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Please cite this article as: Seewoo BJ, Feindel KW, Etherington SJ, Rodger J, Frequency-specific effects of low-intensity rTMS can persist for up to 2 weeks post-stimulation: A longitudinal rs-fMRI/MRS study in rats, Brain Stimulation,

Validation of chronic restraint stress model in young adult rats for the study of depression using longitudinal multimodal MR imaging MRI-based validation of CRS depression model

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used to treat many neuropsychiatric conditions. However, the mechanisms underlying its mode of action are still unclear. This is the first rodent study using resting-state functional MRI (rs-fMRI) to examine low-intensity (LI) rTMS effects, in an effort to provide a direct means of comparison between rodent and human studies. Using anaesthetised Sprague-Dawley rats, rs-fMRI data were acquired before and after control or LI-rTMS at 1 Hz, 10 Hz, continuous theta burst stimulation (cTBS) or biomimetic high-frequency stimulation (BHFS). Independent component analysis revealed LI-rTMS-induced changes in the resting-state networks (RSN): (i) in the somatosensory cortex, the synchrony of resting activity decreased ipsilaterally following 10 Hz and bilaterally following 1 Hz stimulation and BHFS, and increased ipsilaterally following cTBS; (ii) the motor cortex showed bilateral changes following 1 Hz and 10 Hz stimulation, a contralateral decrease in synchrony following BHFS, and an ipsilateral increase following cTBS; and (iii) hippocampal synchrony decreased ipsilaterally following 10 Hz, and bilaterally following 1 Hz stimulation and BHFS. The present findings demonstrate that LI-rTMS modulates functional links within the rat RSN with frequency-specific outcomes, and the observed changes are similar to those described in humans following rTMS.

The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy (1 H-MRS) at 3 T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluidcorrected ACC metabolite concentrations were compared between healthy control (HC, n = 16), depressed without SI (Dep/SI−, n = 13), and depressed with SI (Dep/SI+, n = 11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI− and Dep/SI+ adolescents. Dep/SI+ adolescents had higher Glx than Dep/SI− participants (p adj = 0.012) and had lower NAA/Glx than both Dep/SI− (p adj = 0.002) and HC adolescents (p adj = 0.039). There were significant relationships between SI intensity and Glx (p FDR = 0.026), SI severity and NAA/Glx (p FDR = 0.012), and SI intensity and NAA/Glx (p FDR = 0.004). ACC Glx and NAA/Glx discriminated Dep/SI− from Dep/SI+ participants. Uncoupled NAA−glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.

studies from other species 12,13 , we have freely released all data and the generated code.

Gut microbiome composition is associated with mood-relating behaviours, including those reflecting depression-like phenotypes. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, is an effective treatment for depression, but its effects on the gut microbiome remain largely unknown. This study assessed microbial changes from rat faecal samples longitudinally following chronic restraint stress (CRS) and 10 Hz low-intensity rTMS treatment. CRS increased abundance within the Proteobacteria (Deltaproteobacteria, Desulfovibrionales) and Firmicutes ( Anaerostipes, Frinsingococcus ) , with decreases in Firmicutes family (Acidaminococcaceae) and genera ( Roseburia , Phascolarctobacterium and Fusicatenibacter ) persisting for up to 4 weeks post CRS. The decrease in Firmicutes was not observed in the handling control and LI-rTMS groups, suggesting that handling alone may have sustained changes in gut microbiome associated with CRS. Nonetheless, LI-rTMS was specifically associated with an increase in Roseburia genus that developed 2 weeks after treatment, and the abundance of both Roseburia and Fusicatenibacter genera was significantly correlated with rTMS behavioural and MRI outcomes. In addition, LI-rTMS treated rats had a reduction in apoptosis pathways and several indicators of reduced inflammatory processes. These findings provide evidence that the brain can influence the gut microbiome in a “top-down” manner, presumably via stimulation of descending pathways, and/or indirectly via behavioural modification.

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