GABA and Glutamate in Children with Primary Complex Motor Stereotypies: An¹H-MRS Study at 7T

Abstract

Background and Purpose Complex motor stereotypies (CMS) are rhythmic, repetitive, fixed, purposeful but purposeless movements that stop with distraction. They can occur in otherwise normal healthy children (primary stereotypies), as well in those with autism spectrum disorders (secondary stereotypies). The underlying neurobiological basis for these movements is unknown, but thought to involve cortical-striatal-thalamo-cortical pathways. In order to further clarify potential neurochemical alterations, GABA, glutamate (Glu), glutamine (Gln), N-acetyl aspartate (NAA) and choline (Cho) levels were measured in four frontostriatal regions, using 1H MRS at 7T. Materials and Methods A total of 18 children with primary CMS and 24 typically developing controls, ages 5-10 years completed MRS at 7T. Single voxel STEAM acquisitions from the anterior cingulate cortex (ACC), premotor cortex (PMC), dorsolateral prefrontal cortex (DLPFC) and striatum were obtained and metabolites were quantified with respect to creatine using LCModel. Results The 7T scan was well tolerated by all participants. Compared to controls, children with CMS had lower levels of GABA ACC (GABA/Cr, p=0.049; GABA/Glu: p=0.051) and striatum (GABA/Cr: p= 0.028; GABA/Glu: p=0.0037), but not the DLPFC or PMC. Glu, Gln, NAA, and Cho levels did not differ between groups in any of the aforementioned regions. Within the CMS group, reduced GABA/Cr in the ACC was significantly associated with greater severity of motor stereotypies (r=-0.59, p= 0.021). Conclusions These results suggest possible GABAergic dysfunction within corticostriatal pathways in children with primary CMS.

Anomalous Putamen Volume in Children With Complex Motor Stereotypies

“…Prior studies in younger children with primary CMS 5 have shown a positive association between striatal GABA/Cr and SSS severity (but not ACC), perhaps suggesting the presence of a critical reduction in striatal projection neurons, beyond which there is no further impact on stereotypies. An additional potential explanation is that the expected correlation represents a developmental phenomenon, i.e., neurobiological changes associated with repetitive behavior may evolve over time.…”

“…These findings are generally consistent with results identified in a younger cohort of children with primary CMS (ages 5–9 years) evaluated by single voxel MR spectroscopy. In the latter, affected children had a significant reduction of GABA, the inhibitory neurotransmitter of striatal projection neurons and striatal and cortical interneurons, within both the striatum and ACC, but not prefrontal or premotor cortex 5 . In contrast, our larger sample, including both boys and girls, differ from a smaller earlier study of solely boys with primary CMS 4 , which showed a reduction in caudate and frontal white matter volumes.…”

“…In a small neuroimaging study of 6 boys with primary CMS, volumetric reductions (compared to typically developing boys) were identified in the caudate and frontal white matter 4 . A recent study of 20 primary CMS children, using 1 H-MR spectroscopy, identified a significant reduction of GABA in the striatum and anterior cingulate cortex, but not prefrontal cortex 5 .…”

“…Unlike voluntary movements, stereotypies are not preceded by movement-related cortical potentials 5 . Proposed hypotheses have suggested an alteration within cortico-striato-thalamo-cortical circuits or interconnecting regions 1 .…”

GABA and glutamate in children with Tourette syndrome: A 1 H MR spectroscopy study at 7 T

“…Few studies, however, have employed ultra-high imaging in pediatric populations, and (to our knowledge) only one study has used MRS at 7 T in children under age 10 years (Harris et al, 2016). Among published studies, there is variability in reported findings within 3 T protocols and differences between 3 T and 7 T MRS investigations of TS (see Table 1).…”