Depression in MS patients adds substantially to the morbidity and mortality associated with this disease. TMS is a neurostimulatory and neuromodulatory technique which is based on the electromagnetic induction of an electric field in the brain .
FA has been found to be a sensitive measure of structural brain damage, as it can quantify the degree of water diffusion and reliably visualize the microstructural status . Numerous studies have reported reduced FA values in brains of patients with depression [14, 15]. In the current study, high-frequency repetitive transcranial magnetic stimulation (HF-rTMS)-treated patients had significantly higher post-treatment FA values in left DLPF area compared to patients treated with SSRIs.
Liao et al. reported patients with treatment-resistant depression had reduced left middle frontal gyrus FA values, which significantly improved after 4 weeks of rTMS treatment which agreed with our results .
In the same context, May et al. found a significant structural alteration at the superior temporal cortex reflected as increase in grey matter cortical evoked potential using voxel-based morphometry in regions of the brain stimulated with rTMS after 5 days of 1-Hz rTMS treatments at 110% motor threshold to the superior temporal gyrus . Although these are different stimulated regions, using different rTMS parameters, and different imaging protocol from our study, it still supports the idea that rTMS can induce structural as well as functional changes.
One explanation for the selectively increased FA values after HF-rTMS is that the repeated rTMS induces a positive effect on the white matter organization for the side of the brain stimulated. White matter anatomical connectivity changes following rTMS involve enhanced myelination, axonal and dendritic growth, and remodelling [18, 19]. Other potential mechanisms underlying sustained changes following rTMS is synaptic strength enhancement, through long-term potentiation and long-term depression that can last for several hours, days, or even weeks .
There has been limited research observing how white matter structures change after antidepressant treatment. On comparing FA values before and after administration of SSRIs, our study found no significant difference between pre- and post-treatment values. An explanation could be that SSRIs increase extracellular neurotransmitter activity thus modulating neuron activity in receptor-rich areas rather than inducing structural changes and that they appear to act more as symptom relievers rather than as normalizers of pathophysiologic causality .
In a study done by Avissar et al., resting state functional MRI was acquired in 27 patients suffering from depression and treated with rTMS over the left DLPF cortex. They measured the functional connectivity between the frontal cortex and the corresponding striatal targets based on diffusion tensor imaging, and they concluded that higher functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and striatum predicted better treatment response .
As for the clinical outcome, in the current study, patients who received either rTMS or SSRIs had a significant decrease in their BDI scores post-treatment, thus emphasizing the efficacy of rTMS in the same respect as the SSRIs in treating depression in RRMS patients.
In agreement with our results, George et al. observed that depression scores significantly decreased after treatment with rTMS . In contrast, other studies did not show any benefit of rTMS in treatment of depression [24, 25].
No significant difference was found in this study when comparing therapeutic impact of rTMS on depression to that of SSRIs. This goes in accordance with Bares et al. who compared the efficacy of 1-Hz rTMS over the right prefrontal dorsolateral cortex with venlafaxine in the treatment of resistant depression; clinically relevant reduction of depressive symptomatology was found in both groups, and the rTMS results were comparable to that of venlafaxine .
Nevertheless, RRMS patients, in this study, showed significant improvement of their PASAT scores after receiving either HF-rTMS or SSRIs. This goes with Hulst et al. who investigated the effects of HF-rTMS of the right DLPF area on working memory performance and reported improved N-back accuracy following treatment . In another study by Culang-Reinlieb et al., conducted on patients with major depressive disorder on SSRIs, verbal learning improvement was noticed regardless of the patients’ response to therapy .
Limitations of our study include relatively small group numbers and lack of placebo and sham rTMS arms to compare with both the SSRI and rTMS groups. Also the use of ROI measurements on FA maps is inherently limited when compared to voxel-based analysis such as TBSS; however, this depends on the software availability.