Introduction

Transcranial magnetic stimulation (TMS) is approved for treating major-depressive-disorder (MDD), a condition that affects 1 in 7 people during their lifetime¹. An increasingly popular protocol, due to short session time, is intermittent theta burst stimulation (iTBS), in which TMS pulse triplets repeat at 5Hz (a “theta” frequency)². Response to TMS, including iTBS, is highly variable^3,4. We are examining a relatively inexpensive, easy-to-implement, approach to make iTBS act faster, for more people, by modifying “brain state” at the time of stimulation.

Materials / Methods

One aspect of “brain state” is oscillatory activity, generated by neural-circuit dynamics. Oscillatory activity mediates excitability within brain areas and connectivity between areas⁵. Pre-treatment fronto-central theta oscillatory power, measured with electroencephalography (EEG), is correlated with response to antidepressant medications⁶. Li et al.⁷ found that performance of a theta-eliciting task prior to TMS was associated with better clinical response, and post-task theta predicted response. However, task-based augmentation is unsuitable for people with more severe depression, characterised by cognitive and motivational difficulties^8,9.

Our approach seeks to enhance theta activity during and after iTBS (and thus augment iTBS efficacy) using concurrent, synchronised, transcranial alternating-current stimulation (tACS). (Building on work showing combined tACS-TMS enhances oscillatory power for traditional “rTMS” protocols¹⁰). tACS is delivered at a theta-frequency (5Hz), with 1mA peak-to-peak amplitude, using 9cm² round-electrodes at F3 (anode) and TP9 (cathode). iTBS at 80% resting-motor-threshold (20 cycles - 600 pulses, 3.3 minutes) is delivered via a 70mm figure-eight coil over F3, with pulse triplets timed to occur at the tACS peaks (Fig.1A).

Results

In an ongoing non-patient study (current N=12, 6 female, age±SD 24.1±5.6 years), theta activity during an n-back working-memory task is recorded before, and 1/8/15-minutes after, one session of “tACS-synchronised TMS” (tsTMS), TMS with sham-tACS, or double-sham. In the double-sham condition, theta decreased with repetition of the n-back task. In both stimulation conditions, this reduction was arrested, with an increase in theta (relative to pre-stimulation) at the 8/15-minute time points. At 15-minutes, theta was greatest in the tsTMS condition (Fig.1B,2A). At 20-minutes, positive emotional bias (a marker of potential antidepressant efficacy^11,12, obtained from ratings of “happy” or “sad” to briefly-presented facial expressions) was greatest after tsTMS (followed by TMS alone, Fig.2B).

Discussion

The results suggest tACS-synchronisation may be able to augment the antidepressant effects of TMS. tsTMS was equally well-tolerated to TMS-alone.

Conclusions

Our next step is a pilot of multiple sessions of tsTMS with patients, to obtain further mechanistic evidence and estimates of clinical effect-size.

References

¹Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:369-388. doi:10.1146/annurev-publhealth-031912-114409

²Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201-206. doi:10.1016/j.neuron.2004.12.033

³López-Alonso V, Cheeran B, Río-Rodríguez D, Fernández-Del-Olmo M. Inter-individual variability in response to non-invasive brain stimulation paradigms. Brain Stimul. 2014;7(3):372-380. doi:10.1016/j.brs.2014.02.004

⁴Kaster TS, Downar J, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Blumberger DM. Trajectories of response to dorsolateral prefrontal rTMS in major depression: A three-D study. Am J Psychiatry. 2019;176(5):367-375. doi:10.1176/appi.ajp.2018.18091096

⁵To WT, de Ridder D, Hart J, Vanneste S. Changing brain networks through non-invasive neuromodulation. Front Hum Neurosci. 2018;12:128. doi:10.3389/fnhum.2018.00128

⁶Spronk D, Arns M, Barnett KJ, Cooper NJ, Gordon E. An investigation of EEG, genetic and cognitive markers of treatment response to antidepressant medication in patients with major depressive disorder: A pilot study. J Affect Disord. 2011;128(1-2):41-48. doi:10.1016/j.jad.2010.06.021

⁷Li CT, Hsieh JC, Huang HH, et al. Cognition-modulated frontal activity in prediction and augmentation of antidepressant efficacy: a randomized controlled pilot study. Cereb Cortex. 2016;26(1). doi:10.1093/cercor/bhu191

⁸Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry. 2001;178:200-206. doi:10.1192/bjp.178.3.200

⁹McDermott LM, Ebmeier KP. A meta-analysis of depression severity and cognitive function. J Affect Disord. 2009;119:1-8. doi:10.1016/j.jad.2009.04.022

¹⁰Hosseinian T, Yavari F, Biagi MC, et al. External induction and stabilization of brain oscillations in the human. Brain Stimul. 2021;14(3):579-587. doi:10.1016/j.brs.2021.03.011

¹¹Harmer CJ, Mackay CE, Reid CB, Cowen PJ, Goodwin GM. Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry. 2006;59(9):816-820. doi:10.1016/j.biopsych.2005.10.015

¹²Harmer CJ, Cowen PJ. “It's the way that you look at it”—a cognitive neuropsychological account of SSRI action in depression. Philos Trans R Soc B: Biol Sci. 2013;368:201204073. doi:10.1098/rstb.2012.0407.

Learning Objectives

1. Gain awareness of current use of TMS in major depressive disorder

2. Understand how tACS-synchronisation can be achieved alongside TMS ("tsTMS")

3. Understand how tsTMS modifies markers of potential antidepressant efficacy (oscillatory activity, emotional bias)