Neuromodulatory effects of theta burst stimulation, a molecular and functional assessment

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a therapeutic tool to alleviate symptoms of neurological and psychiatric disorders. Although the therapeutic potential of rTMS has been widely explored, the neurobiological basis of its effects is still not fully understood. This thesis used in vivo imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) in parallel with post-mortem evaluations to investigate the effects of a clinical course of theta burst stimulation (TBS) – a patterned form of rTMS – at the molecular and functional level in non-human primates (NHP). These techniques were employed to investigate rTMS-induced modulation of dopaminergic and glutamatergic neurotransmission, its effects on brain activity and connectivity, and glial reactivity modulation. Specifically, we evaluated the effects of rTMS in the healthy brain of NHP. Neuroimaging evaluations and cortical excitability assessments were performed before and one day after a clinical course of intermittent (iTBS), continuous (cTBS), or sham stimulation over the left motor cortex. Dopaminergic assessment using PET was also acquired immediately after the first stimulation session. Neurotransmission assessment revealed a decrease in dopamine release in the left and right putamen immediately after cTBS delivery, while no changes in neurotransmission were found in the striatum after multiple cTBS, iTBS, or sham sessions. Functional MRI revealed modulatory effects of cTBS and iTBS, but not sham delivery, between the regions of the cortico-striatal-thalamo-cortical motor loop. We found increased connectivity between the stimulated and the contralateral motor cortex. Furthermore, we found that baseline connectivity measurements were correlated to changes in dopamine release after a single stimulation session. Assessment of metabolic connectivity with PET revealed a brain-wide effect post-iTBS with no effects observed after cTBS and sham delivery. Finally, evaluation of glial reactivity with PET-PBR28 and MRS-myoinositol suggested no significant changes in glial activation after stimulation that would suggest neuroinflammation. Overall, this work suggests TBS induced long lasting changes in cortical excitability, functional and metabolic connectivity in the absence of neuroinflammatory response and lasting changes in striatal dopamine and glutamate.Medicine, Faculty ofGraduat

Evaluation of microglia activation related markers following a clinical course of TBS: A non-human primate study.

While the applicability and popularity of theta burst stimulation (TBS) paradigms remain, current knowledge of their neurobiological effects is still limited, especially with respect to their impact on glial cells and neuroinflammatory processes. We used a multimodal imaging approach to assess the effects of a clinical course of TBS on markers for microglia activation and tissue injury as an indirect assessment of neuroinflammatory processes. Healthy non-human primates received continuous TBS (cTBS), intermittent TBS (iTBS), or sham stimulation over the motor cortex at 90% of resting motor threshold. Stimulation was delivered to the awake subjects 5 times a week for 3-4 weeks. Translocator protein (TSPO) expression was evaluated using Positron Emission Tomography and [11C]PBR28, and myo-inositol (mI) and N-acetyl-aspartate (NAA) concentrations were assessed with Magnetic Resonance Spectroscopy. Animals were then euthanized, and immunofluorescence staining was performed using antibodies against TSPO. Paired t-tests showed no significant changes in [11C]PBR28 measurements after stimulation. Similarly, no significant changes in mI and NAA concentrations were found. Post-mortem TSPO evaluation showed comparable mean immunofluorescence intensity after active TBS and sham delivery. The current study suggests that in healthy brains a clinical course of TBS, as evaluated with in-vivo imaging techniques (PET and MRS), did not measurably modulate the expression of glia related markers and metabolite associated with neural viability