Influence of Repetitive Transcranial Magnetic Stimulation (rTMS) Challenge on Cognitive and Functional Magnetic Resonance Imaging Markers in Healthy Subjects

• Part A: Location of cerebral activities [ Time Frame: Day 1 ] [ Designated as safety issue: No ]

  Primary endpoints:

  The location of cerebral activities elicited by the retrieval session of the episodic memory task during fMRI will be the primary endpoint of PART A.

  PART A will assess task-elicited BOLD signal modifications and determine the target location coordinates and verify the stability of the BOLD signal responses over time and the stability of the target location

  
  
• Part B: Outputs of the memory task [ Time Frame: Change between Day 2 and Day 1 ] [ Designated as safety issue: No ]
  Outputs: the number of correct answers during the retrieval blocks (Hit rates)and the number of false recognition of novel pictures (False Alarms rate).
  
  

• Part A: The outputs of the memory task [ Time Frame: Day 1 and Day 2 ] [ Designated as safety issue: No ]
  Memory task. The output of the task will be the number of correct answers during the retrieval blocks (i.e. correctly recognized images presented during the encoding blocks, Hits rate) and the number of false recognition of novel pictures (False Alarms rate).
  
  
• Part B: Imaging and CANTAB tasks [ Time Frame: Day 1, 2, 3 and 4 ] [ Designated as safety issue: No ]

  Imaging (functional MRI): Modifications will be highlighted by changes in the Blood-Oxygen-Level Dependence (BOLD) signal patterns.

  CANTAB tasks:

  • CANTAB / Rapid Visual Information Processing (RVP) with outcome measures: latency, probabilities and sensitivity and hits, misses, false alarms and rejections;
  • CANTAB / Spatial Working Memory (SWM) with outcome measures: errors, strategy and latency measures.
  • CANTAB / Paired Associates Learning (PAL) with outcome measures: errors, number of trials required to locate the pattern(s) correctly, memory scores.
  
  

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.

This pilot study specifically aims:

• to determine the cerebral region to stimulate using functional neuronavigation,
• to evaluate the effects of rTMS on behavioral and functional imaging data (functional Magnetic Resonance Imaging, fMRI)
• to investigate the stability of the TMS interfering effects by replicating the experimental day up to 4 times.

The study is composed of two parts:

• Part A: on Day 1, the subjects will perform the episodic memory task in the MRI scanner to determine individual main activations. The mean activation peak obtained by a group analysis will be used as the target coordinates during the part B. Two weeks later, on Day 2, the subjects will repeat the episodic memory task in the MRI scanner. The BOLD signal changes will be compared between Day 1 and Day 2 to investigate the stability of the activations elicited by the memory task.

• Part B: subjects will randomly be assigned to Group 1 or 2.

  • GROUP 1: The subjects will come on 4 different days. On each day, the subjects will perform the episodic memory task while being actively stimulated using rTMS over L-DLPFC and Vertex (control region) in random order and will undergo an fMRI session on Day 1 and Day 2. Later, they will undergo another set of behavioral tasks from the CANTAB battery and will be stimulated by rTMS using a placebo coil.
  • GROUP 2: The subjects will come on 4 different days. On each day, the subjects will perform the episodic memory task while being actively stimulated using rTMS over L-DLPFC and Vertex (control region) in random order and will undergo an fMRI session on Day 1 and Day 2. Later, they will undergo another set of behavioral tasks from the CANTAB battery and will be stimulated by rTMS using an active coil.

Total expected number of subjects:

34 subjects for the Parts A and B PART A: 10 subjects PART B: 24 subjects (12 per group)