Hippocampal and striatal responses during motor learning are modulated by prefrontal cortex stimulation

Abstract

While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof-of-concept study employed a multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and the basal ganglia during motor learning. Our results indicate that while stimulation did not modulate motor performance nor task-related brain activity, it influenced connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence, to the best of our knowledge, that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus.

Keywords: GABA; Hippocampus; Motor learning; Prefrontal cortex; Striatum; Theta-burst stimulation.

Fig. 1.

In each experimental session, participants first underwent pre-TMS whole-brain resting-state (RS) fMRI scans and magnetic resonance spectroscopy (MRS) scans of the dorsolateral prefrontal cortex (DLPFC) and the hippocampus (HC) that were followed by T1-neuronavigated intermittent or continuous theta-burst stimulation (iTBS or cTBS) applied to an individually-defined DLPFC target outside the scanner. Motor evoked potentials (MEPs) were measured pre- and post-TBS to probe corticospinal excitability (see Supplemental Fig. S2 and Supplemental Results for MEP results). Immediately following the end of the TMS session, participants were placed in the MR scanner where they were trained on the motor task (sequential [SEQ] or random [RND] versions of the serial reaction time task) while BOLD images were acquired. After task completion, post-TBS/task RS and MRS data of the DLPFC and hippocampus were acquired. The order of the four experimental conditions in this within-subject design [cTBS/SEQ (cSEQ), cTBS/RND (cRND), iTBS/SEQ (iSEQ), iTBS/RND (iRND)] was counterbalanced across participants. Note that the data related to the pre- and post-TBS RS scans are not reported in the present manuscript. TMS: transcranial magnetic stimulation.

Fig. 2.

Group target identification on an independent RS fMRI dataset. (A) Resting State Functional Connectivity (RSFC) maps of the hippocampus (HC, left panel) and the caudate nucleus (right panel). The respective seeds are depicted below the connectivity maps. See Supplemental Table S5 for the complete list of clusters. (B) Conjunction map between the HC and Caudate RSFC maps (displayed within a frontal mask). A 15-mm radius sphere (depicted as a black circle) centered around the peak maxima (−30 22 48 mm) was used as search area for individualized targeting in the current experiment. See Supplemental Table S6 for a list of prefrontal clusters identified in the conjunction analysis and Supplemental Table S7 and Supplemental Fig. S1 for individual TMS targets of the current experiment. Connectivity maps and RSFC seeds are displayed on a T1-weighted template image with a threshold of p_FDR < .05 for the connectivity maps. Color bars represent Z values.

Fig. 3.

MRS data of the DLPFC voxel. (A) Depiction of DLPFC MRS voxel positioning of a randomly selected participant and time point. The MRS voxel is overlaid on the participant- and time point-specific T1 structural scan. A glycerin maker was placed at the site of stimulation and was used to optimize MRS voxel positioning (marker visible on the coronal view). See Supplemental Fig. S3 for heatmaps representing the spatial overlap of voxel placement. (B) Spectra of all DLPFC MRS measurements (N = 150), from all participants and time points. GABA+ peak is visible at 3 ppm. Pre-TBS and post-TBS/task time points are depicted in green and magenta, respectively (mean spectrum across all participants and time points depicted in black). (C) ΔGABA in the four experimental conditions. Note that a pre- to post-intervention GABA+ increase and decrease are represented by values above and below 1 (indicated by the black dashed line), respectively. Exploratory analyses indicate that ΔGABA significantly differed between the iSEQ and iRND conditions. See Supplemental Table S8 for quality metrics and tissue segmentation, Supplemental Table S9 for follow-up tests for significant effects on tissue fractions and Supplemental Table S10 for raw GABA+ values. Error bars indicate SEM. Circles represent individual data points. Asterisk represents significant paired t-test with p < .05 (uncorrected for multiple comparisons). TBS: theta-burst stimulation, i: intermittent, c: continuous, SEQ: sequence, RND: random.

Fig. 4.

Behavioral results. Upper panel: Performance speed (reaction time, RT) improved over the course of training in the sequence task (SEQ) conditions and stayed stable in random task (RND) conditions. Lower panel: Performance accuracy remained stable in all conditions with overall higher accuracy in the SEQ than in the RND condition. The stimulation intervention (c: continuous and i: intermittent) did not affect motor performance nor motor learning.

Fig. 5.

Regressions with DLPFC ΔGABA. (A) Hippocampal (HC) dynamical activity during learning (30 −16 −18 mm, left panel) was differently related to DLPFC ΔGABA between conditions. (B) Learning-related changes in DLPFC-putamen functional connectivity (FC) patterns (20 4 −6 mm, left panel) were differently related to DLPFC ΔGABA between conditions. Regression maps are displayed on a T1-weighted template image with a threshold of p < .005 uncorrected. Color bars represent T values. Circles represent individual data, solid lines represent linear regression fits, dashed lines depict 95% prediction intervals of the linear function. au: arbitrary units, resp.: response, i: intermittent, c: continuous, SEQ: sequence, mod: modulation contrast, GABA = gamma-aminobutyric acid.

Fig. 6.

Stimulation effect on sequence (SEQ) task-related connectivity. (A) Functional connectivity (FC) between the right putamen and the sensorimotor putamen (28 −8 −2 mm, upper panel) increased more as a function of learning after iTBS compared to cTBS. FC with the caudate nucleus (10 12 −8 mm, lower panel) showed the opposite pattern. (B) FC of the DLPFC TBS target with the hippocampus (HC, 22 −40 0 mm) increased more as a function of learning in the cTBS as compared to the iTBS condition. Connectivity maps are displayed on a T1-weighted template image with a threshold of p < .005 uncorrected. Color bars represent T values. Error bars indicate SEM. au: arbitrary units, TBS: theta-burst stimulation, i: intermittent, c: continuous.