The use of chronic restraint stress in rodents to evaluate neurometabolite and hippocampal volume changes in depression, and how these are altered by accelerated low-intensity rTMS

Major depressive disorder (MDD) is amongst the most prolific neuropsychiatric disorders and is commonly characterised by hippocampal atrophy and neurometabolite imbalances. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation therapy that is efficacious in the treatment of medication-resistant MDD. However, heterogeneity amongst patients and stimulation parameters has made elucidation of the physiological mechanisms underlying rTMS, and optimisation of stimulation parameters challenging. Recent evidence has suggested that increasing the number of daily rTMS sessions (‘accelerated’ treatment) can maximise therapy benefits, whilst shortening treatment duration. The present study utilises a well-established rodent model of depression, chronic restraint stress (CRS), to investigate the hippocampal volumetric and neurometabolical changes implicated in depression, and how these are influenced by accelerated high-frequency (10 Hz) rTMS. Rats underwent 13 days of CRS, then three 10-minute sessions of 10 Hz low-intensity rTMS (LI-rTMS) to the left prefrontal cortex daily for 10 days. Untreated sham and depression control groups received either sham or no stimulation, respectively. Hippocampal volume was quantified using 9.4T MRI, and neurometabolite changes in the left sensorimotor cortex were evaluated using magnetic resonance spectroscopy (MRS). Animals were imaged weekly, starting prior to CRS until two weeks post-treatment. Significant right hippocampal volume increases were observed following CRS compared to baseline, suggesting stress-reactive changes rather than the expected depression-related atrophy. rTMS restored right hippocampal volume to baseline levels, whilst untreated groups continued to display volume increases up to three weeks post-CRS. Longitudinal alterations in
Glu/tCr, Gln/tCr, and Cho/NAA were observed in untreated rats, all of which were reversed or normalised by LI-rTMS. Neuroprotective increases in Tau/NAA were present in all animals, but were most pronounced in the rTMS-treated group. The present study provides evidence to support the ability of accelerated LI-rTMS to reverse stress-reactive neurological changes and emphasises the need for further investigation into the use of rTMS as a depression and/or anxiety treatment.