A Preclinical Study of Standard Versus Accelerated Transcranial Magnetic Stimulation for Depression in Adolescents

Abstract

Objective: Ongoing studies are focused on adapting transcranial magnetic stimulation (TMS) for the treatment of major depressive disorder in adolescent humans. Most protocols in adolescent humans to date have delivered daily 10 Hz prefrontal stimulation with mixed results. Novel TMS dosing strategies such as accelerated TMS have recently been considered. There are knowledge gaps related to the potential clinical and pragmatic advantages of accelerated TMS. This pilot study compared the behavioral effects of a standard daily and accelerated low-intensity TMS (LI-TMS) protocol in an adolescent murine model of depression. Methods: Male adolescent Sprague Dawley rats were placed in transparent plexiglass tubes for 2.5 hours daily for 13 days as part of a study to validate the chronic restraint stress (CRS) protocol. Rats subsequently received 10 minutes of active or sham 10 Hz LI-TMS daily for 2 weeks (standard) or three times daily for 1 week (accelerated). Behavior was assessed using the elevated plus maze and forced swim test (FST). Hippocampal neurogenesis was assessed by injection of the thymidine analogue 5-ethynyl-2¢-deoxyuridine at the end of LI-TMS treatment (2 weeks standard, 1 week accelerated), followed by postmortem histological analysis. Results: There were no significant differences in behavioral outcomes among animals receiving once-daily sham or active LI-TMS treatment. However, animals treated with accelerated LI-TMS demonstrated significant improvements in behavioral outcomes compared with sham treatment. Specifically, animals receiving active accelerated treatment showed greater latency to the first immobility behavior ( p < 0.05; active: 130 -46 seconds; sham: 54 -39 seconds) and increased climbing behaviors ( p < 0.05; active: 16 -5; sham: 9 -5) during FST. There were no changes in hippocampal neurogenesis nor any evidence of cell death in histological sections. Conclusions: An accelerated LI-TMS protocol outperformed the standard (once-daily) protocol in adolescent male animals with depression-like behaviors induced by CRS and was not accompanied by any toxicity or tolerability concerns. These preliminary findings support the speculation that novel TMS dosing strategies should be studied in adolescent humans and will inform future clinical protocols.

Accelerated low-intensity rTMS does not rescue anxiety behaviour or abnormal connectivity in young adult rats following chronic restraint stress

“…However, treatment with accelerated 10 Hz LI-rTMS did not alter behaviour or brain-based measures. Our findings contrast with the positive outcomes previously reported after accelerated LI-rTMS in younger adolescent rats (6–7 weeks, at the start of the experiment ( Seewoo et al, 2021b )). One possible interpretation is that the response to CRS and potentially LI-rTMS depends on the age and/or weight and size of the animals, and these factors are discussed in detail at the end of the discussion.…”

“…We did not observe any changes in brain or behavioural measures following ten sessions of accelerated LI-rTMS over two weeks. This was surprising given the results from our pilot study suggesting that just one week of accelerated LI-rTMS rescued the effects of CRS ( Seewoo et al, 2021b ). We cannot rule out that the pilot study produced a false positive result due to a small sample size (n = 5 per group), or that the reduced statistical power due to multiple timepoints in the current study resulted in a false negative, despite the larger group size of n = 12.…”

“…Following CRS, animals in the treatment groups received 3 sessions of active or sham 10 Hz stimulation per day (spaced 1 h apart), for 5 consecutive days per week, for 2 weeks. Each stimulation session consisted of 10 min of 10 Hz low-intensity stimulation, in line with previous animal studies ( Makowiecki et al, 2018 ; Moretti et al, 2020 ; Poh et al, 2019 ; Seewoo et al 2018 , 2019b , 2021a , 2021b ). For all animals, behavioural tests and magnetic resonance imaging procedures were conducted at baseline, after the chronic restraint stress period, midway through treatment, post-treatment, and at one-week and two-week follow-up time points ( Fig.…”

“…MRI-based experiments have shown that changes in brain connectivity in rodents following low-intensity magnetic fields (LI-rTMS; to maximise focality ( Rodger et al, 2012 )) reflect those observed in healthy humans after conventional TMS ( Seewoo et al 2018 , 2019b ). LI-rTMS has also been applied in rodent models of depression with promising behavioural results: LI-rTMS successfully rescued behavioural and neurological symptoms in a mouse model of depression ( Heath et al, 2018 ), and a study in adolescent rats suggested a benefit of low-intensity 10 Hz accelerated compared to standard rTMS protocol on depression-like behaviours ( Seewoo et al, 2021b ). However, to date there have been no studies correlating behavioural and brain-based outcomes of rTMS in an animal model of depression.…”

“…Furthermore, changes in behaviour post CRS in rodents are associated with changes in connectivity ( Seewoo et al, 2020 ). We chose to study accelerated rTMS because recent clinical studies suggest that an accelerated delivery that provides a higher dose of stimulation may be as effective as standard delivery and may have advantages in some populations ( Baeken et al, 2021 ; Baeken et al, 2020 ; Cole et al, 2020 ; Seewoo et al, 2021b ; Williams et al, 2018 ). Our results show that although CRS successfully induced an agitated depression-like phenotype that was detected in behavioural and brain imaging measures, two weeks of accelerated 10 Hz LI-rTMS did not influence behaviour, brain connectivity, hippocampal volume or neurotransmitter levels.…”