Stability of rTMS on Cognition and Brain Networks on Healthy Subjects.

Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Cognition and Brain Networks in Healthy Subjects in 2 Sessions 15 Days Apart

Episodic and working memory processes are the most affected cognitive domains in Alzheimer's Disease (AD) and its early stage, Mild Cognitive Impairment (MCI).

Transcranial Magnetic Stimulation (TMS) is a unique tool to interfere with cognitive processes by inducing "virtual and transient lesions", mimicking those observed in MCI. It has proven repeatedly its capacity to interfere with encoding-retrieval memory task. However, to date, only few imaging data exist on the cerebral pathways involved in encoding memory task. Moreover, the stability of TMS effects over time remains to be investigated. If proven to be a stable interfering challenge, TMS could be used to investigate the potential restoring effect of new medication in AD.

The study is the pilot study of a larger clinical trial which aims to prove the utility of rTMS as a potential model for prediction of clinical efficacy using a combination of cognitive and neuroimaging endpoints.

Study Overview

• Status: Terminated
• Conditions: Healthy
• Intervention / Treatment: Device: ineffective rTMS; Device: active TBS; Device: fMRI; Device: Effective rTMS; Device: Sham TBS; Device: EEG

• Study Type: Interventional
• Enrollment (Actual): 158
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Marseille, France, 13005
    • Cic-Cpcet
• Spain
  • Barcelona, Spain, 08036
    • IDIBAPS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy male subjects aged between 18 and 40 years-old inclusive.
• Education level: at least secondary.
• Right-handed (Edinburgh Handedness Inventory).
• The subjects are in good health on the basis of the medical interview (medical history, symptoms), the physical examination and vital signs.
• No history of psychiatric disorders (assessed by Structured Clinical Interview for DSM IV Disorders (SCID) for Barcelona and by the Mini International Neuropsychiatric Interview (MINI) for Marseille).
• No history of neurological disorders
• No history of concussion (cranial or facial trauma) without or with loss of consciousness.
• Subject without history of brain disease (severe brain trauma, stroke, cerebral tumor...).
• Subject without lesion on MRI.
• Subject without abnormal electrical activities on standard clinical EEG.
• No history of drug or alcohol abuse.
• No smoker or ≤ 5 cg/ day.
• The subject can complete the neuropsychological test battery during the training session.
• Subject without contraindication to MRI.
• The subject is able to read and understand the Information Form and comply with the protocol instructions and restrictions.
• The subject is covered by a social insurance.
• The subject has provided written informed consent.

Exclusion Criteria:

• History or presence of psychiatric illness (Psychiatric interview).
• History or presence of neurologic illness.
• The subject, in the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any other reason.
• The subject participates in another clinical trial or is still being within a washout period of 1 month since last taking of a previous clinical trial, or subjects who have received more than 4500 Euros in the previous 12 months for participating in clinical trials.
• Presence of metallic objects within the body.
• Subjects with pacemaker.
• Claustrophobia.
• Individual and familial history of epileptic seizure.
• Any medication listed (see annexe) in the safety guidelines published by the Safety of TMS Consensus Group (Rossi et al., 2009) will be forbidden.
• Subject with a correct hit rate during the retrieval session of the memory task

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ineffective rTMS - Active TBS - fMRI	Device: ineffective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an ineffective stimulation.; Device: active TBS; A continuous Theta-Burst Stimulation (cTBS) protocol will be applied over the L-DLPFC. Three stimuli at 50Hz, 80% of individual Motor Threshold will be repeated every 200ms for 40sec; Device: fMRI; Functional MRI data will be acquired during the performance of the memory task. Functional data will be acquired with a blood oxygenation level dependant (BOLD) contrast sensitive gradient echo, T2*-weighted echo-planar imaging sequence
Experimental: Effective rTMS - Active TBS - fMRI	Device: active TBS; A continuous Theta-Burst Stimulation (cTBS) protocol will be applied over the L-DLPFC. Three stimuli at 50Hz, 80% of individual Motor Threshold will be repeated every 200ms for 40sec; Device: fMRI; Functional MRI data will be acquired during the performance of the memory task. Functional data will be acquired with a blood oxygenation level dependant (BOLD) contrast sensitive gradient echo, T2*-weighted echo-planar imaging sequence; Device: Effective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an effective stimulation.
Sham Comparator: ineffective rTMS - Sham TBS - fMRI	Device: ineffective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an ineffective stimulation.; Device: fMRI; Functional MRI data will be acquired during the performance of the memory task. Functional data will be acquired with a blood oxygenation level dependant (BOLD) contrast sensitive gradient echo, T2*-weighted echo-planar imaging sequence; Device: Sham TBS; A Sham stimulation will be applied over the L-DLPFC. a placebo coil will be used.
Sham Comparator: Effective rTMS - Sham TBS - fMRI	Device: fMRI; Functional MRI data will be acquired during the performance of the memory task. Functional data will be acquired with a blood oxygenation level dependant (BOLD) contrast sensitive gradient echo, T2*-weighted echo-planar imaging sequence; Device: Effective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an effective stimulation.; Device: Sham TBS; A Sham stimulation will be applied over the L-DLPFC. a placebo coil will be used.
Experimental: ineffective rTMS - Active TBS - EEG	Device: ineffective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an ineffective stimulation.; Device: active TBS; A continuous Theta-Burst Stimulation (cTBS) protocol will be applied over the L-DLPFC. Three stimuli at 50Hz, 80% of individual Motor Threshold will be repeated every 200ms for 40sec; Device: EEG; EEG will be coupled with task performance in an event-related manner to be able to isolate brain activity of each type of stimuli presented. EEG imaging data will be acquired during the memory task.
Experimental: Effective rTMS - Active TBS - EEG	Device: active TBS; A continuous Theta-Burst Stimulation (cTBS) protocol will be applied over the L-DLPFC. Three stimuli at 50Hz, 80% of individual Motor Threshold will be repeated every 200ms for 40sec; Device: Effective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an effective stimulation.; Device: EEG; EEG will be coupled with task performance in an event-related manner to be able to isolate brain activity of each type of stimuli presented. EEG imaging data will be acquired during the memory task.
Sham Comparator: ineffective rTMS - Sham TBS - EEG	Device: ineffective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an ineffective stimulation.; Device: Sham TBS; A Sham stimulation will be applied over the L-DLPFC. a placebo coil will be used.; Device: EEG; EEG will be coupled with task performance in an event-related manner to be able to isolate brain activity of each type of stimuli presented. EEG imaging data will be acquired during the memory task.
Sham Comparator: Effective rTMS - Sham TBS - EEG	Device: Effective rTMS; A 20Hz repetitive transcranial magnetic stimulation (rTMS) will be applied for 900 ms with an intensity of 90% of motor threshold. Active stimulation will be applied on the L-DLPFC compared to an effective stimulation.; Device: Sham TBS; A Sham stimulation will be applied over the L-DLPFC. a placebo coil will be used.; Device: EEG; EEG will be coupled with task performance in an event-related manner to be able to isolate brain activity of each type of stimuli presented. EEG imaging data will be acquired during the memory task.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Outputs of the memory task	outputs: number of correct answers during the retrieval event-related task (Hit rate) and the rate of false recognition of novel pictures (False Alarms rate).	up to Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CANTAB task	CANTAB / Rapid Visual Information Processing (RVIP); CANTAB / Spatial Working Memory (SWM); CANTAB / Paired Associates Learning (PAL)	Day 1 and Day 15
Gene expression	Interest genes expression will be investigated depending on the impact of TMS on behavioral and functional brain responses.	Day 1
Imaging	Functional MRI (Barcelona): modifications will be highlighted by changes in Blood Oxydation level Dependence (BOLD)signal patterns EEG (Marseille): modifications will be highlighted by changes in EEG markers	Day1 and Day 15

Collaborators and Investigators

• Sponsor: Qualissima
• Investigators: Principal Investigator: Christine Audebert, Cic-Cpcet

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: May 16, 2013
• First Submitted That Met QC Criteria: May 22, 2013
• First Posted (Estimate): May 23, 2013

Study Record Updates

• Last Update Posted (Estimate): April 19, 2016
• Last Update Submitted That Met QC Criteria: April 18, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Other Study ID Numbers: WP1P003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No