Maturation of EEG oscillations in children with sodium channel mutations

Abstract

Dravet syndrome (DS) is a severe epileptic encephalopathy beginning in infancy in which children have difficult to control seizures and cognitive impairment. The majority of children with DS carry mutate,ons of the gene Scn1a, which codes for the alpha subunit of the type 1 voltage-gated sodium channel and is important for the function of interneurons. Interneurons have a critical role in the generation of brain rhythms involved in cognitive processing. We hypothesized that children with DS with Scn1a mutations would have abnormal oscillatory activity. To address this hypothesis, we used EEG power spectral analysis during the wakening to determine if frequency and power are altered in 23 EEGs from 12 children with DS compared to 18 age-matched controls. While there were few differences between the EEG power spectra in DS and controls in children under 2 years, in older children group differences were apparent. In DS children between 3-5 years there were significant decreases in percentage of alpha power compared to controls and in DS children over age 6 years there was a marked increase of theta and decrease of alpha compared to controls. Developmental status paralleled the power spectral analysis with an increasing likelihood of having severe cognitive problems with increasing age. These results demonstrate that Scn1a mutations result in an age-dependent alteration in oscillatory process. Such abnormalities in developmental progression of oscillations may play an important role in poor cognitive development in children with DS.

Focal Scn1a knockdown induces cognitive impairment without seizures

“…A similar magnitude reduction of theta frequency was also found by Chauvière et al, 2009 in association with an impaired reaction to spatial change in a temporal lobe epilepsy model (Chauvière et al, 2009). Consistent with our findings in rodents, an altered pattern of brain oscillations has been observed in children with DS characterized by a shift toward slower frequencies on the cortical EEG (Holmes et al, 2011). In adults with DS, the presence/absence of background alpha oscillations also significantly correlates with the severity of mental deficits (Akiyama et al, 2010).…”

Early EEG and behavioral alterations in Dravet mice

“…When analyzing this way, the homogenous reduction in PSD at the worsening stage, from 0.5 Hz up to 30 Hz, resulted in similar percentage contribution ( Fig. 2I), resembling data from young Dravet patients (up to 2 years as tested by (Holmes et al, 2012)). However, since the absolute power in the gamma band was not reduced in DS mice (Fig.…”

Tau reduction prevents disease in a mouse model of Dravet syndrome

“…29,72,73 However, cognitive and behavioral abnormalities in patients with Dravet syndrome often do not improve upon treatment with antiepileptic medications, [12][13][14]64 which could simply be due to currently available antiepileptic drugs not being very effective at suppressing epileptic activity in this syndrome. 23,24 In addition, the frequency of convulsive seizures does not appear to correlate with cognitive outcomes in patients with Dravet syndrome, [74][75][76] which makes it interesting to consider additional mechanisms that could underlie the beneficial effects of tau reduction in Scn1a RX/1 mice. Such mechanisms may include alterations in excitation/ inhibition balance 4,77 and brain rhythms 76,[78][79][80] and deserve to be explored in future studies.…”

“…23,24 In addition, the frequency of convulsive seizures does not appear to correlate with cognitive outcomes in patients with Dravet syndrome, [74][75][76] which makes it interesting to consider additional mechanisms that could underlie the beneficial effects of tau reduction in Scn1a RX/1 mice. Such mechanisms may include alterations in excitation/ inhibition balance 4,77 and brain rhythms 76,[78][79][80] and deserve to be explored in future studies.…”