Most mouse models of Dravet syndrome have supported the theory that SCN1A mutations affect inhibitory neurons more than excitatory neurons, resulting in a the inhibitory neurons’ failure to activate and counteract excitation. Various theories exist for why excitatory neurons are able to compensate for the loss of SCN1A function due to mutations, including the ability of excitatory neurons to increase expression of other ion channels. While neurons in vitro such as iPSCs have supported the inhibition theory, it has been difficult to test the theory in functioning human brains. This study, published in Neurology, used transcranial magnetic stimulation (TMS) to excite specific neuronal networks in 6 adult patients with Dravet syndrome, 10 adults with epilepsy (not DS), and 10 healthy controls, then measured the electrical response rate. No short interval intracortical inhibition (SICI) was found in the DS patients while the other epilepsy patients and healthy controls all had measurable inhibition. Long interval intracortical inhibition (LICI), on the other hand, was similar among all groups. Possible explanations for this difference include the differences between the pulses used in each system, the fact that SICI is believed to be mediated by GABAA receptors while LICI is believed to be mediated by GABAB receptors, the higher average number of anti-epileptic medications taken by DS patients, and a possible difference in measurement due to other SCN1A effects. Regardless, the finding that SICI is lower in DS patients while LICI remains normal supports the previous animal models and suggests the inhibitory networks are intact but have a “reduced sensitivity to low-intensity stimuli.”

Stern WM, Sander JW, Rothwell JC, Sisodiya SM. Impaired intracortical inhibition demonstrated in vivo in people with Dravet syndrome. Neurology. 2017 Mar 29. pii: 10.1212/WNL.0000000000003868. doi: 10.1212/WNL.0000000000003868. [Epub ahead of print] PubMed PMID: 28356460.