Clinical trial NCT04490616: TMS Treatment of Social Cognition Skills in Mild Cognitive Impairment
Official title: EFFECTS of RTMS TREATMENT on SOCIAL COGNITION DYSFUNCTIONS in MILD COGNITIVE IMPAIRMENT: an PROSPECTIVE, DOUBLE-BINDING, RANDOMIZED, SINGLE CENTRE, EXPLORATIVE STUDY
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Mild Cognitive Impairment
Keywords: ripetitive transcranial magnetic stimulation treatment
social cognition
theory of mind
empathy
social perception
social behavior
Lead sponsor: Ospedale Regionale di Lugano
Sponsor class: OTHER
First posted: 2020-07-29
Enrollment: 28
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Subjects aged 50 to 85 years old, inclusive, at the time of informed consent;
* Must have at least 5 years of education or work experience to exclude mental deficits other than MCI;
* Must meet Petersen's criteria for mild cognitive impairment, and must have:
* Clinical dementia rating global score of 0.5;
* Mini-Mental State Examination score between 24 and 30;
* Must have a score ≥ 26.5 at Token test to ensure that subjects have the ability to understand the instructions and procedures;
* Must have a score \< 29 at Beck Depression Inventory to exclude major depression that could compromise the patient's ability to engage in the study;
* Apart from a clinical diagnosis of MCI, the subject must be in good health;
* Must be on stable dose of antidepressant (if applicable) for at least 2 months prior to the enrolment.

Exclusion Criteria:

* Any uncontrolled medical or neurological/neurodegenerative condition (other than MCI);
* Clinical significant unstable psychiatric illness requiring treatment with neuroleptic;
* Transient ischemic attack, stroke, or any unexplained loss of consciousness or severe ongoing stressor within 1 year prior to screening;
* History of seizure within10 years prior to screening;
* Recent history of alcohol or substance abuse or use of cannabinoids;
* Any other medical conditions that are not stable or controlled, or could affect the subject's safety or interfere with the study assessments and treatment;
* Contraindication to having TMS treatment;
* Inability to understand the purpose of the study or to comply with study requirements.

Primary outcomes:
measure: Comparison of Deceptive Box Task score
timeFrame: Week 2
measure: Comparison of Look-prediction/say-prediction test score
timeFrame: Week 2
measure: Comparison of Empathy Quotient score
timeFrame: Week 2
measure: Comparison of Ekman 60 test score
timeFrame: Week 2
measure: Comparison of Frontal Behavioral Inventory score
timeFrame: Week 2
measure: Comparison of Deceptive Box Task score
timeFrame: Week 4
measure: Comparison of Look-prediction/say-prediction test
timeFrame: Week 4
measure: Comparison of Empathy Quotient score
timeFrame: Week 4
measure: Comparison of Ekman 60 test score
timeFrame: Week 4
measure: Comparison of Frontal Behavioral Inventory score
timeFrame: Week 4
Secondary outcomes:
measure: Changes from baseline in Deceptive Box Task Test.
timeFrame: Week 12
measure: Changes from baseline in Look/say Test
timeFrame: Week 12
measure: Changes from baseline in Empathy Quotient scale
timeFrame: Week 12
measure: Changes from baseline in Ekman 60 Test
timeFrame: Week 12
measure: Changes from baseline in Frontal Behavioral Inventory
timeFrame: Week 12
measure: Comparison Montreal Cognitive Assessment
timeFrame: through study completion, an average of 12 weeks
measure: Comparison of Geriatric Depression Scale score
timeFrame: through study completion, an average of 12 weeks
measure: Comparison of Euroquol-5 dimensions score
timeFrame: athrough study completion, an average of 12 weeks
Other outcomes:
Locations:
city: Lugano
country: Switzerland
facility: Neurocentro della Svizzera italiana,Ospedale Regionale di Lugano
state: Ticino
Study officials:
affiliation: +41 091 811 6921
name: Leonardo Sacco, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baumgardner DJ, Christopherson A, Momont S. Chlamydia in pregnant women: southeastern Wisconsin. Wis Med J. 1989 Sep;88(9):12-5.
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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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.