Interference with existing memories alters offline intrinsic functional brain connectivity

Abstract

The notion that already existing memories can be modified after their reactivation has received an increasing amount of experimental support, with empirical data accumulating across species and memory paradigms. However, there is no evidence for systems-level task-free intrinsic signatures of memory modification. Here, using a combination of behavioral, brain stimulation, and neuroimaging paradigms, we report that noninvasive transcranial magnetic stimulation interference with a reactivated motor memory altered offline task-free corticostriatal interregional functional connectivity, reducing it compared to stimulation in which the reactivated memory was intact. Furthermore, the modulated functional connectivity predicted offline memory modification. This reduction in functional connectivity recovered after additional execution of the memorized task, and the interference did not affect control cerebellar-cortical functional connectivity. This demonstrates that intrinsic task-free offline brain activity can be modulated by noninvasive interaction with existing memories and strongly correlates with behavioral measurements of changes in memory strength.

Figure 1. Experimental Design Enabling to Test the Effects of Memory Interference on Intrinsic Resting Brain Functional Connectivity

The task required to tap a 5-digit sequence with performance measured as the number of correct sequences during each fixed 10s trial. Participants were trained on a motor memory task (Figure S1). On a separate day, subjects completed the Memory Test and subsequently were divided into 2 groups. One group was stimulated with 1-Hz rTMS applied to the primary motor cortex (M1) synchronous with memory reactivation. The memory was reactivated by having the participants perform additional trials of the task. The control group received rTMS to a vertex position applied simultaneously with peripheral ulnar nerve stimulation, disrupting manual performance present when stimulating M1 but without disrupting memory modification. Both groups returned the following day for Memory Retest. Rest scans were performed before and after Memory Test and Memory Retest.

Figure 2. Memory Modification Interference

Control stimulation resulted in intact memory modification (improved performance between Test and Retest) while Interference stimulation did not, with significant differences in memory modification between the groups. Error bars represent standard error of the mean. *, P<0.05; ** P<0.005.

Figure 3. Alteration of Resting Cortico-Striatal Functional Connectivity Following Memory Interference

(A) M1 and sensorimotor striatum ROIs, identified from a baseline measurement of tapping vs. rest BOLD contrast before the experiment. Color indicates the value of the t-statistics. (B) Single subjects’ examples of time courses for M1 and sensorimotor striatum before (Post-Test) and after (Pre-Retest) interference with memory modification (upper quadrants) and control stimulation (lower quadrants). Correlations depicted for each ROI pair. (C) Mean correlations between sensorimotor striatum and M1 for each group before and after test and retest. Interference with memory modification resulted in weaker pre-retest functional connectivity between sensorimotor striatum and M1 compared to controls. Notably, functional connectivity in the interference group recovered following additional execution of the memorized task during retest. (D) The magnitude of memory modification (offline performance gains between test and retest, see Experimental Procedures) was predicted by pre-retest functional connectivity between sensorimotor striatum and M1 (Green - interference group; Gray – control stimulation group). Error bars represent standard error of the mean.

Figure 4. Visuomotor cerebellar-cortical connectivity

(A) Cerebellum ROI, identified from a baseline measurement of tapping vs. rest BOLD contrast before the experiment. Color indicates the value of the t-statistics. (B) Mean correlations between the anterior cerebellum and M1 for each of the groups before and after test and retest. Interference during memory reactivation did not alter pre-retest M1-cerebellar functional connectivity with no significant difference compared to controls. Increase in functional connectivity in the interference group following additional execution of the memorized task, however with no significant differences between the groups post-retest, may reflect resetting of the cerebellar-cortical circuit following memory interference. This is consistent with the involvement of this circuit in initial skill acquisition, thereby allowing within-session memory strengthening (Dayan and Cohen, 2011; Hikosaka et al., 2002; Ungerleider et al., 2002). Error bars represent standard error of the mean.