of
      predominant social cognition alteration in early phases of cognitive decline might be
      potentially helpful to differentiate individuals who will develop frontotemporal dementia.
      Therefore, it is important to investigate and define a treatment protocol to limit social
      cognition disturbances in MCI.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: In the project will be applied a two-site repetitive transcranial magnetic stimulation (rTMS) stimulation.
MCI patients that obtained a score ≤ 10 percentiles, at least one performance/domain of social cognition assessment will be considered impaired at social cognition abilities. In the same day of cognitive-behavioral assessment, patients will be randomly assigned to one of the two groups:
1) RR-Gr received 4 weeks of rTMS stimulation of the RTPJ and MPFC; (2) SR-Gr received of the RTPJ and MPFC sham stimulation during the first 2 weeks followed by 2 weeks of real stimulation. Each week of rTMS treatment consisted of five sessions. This paradigm has proven to be effective for improve cognitive performances in AD patients. In the sham condition, a sham coil will be used.
primary purpose: Treatment
masking: Double (Participant, Care Provider)
measure: Comparison of Deceptive Box Task score
time frame: Week 2
description: (5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.
measure: Comparison of Look-prediction/say-prediction test score
time frame: Week 2
description: (5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.
measure: Comparison of Empathy Quotient score
time frame: Week 2
description: (60 items). Minimum value=0, maximum value=80. A higher score means a better outcome.
measure: Comparison of Ekman 60 test score
time frame: Week 2
description: (60 b/w pictures). Minimum value=0, maximum value=60. Higher score means a better outcome.
measure: Comparison of Frontal Behavioral Inventory score
time frame: Week 2
description: (24 items). Minimum value=0, maximum value=69. Higher score means a worse outcome.
measure: Comparison of Deceptive Box Task score
time frame: Week 4
description: (5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.
measure: Comparison of Look-prediction/say-prediction test
time frame: Week 4
description: (5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.
measure: Comparison of Empathy Quotient score
time frame: Week 4
description: (60 items). Minimum value=0, maximum value=80. A higher score means a better outcome.
measure: Comparison of Ekman 60 test score
time frame: Week 4
description: (60 b/w pictures). Minimum value=0, maximum value=60. Higher score means a better outcome.
measure: Comparison of Frontal Behavioral Inventory score
time frame: Week 4
description: (24 items). Minimum value=0, maximum value=69. Higher score means a worse outcome.
measure: Changes from baseline in Deceptive Box Task Test.
time frame: Week 12
description: (5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.
measure: Changes from baseline in Look/say Test
time frame: Week 12
description: (5 items). Minimum value=0, maximum value=5. A higher score means a better outcome.
measure: Changes from baseline in Empathy Quotient scale
time frame: Week 12
description: (60 items). Minimum value=0, maximum value=80. A higher score means a better outcome.
measure: Changes from baseline in Ekman 60 Test
time frame: Week 12
description: (60 b/w pictures). Minimum value=0, maximum value=60. Higher score means a better outcome.
measure: Changes from baseline in Frontal Behavioral Inventory
time frame: Week 12
description: (24 items). Minimum value=0, maximum value=69. Higher score means a worse outcome.
measure: Comparison Montreal Cognitive Assessment
time frame: through study completion, an average of 12 weeks
description: (30 items). Minimum value=0, maximum value=30. Higher score means a better outcome.
measure: Comparison of Geriatric Depression Scale score
time frame: through study completion, an average of 12 weeks
description: (30 items). Minimum value=0, maximum value=30. Higher score means a better outcome.
measure: Comparison of Euroquol-5 dimensions score
time frame: athrough study completion, an average of 12 weeks
description: (visual analogue scale with 100-point scale). Minimum value=0, maximum value=100. Higher score means a better outcome.
arm group label: RR-GR
arm group type: Experimental
description: MCI patients with social cognition deficits will receive 4 weeks of rTMS stimulation
arm group label: SR-GR
arm group type: Other
description: MCI patients with social cognition deficits will receive 2 weeks of placebo treatment, followed by 2 weeks of real rTMS stimulation
intervention type: Other
intervention name: rTMS treatment
description: A two-site rTMS stimulation delivered by a Magstim unit featuring a double 70 mm cooled coil will be applied.
MCI patients will be randomly assigned to one of the two study groups:
RR-Gr will receive 4 weeks of rTMS stimulation of the right temporo-parietal junction (RTPJ) and medial prefrontal cortex (MPFC);
PL-Gr will receive sham stimulation of the RTPJ and MPFC during the first 2 weeks followed by 2 weeks of real stimulation. Each week of rTMS treatment will consist of five sessions (50 min, one per day).
For each area target, a total of 2000 pulses at 20Hz, 3-s train duration, and 28-s inter-train interval at 100% motor threshold (MT) will be delivered per session. A fixed intensity of MT will ensure a more consistent spatial spread of TMS effects in subjects' brains not influenced by differences in individual MT. In the sham condition, a sham coil will be used.
Each session lasted for about 60 min including time for set up and 50 min of stimulation.
arm group label: RR-GR
arm group label: SR-GR
criteria: 
gender: All
minimum age: 50 Years
maximum age: 80 Years
healthy volunteers: No
last name: Leonardo Sacco, Dr
role: Principal Investigator
affiliation: +41 091 811 6921
last name: Leonardo Sacco, Dr
phone: +41 091 811 6921
email: leonardo.sacco@eoc.ch
last name: Gianna C. Riccitelli, Dr
phone: +41 091 811 6921
email: gianna.riccitelli@eoc.ch
facility: 
status: Recruiting
contact: 
contact backup: 
country: Switzerland
citation: Freedman M, Binns MA, Black SE, Murphy C, Stuss DT. Theory of mind and recognition of facial emotion in dementia: challenge to current concepts. Alzheimer Dis Assoc Disord. 2013 Jan-Mar;27(1):56-61. doi: 10.1097/WAD.0b013e31824ea5db.
PMID: 22407224
citation: Adolphs R. The social brain: neural basis of social knowledge. Annu Rev Psychol. 2009;60:693-716. doi: 10.1146/annurev.psych.60.110707.163514.
PMID: 18771388
citation: Wondra JD, Ellsworth PC. An appraisal theory of empathy and other vicarious emotional experiences. Psychol Rev. 2015 Jul;122(3):411-28. doi: 10.1037/a0039252. Epub 2015 May 11.
PMID: 25961468
citation: Apperly IA, Samson D, Chiavarino C, Humphreys GW. Frontal and temporo-parietal lobe contributions to theory of mind: neuropsychological evidence from a false-belief task with reduced language and executive demands. J Cogn Neurosci. 2004 Dec;16(10):1773-84. doi: 10.1162/0898929042947928.
PMID: 15701227
citation: Wood JN, Knutson KM, Grafman J. Psychological structure and neural correlates of event knowledge. Cereb Cortex. 2005 Aug;15(8):1155-61. doi: 10.1093/cercor/bhh215. Epub 2004 Nov 24.
PMID: 15563720
citation: Van Overwalle F. Social cognition and the brain: a meta-analysis. Hum Brain Mapp. 2009 Mar;30(3):829-58. doi: 10.1002/hbm.20547.
PMID: 18381770
citation: Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006 Apr;7(4):268-77. doi: 10.1038/nrn1884.
PMID: 16552413
citation: Cabeza R, Ciaramelli E, Moscovitch M. Cognitive contributions of the ventral parietal cortex: an integrative theoretical account. Trends Cogn Sci. 2012 Jun;16(6):338-52. doi: 10.1016/j.tics.2012.04.008. Epub 2012 May 19.
PMID: 22609315
citation: Dodich A, Cerami C, Crespi C, Canessa N, Lettieri G, Iannaccone S, Marcone A, Cappa SF, Cacioppo JT. Differential Impairment of Cognitive and Affective Mentalizing Abilities in Neurodegenerative Dementias: Evidence from Behavioral Variant of Frontotemporal Dementia, Alzheimer's Disease, and Mild Cognitive Impairment. J Alzheimers Dis. 2016;50(4):1011-22. doi: 10.3233/JAD-150605.
PMID: 26836153
citation: Padala PR, Padala KP, Lensing SY, Jackson AN, Hunter CR, Parkes CM, Dennis RA, Bopp MM, Caceda R, Mennemeier MS, Roberson PK, Sullivan DH. Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study. Psychiatry Res. 2018 Mar;261:312-318. doi: 10.1016/j.psychres.2017.12.063. Epub 2018 Jan 5.
PMID: 29331848
citation: Ferrari C, Vecchi T, Todorov A, Cattaneo Z. Interfering with activity in the dorsomedial prefrontal cortex via TMS affects social impressions updating. Cogn Affect Behav Neurosci. 2016 Aug;16(4):626-34. doi: 10.3758/s13415-016-0419-2.
PMID: 27012713
citation: Cotelli M, Manenti R, Cappa SF, Zanetti O, Miniussi C. Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline. Eur J Neurol. 2008 Dec;15(12):1286-92. doi: 10.1111/j.1468-1331.2008.02202.x.
PMID: 19049544
citation: Cotelli M, Calabria M, Zanetti O. Cognitive rehabilitation in Alzheimer's Disease. Aging Clin Exp Res. 2006 Apr;18(2):141-3. doi: 10.1007/BF03327429.
PMID: 16702783
responsible party type: Principal Investigator
investigator affiliation: Ospedale Regionale di Lugano
investigator full name: Leonardo Sacco
investigator title: Principal Investigator
mesh term: Cognitive Dysfunction
sharing ipd: No