A functional magnetic resonance imaging investigation of prefrontal cortex deep transcranial magnetic stimulation efficacy in adults with attention deficit/hyperactive disorder: A double blind, randomized clinical trial

Maya Bleich-Cohen, Guy Gurevitch, Noa Carmi, Mordekhay Medvedovsky, Noa Bregman, Naomi Nevler, Karin Elman, Amit Ginou, Abraham Zangen, Elissa L Ash, Maya Bleich-Cohen, Guy Gurevitch, Noa Carmi, Mordekhay Medvedovsky, Noa Bregman, Naomi Nevler, Karin Elman, Amit Ginou, Abraham Zangen, Elissa L Ash

Abstract

ADHD is one of the most prevalent neurocognitive disorders. Deep Transcranial Magnetic Stimulation (dTMS) is a non-invasive neuromodulation tool that holds promise in treatment of neurocognitive disorders. Hypoactivity of the prefrontal cortex (PFC) has been observed in ADHD. This study examined the clinical, cognitive, and neural effects of dTMS to the PFC in adults with ADHD by using functional magnetic resonance imaging (fMRI). High frequency repetitive dTMS was applied to either the right or left PFC in 62 adults with ADHD in a randomized, double blind, placebo controlled protocol with 3 study groups: 2 treatment arms (rPFC, or lPFC) and a Sham arm. The study included 15 dTMS/cognitive training treatment sessions. Clinical effects were assessed with the Conners Adult ADHD Rating Scale (CAARS) self-report and the Clinical Global Impression score (CGI) as primary outcome measures. Self-report/observer questionnaires and computerized cognitive testing were also performed to assess clinical and cognitive effects. Neural effects were assessed with fMRI using working-memory (WM) and resting-state paradigms. While the study did not show improvement in the primary endpoints, significant improvements were observed in the CAARS (self-report) inattention/memory sub-scale, as well as increased activations in the rDLPFC, right parietal-cortex and right insula/IFG during WM conditions after treatment in the right stimulation group. Increased rDLPFC activation was associated with larger symptom improvement in the right stimulation group. This study indicates that dTMS is effective in modulating attention related brain networks, and is a feasible technique that may improve attention symptoms in adults with ADHD.

Trial registration: ClinicalTrials.gov NCT01196910.

Keywords: ADHD; Inattention; PFC; Working-memory; dTMS; fMRI.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
(A) A time line of the study protocol. (B) Electric field distribution maps at 120% RMT of the right, left and sham H6 coils targeting PFC.
Fig. 2
Fig. 2
Clinical sub-scales. A line chart depicting the change from baseline scores of the two treatment groups (Right stimulation in red; left stimulation in blue) and Sham group (green) across time (Screening, visit 15, visit 16 and visit 17) of the (A) CAARS (observer) total subscale (B) CAARS (self-report) total subscale and (C) CAARS (self-report) inattention/memory subscale. Error bars represent standard errors. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Right DLPFC activation before and after treatment phase during the WM task. (a) Sagittal slice showing brain region of interest located in the right DLPFC (purple). The bar graph presents the brain activation (beta values) from right DLPFC in the three groups across conditions before (full bars) and after (clear bars) the 3 weeks of treatment. * P < 0.05. (b) Significant correlation r = 0.43, (P < 0.05) between activation change in the right DLPFC following treatment and improvement in inattention symptoms score shown in the right PFC stimulation group. DLPFC, Dorsolateral Prefrontal Cortex. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Right IPs activation before and after treatment phase during the WM task. Sagittal slice showing brain region of interest located in the right IPs (cyan). The bar graph presents the brain activation (beta values) from right IPs in the three groups across conditions before (full bars) and after (clear bars) following the 3 weeks of treatment. * P < 0.05 t. IPs, Intra Parietal sulcus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
Right IFG/ant. Insula activation before and after treatment phase during the WM task. Sagittal slice showing brain region of interest located in the right IFG/ant. Insula (light blue). The bar graph presents the brain activation from right IFG/ant. Insula in the three groups across conditions before (full bars) and after (clear bars) following the 3 weeks of treatment. * P < 0.05. IFG, Inferior Frontal Gyrus, ant., anterior. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 6
Fig. 6
Connectivity between mPFC & Right and Left Middle Insula during the WM task. Axial slice showing increased functional connectivity between mPFC (yellow) and the right & left middle insula (orange). The image was thresholded at q < 0.05, FDR corrected. Extracted beta values from the right middle insula (the left bar graph) and from the left middle insula (the right bar graph) showed that the treatment specifically enhanced mPFC-bilateral middle insula functional connectivity only for the right PFC stimulation group (in red). * P < 0.05; ** P < 0.005. Error bars represent standard errors. mPFC, medial prefrontal cortex. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 7
Fig. 7
Connectivity between mPFC & PCC during Resting State. Axial slice showing the seed region, mPFC (in yellow) and in midsagittal view increased functional connectivity with the PCC (orange). The image was thresholded at q < 0.05, FDR corrected. Extracted beta values from the PCC showed that the treatment specifically enhanced mPFC-PCC functional connectivity only for the right PFC stimulation group (in red). * P < 0.01; ** P < 0.005. Error bars represent standard errors. PCC, posterior cingulate cortex. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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