Repetitive Transcranial Magnetic Stimulation; A Comparative Trial of Low Frequency Treatments

Background and Aims: Repetitive Transcranial Magnetic Stimulation (rTMS) is a non‐invasive technique capable of altering cortical excitability and treating disease through effects on long term potentiation and depression. In general, high frequency stimulation is thought to produce facilitation, whereas low frequencies (1 Hz or less) produce inhibition. Few studies have investigated inhibitory rTMS using frequencies less than 1 Hz. One potential indication for inhibitory rTMS is hemispheric stroke, where hyperexcitability in the unaffected cortex may be detrimental, due to upregulated transcallosal inhibitory influences. Inhibitory rTMS to the unaffected hemisphere may be of benefit. Simple motor reaction times SRT) are slower when performed bimanually versus unimanually, in an effect termed Bimanual Cost (BC). BC is probably mediated by similar transcallosal mechanisms. The aims of this study were firstly to compare the effects of different low frequency rTMS protocols, and secondly, to determine if BC as a functional model for transcallosal effects in stroke could be modulated by rTMS. Methods: Three stimulation frequencies (1, 0.2 and 0.05 Hz) delivered to the right motor cortex at two intensities (110% and 80% of resting motor threshold) were compared in 20 normal volunteers aged 45 to 75 years, using a counterbalanced cross over design. TMS was carried out using a 70 mm figure of eight coil and was preceded and followed by assessment of neurophysiology with single pulse TMS, SRT and strength dynamometry. Each subject received four out of six possible combinations of frequency and intensity in sessions spaced at least 4 days apart. Results: Contrary to expectations, the predominant effect of rTMS protocols was to increase resting MEP (RMEP) amplitudes, indicating cortical excitation rather than inhibition. Comparison of protocols using a mixed linear statistical model revealed significant effects of frequency and intensity. Frequency was a significant determinant of RMEP (p= 0.026), CSP (p< 0.001) and unimanual SRT (Right and left hand, p= 0.02 and p<0.001 respectively). 1 Hz was more effective than both 0.2 and 0.05 Hz at raising RMEP amplitude (p< 0.001). Low intensity was more effective than high intensity at raising RMEP (p< 0.001) and caused a slight reduction in pinch grip strength (p= 0.044). There was significant interaction between frequency and intensity (p< 0.001) and the 1 Hz low intensity combination was the most effective at raising RMEP amplitude (p<0.001). BC was increased ipsilaterally with low intensity 1 Hz stimulation significantly more than high intensity at1 Hz (p= 0.021) and 0.05 Hz (p< 0.001). Conclusions: In this study, low frequency rTMS produced excitatory rather than inhibitory effects. Possible reasons for this are the older age group of participants and biphasic rather than monophasic stimulation. This study highlights the unreliability of low frequency rTMS as a means of inducing cortical inhibition and the need for better protocols. It also demonstrates that rTMS can modulate BC in a way analogous to hemispheric stroke, providing further support for the hypothesis that hyperexcitability of the unaffected motor cortex may have detrimental effects on recovery