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Neuronal and Cerebrovascular Response to tDCS in Multiple Sclerosis: A Simultaneous tDCS-MRI Study

Marco Muccio^1,2, Giuseppina Pilloni³, Lauren Krupp³, Abhishek Datta⁴, Marom Bikson⁵, Leigh Charvet³, and Yulin Ge^1,2
¹Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York City, NY, United States, ²Center for Advanced Imaging Innovation and Research (CAI2R), Department of Radiology, New York University Grossman School of Medicine, New York City, NY, United States, ³Neurology, New York University Grossman School of Medicine, New York City, NY, United States, ⁴Research and Development, Soterix Medical Inc, Woodbridge Township, NJ, United States, ⁵Biomedical Engineering, City College of New York, New York City, NY, United States

Synopsis

Keywords: Multiple Sclerosis, Metabolism, cerebral metabolism, neural stimulation. blood flow

Motivation: The cerebral metabolic underpinnings of tDCS, both during the stimulation itself and as result of repeated sessions are still not fully understood.

Goal(s): To quantify the immediate tDCS effects (simultaneous) using real-time tDCS-MRI and treatment-related effects (cumulative after repeated sessions) in multiple sclerosis (MS) patients.

Approach: MS patients had tDCS-MRI performed at baseline and after 20 tDCS treatment sessions. Imaging measurements were acquired pre-, during- (2.0mA left frontal anodal) and post-tDCS.

Results: During tDCS, at baseline, we observed a 7.6% increase in cerebral metabolic rate of oxygen (CMRO₂). tDCS-treatment induced a 9.6% increase of the pre-tDCS CMRO₂ levels.

Impact: The significant increase in neuronal metabolism following both real-time and repeated tDCS treatment in MS patients offers valuable insights into the biophysiological mechanisms regarding acute and cumulative tDCS effects, informing future clinical applications in MS and other neurodegenerative diseases.

Introduction

Transcranial direct current stimulation (tDCS) is a safe and well-tolerated method which uses weak electrical currents to modulate cortical excitability[1]. TDCS studies of multiple sclerosis (MS) have shown clinical improvements in fatigue[2], motor function[3] and cognitive performance[4]. Recently, cumulative neuronal effects of repeated tDCS sessions have been observed in both healthy[5] and neurological disorders[6,7], with studies showing tDCS-induced cumulative effects that surpass what observed after a single tDCS session[8]. Although extensive research has been done focusing on the clinical outcomes of tDCS, neuronal metabolic response to the stimulation, an important measure of tDCS-induced neuronal activity change, has not been explored in MS. Recent advances in MRI enable cerebral metabolic rate of oxygen (CMRO2) to be rapidly and reliably quantified [9-11]. In this study, we investigated CMRO2 response to tDCS in MS to gain more in-depth understanding of the simultaneous (during tDCS) and cumulative (after repeated tDCS sessions) tDCS effects on neuronal metabolic response.

Methods

20 patients (age=45±13 years, 7 males) with MS diagnosis were recruited to participate in this simultaneous tDCS-MRI study. Stimulation was given via an MRI-compatible tDCS device (Soterix Medical) and consisted in a 15 minutes left anodal dorsolateral prefrontal cortex (DPFC, F3) direct current stimulation at 2.0mA (Fig.1A). The study included an initial tDCS-MRI baseline visit, followed by 20 at-home tDCS treatment sessions, and a follow-up tDCS-MRI visit. Each scanning visit consisted of three timepoints: pre-, during- and post-tDCS(Fig.1B). Imaging data was acquired in a 3T scanner fitted with a 64 channels head coil and comprised of the following sequences: phase contrast MRI (PC-MRI) to measure total blood influx through bilateral carotid and vertebral arteries (Fig.2A,B), subsequently normalized for subject-specific brain volumes, from a 3D-T1-MPRAGE, to obtain a global measure of cerebral blood flow (CBF) and a T2-Relaxation-Under-Spin-Tagging (TRUST)[10] was used to measure venous oxygenation (Yv) in the superior sagittal sinus, just above the venous confluence (Fig.2C,D). To investigate the tDCS-induced neuronal changes we calculated CMRO2 combining CBF and Yv measures, as reported previously[9,11]. Paired t-test was used to compare measurements of each imaging parameter amongst combination of the three timepoints as well as baseline vs follow-up.

Results

At baseline, global CBF increased from pre-tDCS (39.80±5.75 mL/100g/min) to during-tDCS (43.92±5.74 mL/100g/min; p<0.0001; Fig.3A). Yv exhibited a slight increase from pre-tDCS (58.83±3.39%) to during-tDCS (59.93±3.34%; p=0.006; Fig.3B). CMRO2 showed a notable 7.6% increase from pre-tDCS (128.30±14.00 µmol/100g/min) to during-tDCS (137.77±14.17 µmol/100g/min; p=0.002; Fig.3C). Across all parameters, at baseline, post-tDCS results remained elevated. At follow-up, after tDCS treatment, different tDCS simultaneous effects were observed. Just as similar to baseline measurements, CBF was higher during-tDCS (44.44±4.41 mL/100g/min) compared to pre-tDCS (43.02±4.85 mL/100g/min; p=0.014). Notably, there was a significant decrease of CBF in post-tDCS (42.70±3.52 mL/100g/min; p=0.031; Fig.3A). In contrast, both Yv and CMRO2 remained stable throughout the follow-up scan, with no significant changes observed (~58% and ~14 µmol/100g/min respectively; Fig.3B,C). Cumulative effects analysis showed increased CBF and CMRO2 pre-tDCS levels, before re-applying the stimulation, from baseline to follow-up (p=0.048 and p=0.006 respectively), while no such change was observed in Yv (Fig.4A-C). The overall mechanics are represented in figure 5.

Discussion

During the initial tDCS-MRI visit, we observed a significant immediate increase in CBF during the stimulation, which notably exceeded the increase observed in Yv (11.0% CBF vs 1.9% Yv). This suggests that the stimulated neurons quickly utilized most of the surplus oxygen, leading to the observed increase in CMRO2 (7.6%). This aligns with the current understanding that anodal tDCS enhances neuronal firing by further depolarization of the neuronal membrane[12,13]. Regarding the cumulative effects, MS patients exhibited a ~10% increase in pre-tDCS levels for both CBF and CMRO2, from baseline to follow-up. This suggests that repeated tDCS sessions may lead to prolonged elevation of neuronal activity in these patients. Notably, the absence of further simultaneous changes at follow-up indicates a potential plateau in stimulation effectiveness. Interestingly, tDCS effects persisted after the stimulation was removed (post-tDCS) in both visits, as noted in other studies [14,15]. This suggests that the stimulation-induced neuronal excitation does not quickly dissipate in MS subjects, offering valuable insights into predicting response to tDCS treatment.

Conclusion

In summary, our study showed that tDCS leads to immediate increases in cerebrovascular supply and neuronal activity in MS patients. Notably, these effects do not rapidly dissipate after stimulation cessation but instead tend to persist or linger. Importantly, our findings suggest that tDCS has cumulative properties, with repeated exposure (treatment) having long-lasting effects on the neuronal metabolic activity observed in MS patients.

Acknowledgements

This study was funded by National Institute of Health (NIH/NICHD: R21 HD094424) and was performed under the rubric of the Center for Advanced Imaging Innovation and Research (CAI2R, www.cai2r.net), an NIBIB National Center for Biomedical Imaging and Bioengineering (NIH P41 EB017183).

References

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2. Charvet, L.E., Dobbs, B., Shaw, M.T., Bikson, M., Datta, A. and Krupp, L.B., 2018. Remotely supervised transcranial direct current stimulation for the treatment of fatigue in multiple sclerosis: results from a randomized, sham-controlled trial. Multiple Sclerosis Journal, 24(13), pp.1760-1769.

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Figures

Figure 1. (A) TDCS montage with anode placed on the left dorsolateral prefrontal cortex (DLPFC; F3). (B) Study experimental design consisted of an initial simultaneous tDCS-MRI baseline session, followed by a 20 at-home tDCS treatment sessions, and a subsequent follow-up tDCS-MRI scan. During each MRI visit, image acquisition was divided into three sessions: before the stimulation (pre-tDCS), during 15 minutes 2.0mA stimulation (during-tDCS) and immediately after turning off the stimulation (post-tDCS).

Figure 2. (A) Angiographic reference frame from a time-of-flight (TOF) used for imaging slice placement of phase contrast (PC)-MRI. (B) PC-MRI magnitude and phase image output used for drawing regions of interest (ROIs) of: bilateral internal carotid (LICA, RICA) and bilateral vertebral arteries (LVA, RVA). (C) T2-Relaxation-Under-Spin-Tagging (TRUST) sequence set up(left) and the obtained labelled and control magnitude images (right). (D) The calibration correlation curve of T2 signal used to estimate corresponding venous blood oxygenation (Yv).

Figure 3. Imaging data acquired pre-, dur- and post-tDCS for cerebral blood flow (CBF; A), venous blood oxygenation (Yv; B) and calculated cerebral metabolic rate of oxygen (CMRO2; C) at both baseline (white bar plots) and follow-up visit (gray bar plots). Notice that simultaneous tDCS effects, characterized by an increase from pre- to dur-tDCS, were observed at baseline across all three measures but only in CBF at follow-up. Moreover, the increases persist after the stimulation is removed (post-tDCS), except for CBF at follow-up, which decreases in the post-tDCS.

Figure 4. Pre-tDCS imaging results for cerebral blood flow (CBF; A), venous blood oxygenation (Yv; B) and calculated cerebral metabolic rate of oxygen (CMRO2; C) at baseline (white bars) and follow-up (gray bars). It is noteworthy how repeated treatment sessions, via daily tDCS sessions, significantly contribute to an increase in pre-tDCS levels of both CBF and CMRO2 after the treatment, thus supporting the hypothesis of tDCS-induced cumulative effects.

Figure 5. A diagram summarizing the simultaneous and cumulative effects of tDCS as reported in this study. Notice how the stimulated neuros immediately increase their firing in response to tDCS (CMRO2 increase; white arrows), supported by an increase of blood supplied to the brain (CBF increase; red arrows). Notice also how the treatment (repeated tDCS sessions) causes the neuros to remain in the stimulated condition of increased activity measured pre-tDCS at follow-up and that re-introduction of the stimulation does not cause ulterior increase in CMRO2 but a slight increase in CBF.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)

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DOI: https://doi.org/10.58530/2024/0980