Probing the frontostriatal loops involved in executive and limbic processing via interleaved TMS and functional MRI at two prefrontal locations: a pilot study

Abstract

Background: The prefrontal cortex (PFC) is an anatomically and functionally heterogeneous area which influences cognitive and limbic processing through connectivity to subcortical targets. As proposed by Alexander et al. (1986) the lateral and medial aspects of the PFC project to distinct areas of the striatum in parallel but functionally distinct circuits. The purpose of this preliminary study was to determine if we could differentially and consistently activate these lateral and medial cortical-subcortical circuits involved in executive and limbic processing though interleaved transcranial magnetic stimulation (TMS) in the MR environment.

Methods: Seventeen healthy individuals received interleaved TMS-BOLD imaging with the coil positioned over the dorsolateral (EEG: F3) and ventromedial PFC (EEG: FP1). BOLD signal change was calculated in the areas directly stimulated by the coil and in subcortical regions with afferent and efferent connectivity to the TMS target areas. Additionally, five individuals were tested on two occasions to determine test-retest reliability.

Results: Region of interest analysis revealed that TMS at both prefrontal sites led to significant BOLD signal increases in the cortex under the coil, in the striatum, and the thalamus, but not in the visual cortex (negative control region). There was a significantly larger BOLD signal change in the caudate following medial PFC TMS, relative to lateral TMS. The hippocampus in contrast was significantly more activated by lateral TMS. Post-hoc voxel-based analysis revealed that within the caudate the location of peak activity was in the ventral caudate following medial TMS and the dorsal caudate following lateral TMS. Test-retest reliability data revealed consistent BOLD responses to TMS within each individual but a large variation between individuals.

Conclusion: These data demonstrate that, through an optimized TMS/BOLD sequence over two unique prefrontal targets, it is possible to selectively interrogate the patency of these established cortical-subcortical networks in healthy individuals, and potentially patient populations.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. TMS stimulation sites and anatomical regions of interest.

TMS was applied at two locations the DLPFC (F3, blue circle) and the MPFC (FP1, red circle), shown here on a standardized anatomical image (black circles = standard positions in the 10–20 system) (A). Regions of interest for analysis were defined apriori using standardized regions from the Automated Anatomical Labeling atlas (AAL) and included the middle frontal gyrus (blue), superior and middle orbital gyri (red)), caudate (pink), putamen (yellow), amygdale (orange), hippocampus (teal), and thalamus (green) (B). Additionally the cuneus was chosen as a control region (dark gray).

Figure 2. The location of the peak BOLD response for each individual following TMS pulses to the F3 location (blue spheres) and to the FP1 location (red spheres).

The locations of the peak BOLD response for each individual have be normalized to standard space and projected to the surface of standard cortical mask such that all points are visible in a common space. The mean location of peak activity in the cluster beneath the coil is shown (larger blue and red spheres).

Figure 3. Hemodynamic response in the left DLPFC and MPFC following stimulation at F3 and FP1.

Figure 4. Percent BOLD signal change in subcortical brain regions monosynaptically connected to the left DLPFC or MPFC following stimulation at the DLPFC site (F3) (gray) and the MPFC site ((FP1) (black).

The left and right portions of each ROI are displayed. *p

Figure 5. Spatial distribution of regions significantly activated by single-pulse TMS to the left DLPFC (A) and the MPFC (B).

A model of the placement of the TMS coil in the MR environment is shown in the far left panel. Statistical contrast maps of change in BOLD signal following a TMS pulse are shown in the panels to the right (t values displayed on colorbar, maximum 5).

Figure 6. Percent signal change in the left DLPFC following stimulation at F3 (A) and the MPFC following stimulation at FP1 (B) for 5 participants who underwent the experiment on two visits at the same threshold of stimulation.