Targeted enhancement of cortical-hippocampal brain networks and associative memory

Abstract

The influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans. We therefore used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation on memory. Multiple-session stimulation increased functional connectivity among distributed cortical-hippocampal network regions and concomitantly improved associative memory performance. These alterations involved localized long-term plasticity because increases were highly selective to the targeted brain regions, and enhancements of connectivity and associative memory persisted for ~24 hours after stimulation. Targeted cortical-hippocampal networks can thus be enhanced noninvasively, demonstrating their role in associative memory.

Fig. 1. Targeted cortical-hippocampal network stimulation

(A) For each subject, a parietal stimulation location was selected based on maximum local fMRI connectivity with a hippocampal target, and stimulation was applied to this location under MRI guidance (6). (B) Timing of assessments and stimulation sessions for the stimulation and sham weeks, with week order counterbalanced (6). Post-Tx assessment was ~24 h after the final stimulation session.

Fig. 2. Stimulation-induced fMRI connectivity increases selective to hippocampal targets

(A) Regions showing significant change in fMRI connectivity with the hippocampal target (Post-Tx versus baseline for stimulation compared to sham) (6) shown on a template brain viewed from the back left. (B) Stimulation-induced changes in whole-brain fMRI connectivity (T values of differences in global average connectivity) are colorized for the target and other locations along the anterior-posterior axis of the left hippocampus (which is displayed in green on the rendered brain) (6). The plot shows changes in fMRI connectivity values for the subject-specific hippocampal target (0 mm) and for 1.5-mm steps along the anterior-posterior hippocampal axis (negative values indicate anterior to the target). (C) The same change values are plotted for the four stimulation-responsive regions shown in (A). *P<0.05 versus zero; ***P<0.001 versus zero. Error bars and line shading indicate standard error of the mean.

Fig. 3. Stimulation-induced fMRI regional interconnectivity scales with baseline connectivity with hippocampal targets

(A) Coloration indicates the effect of stimulation (Post-Tx versus baseline for stimulation relative to sham, T value) on fMRI connectivity among stimulation-responsive regions (6). Regions are sorted by baseline fMRI connectivity with hippocampal targets (top rows and left columns are highest). Region labels are colorized and expanded in Fig. S2. (B) The degree of interconnectivity for a region (number of significant links with other regions surviving P < 0.05 FDR correction) correlated with the strength of baseline connectivity with hippocampal targets for the region. Shading indicates 95% CI.

Fig. 4. Stimulation-induced associative memory enhancement

(A) Structure of the face-cued word recall test of associative memory, involving recall during test of words arbitrarily paired with faces at study (6). Different word-face pairs were used for each assessment. (B) Stimulation increased memory whereas sham did not. Mean performance change for each assessment is expressed as a proportion of baseline. (C) Subset of treatment-responsive regions that demonstrate significant correlation between stimulation-induced fMRI connectivity change with hippocampal targets and memory improvement. (D) Plot of memory improvement values (Post-Tx vs. baseline for treatment relative to sham) and corresponding values of fMRI connectivity increase with respect to hippocampal targets from each subject for the four areas indicated in (C). *P < 0.05 Stimulation versus Sham; **P < 0.01 versus zero.