Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity

Abstract

Although the organization of neuronal circuitry is shaped by activity patterns, the capacity to modify and/or optimize the structure and function of whole projection pathways using external stimuli is poorly defined. We investigate whether neuronal activity induced by pulsed magnetic fields (PMFs) alters brain structure and function. We delivered low-intensity PMFs to the posterior cranium of awake, unrestrained mice (wild-type and ephrin-A2A5(-/-)) that have disorganized retinocollicular circuitry and associated visuomotor deficits. Control groups of each genotype received sham stimulation. Following daily stimulation for 14 d, we measured biochemical, structural (anterograde tracing), and functional (electrophysiology and behavior) changes in the retinocollicular projection. PMFs induced BDNF, GABA, and nNOS expression in the superior colliculus and retina of wild-type and ephrin-A2A5(-/-) mice. Furthermore, in ephrin-A2A5(-/-) mice, PMFs corrected abnormal neuronal responses and selectively removed inaccurate ectopic axon terminals to improve structural and functional organization of their retinocollicular projection and restore normal visual tracking behavior. In contrast, PMFs did not alter the structure or function of the normal projection in wild-type mice. Sham PMF stimulation had no effect on any mice. Thus, PMF-induced biochemical changes are congruent with its capacity to facilitate beneficial reorganization of abnormal neural circuits without disrupting normal connectivity and function.

Long term delivery of pulsed magnetic fields does not improve learning or alter dendritic spine density in the mouse hippocampus

“…Although ephrin-A2 -/- mice have abnormal brain circuitry and associated abnormal behaviours, in the present study, the previously reported learning deficit 17 was not observed due to low levels of food deprivation 18 . The absence of observed behavioural and structural change is consistent with previously reported rTMS specificity for abnormal systems 8, 19 . Furthermore, the lack of adverse effects in our long term study contributes evidence that rTMS is safe to use in healthy control participants 20 .…”

“…Although the mice learned the task, their performance remained suboptimal due to lack of motivation to obtain food rewards through insufficient food restriction 18 and neither learning behaviour, nor hippocampal spine density were affected by long term rTMS. Our negative results are consistent with previous data showing that rTMS has a selective effect on abnormal or injured brain circuitry 19 , and the lack of deleterious side effects observed in normal human subjects 8, 20 .…”

“…To deliver rTMS, we built a small coil created for mice (0.25 mm copper wire (Jaycar, Australia) 300 windings, 16 Ω, outer diameter 8 mm) 19 . The coil was designed to ensure a similar coil-to brain ratio as is used for induction of focal electric fields in humans 23 and was driven by an electromagnetic pulse generator (Global Energy Medicine, Australia) that delivered a magnetic field of 10 mT.…”

“…We chose a complex pattern of stimulation because it has been shown to induce structural changes in mice 19 (59.9-ms trains of 20 pulses at 3 different frequencies as follows: 1 min warm-up at 6.71 Hz, 8 min treatment at 10.1 Hz, and 1 min cool down at 6.26 Hz. The pulse duration was 200 µs, which is within the range used in human rTMS.…”

“…Sham stimulation involved the same procedure but with the stimulator switched off. This control was chosen as our coil did not produce any audible sound 19 .…”