Single Session Low Frequency Left Dorsolateral Prefrontal Transcranial Magnetic Stimulation Changes Neurometabolite Relationships in Healthy Humans

Abstract

Background: Dorsolateral prefrontal cortex (DLPFC) low frequency repetitive transcranial magnetic stimulation (LF-rTMS) has shown promise as a treatment and investigative tool in the medical and research communities. Researchers have made significant progress elucidating DLPFC LF-rTMS effects-primarily in individuals with psychiatric disorders. However, more efforts investigating underlying molecular changes and establishing links to functional and behavioral outcomes in healthy humans are needed. Objective: We aimed to quantify neuromolecular changes and relate these to functional changes following a single session of DLPFC LF-rTMS in healthy participants. Methods: Eleven participants received sham-controlled neuronavigated 1 Hz rTMS to the region most activated by a 7-letter Sternberg working memory task (SWMT) within the left DLPFC. We quantified SWMT performance, functional magnetic resonance activation and proton Magnetic resonance spectroscopy (MRS) neurometabolite measure changes before and after stimulation. Results: A single LF-rTMS session was not sufficient to change DLPFC neurometabolite levels and these changes did not correlate with DLPFC activation changes. Real rTMS, however, significantly altered neurometabolite correlations (compared to sham rTMS), both with baseline levels and between the metabolites themselves. Additionally, real rTMS was associated with diminished reaction time (RT) performance improvements and increased activation within the motor, somatosensory and lateral occipital cortices. Conclusion: These results show that a single session of LF-rTMS is sufficient to influence metabolite relationships and causes widespread activation in healthy humans. Investigating correlational relationships may provide insight into mechanisms underlying LF-rTMS.

Keywords: dorsolateral prefrontal cortex (DLPFC); healthy subjects; low frequency; magnetic resonance spectroscopy; sternberg task; transcranial magnetic stimulation (TMS).

Figure 1

Procedural Outline.

Figure 2

Average pre to post (A) reaction time (RT), (B) N-acetylaspartate/creatine (Naa/Cr), (C) glutamate/glutamine (GlxGlx)/Cr and (D) Choline (Cho)/Cr changes following real (blue) and sham (red) stimulation (*corresponds to real vs. sham comparison, paired t-test p < 0.01; ⁺corresponds to comparison to 0 or no change; one-sample t-test p < 0.01).

Figure 3

Change from baseline correlation vs. baseline metabolite ratio levels for (A) Glx/Cr, (B) total NAA (tNAA)/Cr, (C) Cho/Cr.

Figure 4

Axial view centered on overlapping contrast images: green; (Δ) = (Post Real − Pre Real) > (Post Sham − Pre Sham) red-yellow; (Real) = Post Real > Pre Real, and blue-light blue; (Sham) = Post Sham < Pre Sham. (A) Parietal lobule/primary motor cortex (M1) activation (MNI: X = 2.16 mm, Y = −43.3 mm, Z = 61.8 mm) and (B) occipital cortex activation changes (MNI: X = −40.0 mm, Y = −80.0 mm, Z = 40.0 mm) are primarily a result of significant activation changes following real stimulation (red-yellow colormap). (C) Paracingulate gyrus/ACC changes (MNI: X = −3.48, Y = 52.5, Z = 4.95 mm) are primarily a result of significant activation changes following sham stimulation (blue-light blue colormap).