Neuromodulation‐dependent effect of gated high‐frequency, LFMS‐like electric field stimulation in mouse cortical slices

• Published in: The European journal of neuroscience 2019-05, Vol.49 (10), p.1288-1297
• Main Authors: Negahbani, Ehsan, Schmidt, Stephen L., Mishal, Nadia, Fröhlich, Flavio
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-Agonists - administration & dosage; Animals; Arousal; Carbachol - administration & dosage; cholinergic; Cholinergic Agonists - administration & dosage; Cholinergic transmission; Electric fields; Electric Stimulation; Electromagnetic Fields; Female; Firing rate; Magnetic fields; Mice, Transgenic; Neural Pathways - drug effects; Neural Pathways - physiology; Neuromodulation; Neurons - drug effects; Neurons - physiology; Neurotransmitter Agents - administration & dosage; noradrenergic; Norepinephrine; Norepinephrine - administration & dosage; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; state dependence; transcranial electric stimulation
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14273

Low‐field magnetic stimulation (LFMS) is a gated high‐frequency non‐invasive brain stimulation method (500 Hz gated at 2 Hz) with a proposed antidepressant effect. However, it has remained unknown how such stimulation paradigms modulate neuronal network activity and how the induced changes depend on network state. Here we examined the immediate and outlasting effects of the gated high‐frequency electric field associated with LFMS on the cortical activity as a function of neuromodulatory tone that defines network state. We used a sham‐controlled study design to investigate effects of stimulation (20 min of 0.5 s trains of 500 Hz charge‐balanced pulse stimulation patterned at 0.5 Hz) on neural activity in mouse medial prefrontal cortex in vitro. Bath application of cholinergic and noradrenergic agents enabled us to examine the stimulation effects as a function of neuromodulatory tone. The stimulation attenuated the increase in firing rate of layer V cortical neurons during the post‐stimulation period in the presence of cholinergic activation. The same stimulation had no significant immediate or outlasting effect in the absence of exogenous neuromodulators or in the presence of noradrenergic activation. These results provide electrophysiological insights into the neuromodulatory‐dependent effects of gated high‐frequency stimulation. More broadly, our results are the first to provide a mechanistic demonstration of how behavioral states and arousal levels may modify the effects of non‐invasive brain stimulation. Low‐field magnetic stimulation (LFMS) is under investigation as a treatment for depression, but the electrophysiological and brain‐state dependent effects of this gated high‐frequency stimulation remains unknown. In the presence of cholinergic neuromodulation, LFMS‐like stimulation modulated neuronal firing in layer V after offset of the stimulation. These results demonstrate how neuromodulatory tone can determine the network response to brain stimulation.