Investigating the mechanisms of repetitive transcranial magnetic stimulation using motor learning paradigms and in vivo 2 photon imaging

Modulation of cortical plasticity by the means of repetitive transcranial magnetic stimulation (rTMS) has generated significant interest as it can induce plasticity in clinical and non-clinical populations. In particular, complex pattern rTMS such as intermittent theta burst stimulation (iTBS) has been shown to induce long lasting effects in both humans and rodents. However, the biological mechanisms underpinning rTMS induced plasticity remains poorly understood. Rodent models offer the potential to investigate not only the behavioural, but the structural and molecular mechanisms post stimulation. This study examined changes in skilled motor learning and the extent of reorganisation at the dendritic and synaptic level following iTBS to the motor cortex. We use a rodent specific TMS circular coil to deliver iTBS (600 pulses) over the motor cortex of awake adult male mice. For motor learning paradigms, C57Bl6/J mice receive daily iTBS prior to undergoing a skilled pellet reaching task for 10 days. In a separate group; Thy1-GFPM mice undergo cranial window insertion overlying the right motor cortex to enable visualisation of excitatory cortical neurons in the upper layers of the motor cortex. Images of synaptic structures are collected at regular intervals before and after iTBS and analysed for alterations in connectivity resulting from stimulation. Preliminary analysis suggests daily iTBS significantly increases accuracy (15% over 10 days) but not speed of reaching, relative to sham stimulation (handling control).

These results help address the biological mechanisms underlying rTMS, which will undoubtedly pave the way forward in the therapeutic applications of non-invasive brain stimulation in health and disease.