The peripheral effect of direct current stimulation on brain circuits involving memory

Sven Vanneste, Anusha Mohan, Hye Bin Yoo, Yuefeng Huang, Alison M Luckey, S Lauren McLeod, Michel N Tabet, Rimenez R Souza, Christa K McIntyre, Sandra Chapman, Ian H Robertson, Wing Ting To, Sven Vanneste, Anusha Mohan, Hye Bin Yoo, Yuefeng Huang, Alison M Luckey, S Lauren McLeod, Michel N Tabet, Rimenez R Souza, Christa K McIntyre, Sandra Chapman, Ian H Robertson, Wing Ting To

Abstract

An ongoing debate surrounding transcranial direct current stimulation (tDCS) of the scalp is whether it modulates brain activity both directly and in a regionally constrained manner enough to positively affect symptoms in patients with neurological disorders. One alternative explanation is that direct current stimulation affects neural circuits mainly indirectly, i.e., via peripheral nerves. Here, we report that noninvasive direct current stimulation indirectly affects neural circuits via peripheral nerves. In a series of studies, we show that direct current stimulation can cause activation of the greater occipital nerve (ON-tDCS) and augments memory via the ascending fibers of the occipital nerve to the locus coeruleus, promoting noradrenaline release. This noradrenergic pathway plays a key role in driving hippocampal activity by modifying functional connectivity supporting the consolidation of a memory event.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Figures

Fig. 1. ON-tDCS modulates the LC-NA pathway.
Fig. 1. ON-tDCS modulates the LC-NA pathway.
(A) ON-tDCS increases average pupil size for the active stimulation group, while participants who received sham stimulation had a decreased average pupil size. (B) ON-tDCS increases sAA during and after stimulation from baseline for the active group, while for the sham group, sAA levels remain similar during and after stimulation relative to baseline. (C) Mean average pupil diameter correlates with sAA. (D to F) Difference over the left parietal electrode side (black circle) for the active group relative to the sham group after ON-tDCS for (D) the peak amplitude and (E) mean amplitude over 300 to 600 ms with (F) a maximum difference for scalp electrode P3. (G to J) The difference in (G and I) pupil size and (H and J) sAA (after-before) correlates with the difference peak amplitude (after-before) and difference mean amplitude (after-before) for electrode P3. Error bars, SEM. Asterisks represent significant differences (*P < 0.05 and ***P < 0.001). (K) Source-reconstructed resting-state EEG analysis shows increased synchronization for the theta frequency band in the hippocampus for the active group relative to the sham group after ON-tDCS (corrected for baseline activity; permutation test, t20 = 3.81, P = 0.009). LH; left hemisphere, RH; right hemisphere. (L) Increased theta-gamma phase-amplitude coupling in the hippocampus after active ON-tDCS relative to sham stimulation. (M) A time-frequency analysis and (N) intertrial coherence for the auditory oddball task demonstrates increased theta and gamma power between 150 and 350 ms [see black circles in (D) and (E)] after active ON-tDCS relative to sham ON-tDCS (baseline- and bootstrap-corrected). See fig. S1 for ERP analysis for the standard.
Fig. 2. ON-tDCS modulates the amygdala-hippocampal region…
Fig. 2. ON-tDCS modulates the amygdala-hippocampal region through the LC-NA pathway.
(A) A seed-based approach revealed increased connectivity between LC, dorsal anterior cingulate cortex, and the temporoparietal junction during stimulation (see also table S1) and (B) an increased correlation strength between the LC and the hippocampus after stimulation (see also table S1). FDR, false discovery rate; fcMRI, functional connectivity MRI. (C) A region of interest (ROI)–to-ROI analysis shows an increased correlation strength during stimulation between LC and both the amygdala and the hippocampus (D and E), as well as correlation strength between the LC and the hippocampus after stimulation (F and G) for the active group relative to the sham group (corrected for baseline). (H and I) Differences were obtained for the active ON-tDCS group relative to sham ON-tDCS for the right amygdala and right hippocampus during stimulation. Error bars, SEM. Asterisks represent significant differences (*P < 0.05).
Fig. 3. ON-tDCS paired with training can…
Fig. 3. ON-tDCS paired with training can enhance memory encoding 1.
(A) The timeline for the face recognition task. (B) For the face-name association memory task, participants recognized more old faces but no new faces after active ON-tDCS relative to sham ON-tDCS. (C) Participants who received active ON-tDCS were better at associating the correct name to a face than sham group. (D and E) RTs for correctly classifying a face as old and for correctly associating a name to a face for the active and sham groups. (F) The timeline for the word association memory task. (G) Study design for the word association memory task. (H) During the study phase of the word association memory task, participants in the sham and active groups learn similarly. (I) ON-tDCS during a word association memory task can improve memory recall 7 days after the study phase for the active ON-tDCS group relative to the sham group. (J and K) No differences are obtained between the participants assigned to active or sham group for the time to answer during the study phase or 7 days after the study phase.
Fig. 4. ON-tDCS paired with training can…
Fig. 4. ON-tDCS paired with training can enhance memory encoding 2.
(A) tDCS targeting C2, neck (C5/6), or head [trigeminal nerve (TN)] during the study phase of the word association memory task, participants in the different group learning performed similarly. (B) ON-tDCS paired with a word association memory task can improve memory recall 7 days after the study phase for the active ON-tDCS group relative to the C5/6 or the trigeminal nerve. (C) A positive correlation between memory recall 7 days after the study phase and the difference in sAA before and after stimulation. (D and E) No differences are obtained between the participants assigned to one of the four conditions (C2 left, C2 right, C5/6, and trigeminal nerve), study phase (left), or 7 days after the study phase (right). (F) Memory recall 7 days after the study phase correlates with increased activity in the medial temporal lobe, as well as anterior and posterior cingulate cortex during training for the ON-tDCS group. (G) Stimulation of the C2 left, C2 right, C5/6, and trigeminal nerve revealed no significant difference when comparing the outcome for alertness before and after stimulation. (H to M) POMS questionnaire shows no significant difference before and after stimulation for the active and sham groups for tension-anxiety, anger-hostility, confusion-bewilderment, depression-dejection, fatigue-inertia, and vigor-activity. Error bars, SEM. Asterisks represent significant differences (*P < 0.05 and **P < 0.01). Photo credit: Wing Ting To.
Fig. 5. ON-tDCS immediately after the training…
Fig. 5. ON-tDCS immediately after the training in animals.
(A) Implantation targeting the greater occipital nerve (GON) [dorsal primary ramus of cervical spinal nerve using a cuff electrode (59)]. (B) Design for the objection recognition task and (C) design for the inhibitory avoidance task. (D) During the acquisition phase, time spent exploring the objects is not different between the active and sham groups in rats with a cuff electrode around the greater occipital nerve. (E) During the retention phase 24 hours later, rats in the active group interact more with novel objects relative to the sham group. (F) During acquisition, no difference in latency to enter the dark was obtained between the active and sham groups in rats with a cuff electrode around the greater occipital nerve. (G) Rats are given a single footshock in the dark chamber during the acquisition. During the retention phase 24 hours later, animals in the active group avoid the dark more relative to the sham group. Photo credit: Rimenez R. Souza
Fig. 6. ON-tDCS paired immediately after training…
Fig. 6. ON-tDCS paired immediately after training can enhance memory encoding in humans.
(A) ON-tDCS during or immediately after the study phase of the word association memory task, participants in the sham and active groups perform similarly. (B) ON-tDCS during or immediately after a word association memory task can improve memory recall 7 days after the study phase for the active ON-tDCS groups (independent of ON-tDCS during or immediately after the study phase) relative to the sham group. (C) Memory recall 7 days later correlates with the difference in sAA levels during the first visit (before versus after study phase) (D) Improved memory recall 7 days after stimulation is associated with increased activity in the medial temporal lobe, as well as anterior and posterior cingulate cortex immediately after ON-tDCS. (E) No effect was revealed between the active and sham group for the hours of sleep for the past 7 days after ON-tDCS. (F) No correlation is obtained between sleep and correctly recalled words. (G) Using ON-tDCS for a word association memory task during training did show a difference in memory recall 7 days after the study phase for the no anesthesia group relative to the anesthesia group. (H) ON-tDCS during the test phase (retrieval), 7 days after the participants studied the Swahili-English word associations, did not show a difference between the active and the sham group. Error bars, SEM. Asterisks represent significant differences (*P < 0.05 and **P < 0.01).
Fig. 7. Blinding experiments.
Fig. 7. Blinding experiments.
For all human experiments (experiments 1 to 7 and experiments 9 and 10), no difference was obtained between the active and sham group whether they anticipated active or sham stimulation.
Fig. 8. Meta-analysis.
Fig. 8. Meta-analysis.
A meta-analysis for the behavioral experiment revealed overall a strong effect size.

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