Frontal and thalamic changes of GABA concentration indicate dysfunction of thalamofrontal networks in juvenile myoclonic epilepsy

Abstract

SUMMARYObjective: Juvenile myoclonic epilepsy (JME) has been considered to be a frontal variant of thalamocortical network dysfunction in epilepsy. Changes of c-aminobutyric acid (GABA)ergic neurotransmission may play a key role in this dysfunction. Magnetic resonance spectroscopy (MRS) is the only noninvasive method to measure GABA concentrations in different brain regions. We measured GABA and other metabolite concentrations in the thalamus and frontal lobe of patients with JME. Methods: A specific protocol was used for determining GABA concentrations in the thalamus, frontal lobe, and motor cortex contralateral to the handedness in 15 patients with JME and 15 age-matched controls. In addition, we measured concentrations of glutamate and glutamine, N-acetyl-aspartate (NAA), myoinositol, creatine, and choline using MRS with short echo time. JME-related concentration changes were analyzed comparing patients to controls, also considering potential effects of antiepileptic drugs. Results: In patients with JME, GABA and NAA were reduced in the thalamus (p = 0.03 and p = 0.02), whereas frontal GABA and glutamine were elevated (p = 0.046 and p = 0.03). MRS revealed reduced NAA in the thalamic gray matter contralateral to the handedness (p = 0.04 each). These changes were found consistently in patients treated with new antiepileptic drugs and with valproate, although the extent of metabolic changes differed between these treatments. Significance: Decreased thalamic and increased frontal GABA suggest a dysfunction of GABAergic neurotransmission in these brain regions of patients with JME. The NAA decrease in the gray matter of the thalamus may hint to a damage of GABAergic neurons, whereas frontal increase of GABA and its precursor glutamine may reflect increased density in GABAergic neurons due to subtle cortical disorganization in the thalamofrontal network.

Spectral decomposition for resolving partial volume effects in MRSI

“…Over-estimation in NAA/Cr using the vAvg method seen in the thalamus and putamen can be attributed to bleeding from surrounding white-matter regions due to partial volume effects. This finding is consistent with other reports that indicate higher NAA/Cr in surrounding WM as compared to the thalamus (24). …”

Individual differences in GABA content are reliable but are not uniform across the human cortex

“…Abnormalities in GABA concentrations have been associated with neurological diseases and trauma (Blicher et al, 2015; Dharmadhikari et al, 2015; Draper et al, 2014; Hattingen et al, 2014; van der Hel et al, 2013). Given the reliability observed here in healthy individuals, it may be possible to relate local changes in GABA to patterns of recovery.…”

Sex‐specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy

“…A very recent study in patients with JME, using magnetic resonance spectroscopy with ultra-short echo time, determined that there is a decrease in thalamic GABA neurotransmission with an increase in N-acetyl-aspartate. These observations together suggest damage to thalamic GABAergic neurons (Hattingen et al 2014). Unfortunately, relatively low resolution of this technique does not make possible to investigate relatively small brain structures such as dorsolateral striatum, substantia nigra pars reticulata or amygdala.…”