Network-targeted stimulation engages neurobehavioral hallmarks of age-related memory decline

Abstract

Objective: To test whether targeting hippocampal-cortical brain networks with high-frequency transcranial magnetic stimulation in older adults influences behavioral and neural measures characteristic of age-related memory impairment.

Methods: Fifteen adults aged 64 to 80 years (mean = 72 years) completed a single-blind, sham-controlled experiment. Stimulation targets in parietal cortex were determined based on fMRI connectivity with the hippocampus. Recollection and recognition memory were assessed after 5 consecutive daily sessions of full-intensity stimulation vs low-intensity sham stimulation using a within-subjects crossover design. Neural correlates of recollection and recognition memory formation were obtained via fMRI, measured within the targeted hippocampal-cortical network vs a control frontal-parietal network. These outcomes were measured approximately 24 hours after the final stimulation session.

Results: Recollection was specifically impaired in older adults compared to a young-adult control sample at baseline. Relative to sham, stimulation improved recollection to a greater extent than recognition. Stimulation increased recollection fMRI signals throughout the hippocampal-cortical network, including at the targeted location of the hippocampus. Effects of stimulation on fMRI recollection signals were greater than those for recognition and were greater in the targeted network compared to the control network.

Conclusions: Age-related recollection impairments were causally related to hippocampal-cortical network function in older adults. Stimulation selectively modified neural and behavioral hallmarks of age-related memory impairment, indicating effective engagement of memory intervention targets in older adults.

© 2019 American Academy of Neurology.

Figures

Figure 1. Stimulation increased recollection accuracy

(A) Participant-specific stimulation locations (one sphere shown per participant) were selected based on high seed-based resting-state fMRI connectivity with hippocampal target locations (one sphere shown per participant). (B) Before and approximately 24 hours after 5 consecutive daily sessions of full-intensity or sham stimulation, participants completed fMRI memory assessments. Stimulation and sham were administered in all participants in counterbalanced order using a within-subjects crossover design. Approximately 1 week following the post-stim and post-sham sessions, participants returned for follow-up assessments. Stimulation-induced electrical field for each stimulation condition is displayed for a representative participant with warmer colors representing peak intensity (range: 1–119 V/m). (C) Effects of stimulation on recollection and on recognition calculated for stimulation vs sham at the 24-hour assessment. (D) Recollection changes due to stimulation and sham. (E) Each bar represents a single-participant change in recollection and recognition for stimulation and sham, demonstrating consistent improvement due to stimulation particularly for recollection. Error bars indicate SEM. *p ≤ 0.05, **p ≤ 0.01.

Figure 2. Stimulation coherently increased hippocampal-cortical network activity during memory formation

(A) Mean fMRI activity was extracted from a priori selected network regions of the targeted hippocampal-cortical network and the control frontal-parietal network during object-location memory formation. (B) Mean fMRI activity changes (post-stim vs post-sham) for recollection compared to recognition in the targeted network vs the control network, and for recollection alone in the targeted and control networks. (C) Each bar is a single participant's mean recollection activity change in the targeted and control networks. (D) Mean recollection fMRI activity changes (post-stim vs post-sham) for each region of interest (ROI) in each network (see data available from dryad, table e-4, doi.org/10.5061/dryad.p2qq2d0, for region labels and for raw values for the post-stim and post-sham conditions). (E) Mean coherence change due to stimulation within the targeted network, the control network, and between the targeted and control networks. Error bars indicate SEM. *p ≤ 0.05.

Figure 3. Stimulation increased hippocampal activity during memory formation

(A) Segments along the anterior-posterior long axes of the left and right hippocampus relative to the average a priori target in the left hippocampus (y = −25). (B) Mean difference in recollection fMRI activity for each segment post-stim minus post-sham. Error bars indicate SEM. *p ≤ 0.05.