Moderators of stimulation-induced neural excitability in the left DLPFC: A concurrent iTBS/fNIRS case study

Intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex (lDLPFC) is an effective treatment for major depressive disorder [[1]Blumberger D.M. Vila-Rodriguez F. Thorpe K.E. Feffer K. Noda Y. Giacobbe P. et al.Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.Lancet. 2018; 391: 1683-1692Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar]. However, moderators of the effectiveness of iTBS and its underlying neural mechanisms remain unclear. Here, we measured the real-time neural response to iTBS in the lDLPFC using functional near-infrared spectroscopy (fNIRS), an ideal neuroimaging method for simultaneous measurement of the neural effects of iTBS, as the far infrared light of fNIRS and the magnetic field of iTBS do not interfere each other. We probed the effects of several intra-individual factors on the instantaneous cortical response to iTBS, including caffeine intake, time-of-day, and daily mood. The concurrent iTBS/fNIRS setup (see Supplementary 1.1) also allowed us to investigate the consistency of the real-time hemodynamic response to iTBS over 4 weeks of daily treatment. To conduct an intense within-subject iTBS experiment, we recruited one healthy participant, Mr. L, a 24-year-old, right-handed male (weight: 64 kg, ethnicity: Asian). The participant was instructed to take a 200 mg caffeine supplement exactly 1 h before the session or to abstain from caffeine altogether upon waking; and to attend the stimulation session in the morning (10:00 a.m.) or afternoon (5:00 p.m.). These assignments were randomized in a counterbalanced manner. Daily mood was assessed before the stimulation session using verbal analog scale (VAS, from 0 [lowest mood] to 10 [best mood]). In an exploratory approach, we also investigated further factors including sleep duration, sleep quality, daily energy level and exercise (did/did not go to the gym within 24 hours prior to a stimulation session) using VAS or by yes or no responses. Stimulation-induced pain was also assessed using VAS after each session. The raw data of this study is publicly available on Mendeley Data (https://data.mendeley.com/datasets/mnxd3xs8jk/1). iTBS was applied using 90% of the resting motor threshold (rMT), targeting the lDLPFC via neuronavigation at MNI coordinates, x = −38, y = +44, z = +26 for 20 daily sessions. The fNIRS measurements were conducted simultaneously with iTBS, capturing hemoglobin concentrations in the lDLPFC during stimulation (3 minutes 8 seconds), as well as before and after stimulation (3 minutes each). Stimulation-induced oxygen-hemoglobin concentration changes (ΔHbO) during and after stimulation were calculated by subtracting the corresponding mean of the absolute baseline values of each session. We employed a generalized linear mixed model (GLMM) to probe the effects of above named intra-individual factors on iTBS-induced ΔHbO (see Supplementary 1.2). The analysis indicated that caffeine intake, time-of-day, and session number (treatment progress) were significant moderators of iTBS-induced instantaneous cortical responses, indexed by ΔHbO during stimulation. Specifically, ΔHbO was significantly larger when the participant was not caffeinated (mean ± SE: 0.459 ± 0.106 μM) compared to when caffeine consumed (−0.033 ± 0.110 μM, P = 0.013, see Fig. 1a). iTBS-induced ΔHbO was also larger when the participant received the stimulation in the afternoon (0.554 ± 0.107 μM) compared to when the participant received the stimulation in the morning (−0.128 ± 0.107 μM, P = 0.001, see Fig. 1b). Moreover, there was a negative correlation between session number and iTBS-induced ΔHbO (P = 0.002). That is, iTBS-induced increases in HbO weakened over the course of the treatment, with the effect being reversed (iTBS-induced decreases) at around treatment session 16 (see Fig. 1c). When considering iTBS-induced ΔHbO during the 3 minutes immediately after stimulation as the dependent variable in the GLMM, significant moderating factors included daily mood, in addition to the before mentioned caffeine intake and time-of-day, but not session number (Fig. 1a and b). Specifically, there was a positive correlation between daily mood and iTBS-induced increase in HbO immediately after the stimulation (P = 0.008, see Fig. 1d). Exploratory GLMM including the factors sleep duration, sleep quality, daily energy level and exercise did not reveal any further intra-individual factors that significantly influenced stimulation-induced ΔHbO (see Supplementary 2.1 for details). Our findings highlight the influence of caffeine intake and time-of-day on iTBS-induced prefrontal excitability and further indicate that treatment progress (session number) and daily mood affects prefrontal excitation by iTBS. Common effects of caffeine, a frequently consumed neurostimulant in daily life, include cerebral vasoconstriction and reduced resting cerebral blood flow [[2]Chen Y. Parrish T.B. Caffeine's effects on cerebrovascular reactivity and coupling between cerebral blood flow and oxygen metabolism.Neuroimage. 2009; 44: 647-652Crossref PubMed Scopus (77) Google Scholar,[3]Yang H.S. Liang Z. Yao J.F. Shen X. Frederick B.D. Tong Y. Vascular effects of caffeine found in BOLD fMRI.J Neurosci Res. 2019; 97: 456-466Crossref PubMed Scopus (10) Google Scholar] (see also Supplementary 2.2 for caffeine-related reductions in baseline HbO levels in our participant). Our study adds to this knowledge by showing that the effects of caffeine on brain oxygenation are further enhanced by iTBS. Previous studies demonstrated increased motor cortex excitability in the afternoon, as assessed using paired associative stimulation, PAS [[4]Ridding M.C. Ziemann U. Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects.J Physiol. 2010; 588: 2291-2304Crossref PubMed Scopus (591) Google Scholar]. Our study corroborates these findings and expand them to the lDLPFC. Moreover, our study showed a successive decrease of iTBS-induced ΔHbO over the course of the four-week treatment. This can be explained by neural adaptation, similar to the sensory habituation of the treatment, in terms of reduced pain ratings, as found in our participant (see Supplementary 2.3) and as commonly observed after repeated treatments. Finally, our study showed an association between daily mood and iTBS-induced ΔHbO, indicating the feasibility of investigating the mechanism of mood-related disorders using iTBS-induced cerebral hemoglobin change. However, as this was a case experiment with only one participant, the generalizability of our findings remains unknown. Furthermore, although single-case experimental designs as originally formalized by B.F. Skinner, have the strength of systematically studying a variety of experimental conditions with internal validity being established by replication, any statistical analysis may entail the potential for overfitting. In summary, our study emphasizes the need to consider intra-individual factors when investigating the effects of iTBS on cortical excitability. Future studies are necessary to investigate whether these factors also moderate the therapeutic response to iTBS in a clinical setting. Investigating the real-time neural response to iTBS by means of concurrent fNIRS can provide valuable insights into optimizing the therapeutic benefits of non-invasive brain stimulation techniques. Rebecca L.D. Kan: Conceptualization, Methodology, Formal analysis, Investigation, Writing-Original Draft Tim T.Z. Lin: Conceptualization, Methodology, Formal analysis, Investigation, Writing-Review & Editing Bella B.B. Zhang: Formal analysis, Writing-Review & Editing Cristian G. Giron: Formal analysis, Writing-Review & Editing Minxia Jin: Formal analysis, Writing-Review & Editing Penny P.I. Qin: Formal analysis, Writing-Review & Editing Adam W.L. Xia: Formal analysis, Writing-Review & Editing Sherry K.W. Chan: Formal analysis, Resources, Writing-Review & Editing, Supervision, Bolton K.H. Chau: Formal analysis, Resources, Writing-Review & Editing, Supervision Georg S. Kranz: Conceptualization, Resources, Writing-Original Draft, Supervision, Project administration, Funding acquisition. The abstract of this study was presented at the 34th CINP World Congress of Neuropsychopharmacology (CINP 2023). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was supported by the General Research Fund under the University Grants Committee of the Hong Kong Special Administrative Region (numbers 15100120, 25100219 and 15106222) and the Mental Health Research Center, The Hong Kong Polytechnic University. The following is the Supplementary data to this article: Download .docx (.18 MB) Help with docx files Multimedia component 1