Monday, November 27, 2017

GABA alterations in pediatric sport concussion

Friedman SD, Poliakov AV, Budech C, Shaw DWW, Breiger D, Jinguji T, Krabak B, Coppel D, Lewis TM, Browd S, Ojemann JG. GABA alterations in pediatric sport concussion. Neurology. 2017 Nov 21;89(21):2151-2156.

To evaluate whether frontal-lobe magnetic resonance spectroscopy measures of γ-aminobutyric acid (GABA) would be altered in a sample of adolescents scanned after sport concussion because mild traumatic brain injury is often associated with working memory problems.
Eleven adolescents (age 14-17 years) who had sustained a first-time sport concussion were studied with MRI/magnetic resonance spectroscopy within 23 to 44 days after injury (mean 30.4 ± 6.1 days). Age- and sex-matched healthy controls, being seen for sports-related injuries not involving the head and with no history of concussion, were also examined. GABA/creatine + phosphocreatine (Cre) was measured in left-sided frontal lobe and central posterior cingulate regions. The frontal voxel was positioned to overlap with patient-specific activation on a 1-back working memory task.
Increased GABA/Cre was shown in the frontal lobe for the concussed group. A decreased relationship was observed in the parietal region. High correlations between GABA/Cre and task activation were observed for the control group in the frontal lobe, a relationship not shown in the concussed participants.
GABA/Cre appears increased in a region colocalized with working memory task activation after sport concussion. Further work extending these results in larger samples and at time points across the injury episode will aid in refining the clinical significance of these observations.


From the article:

GABA is the major inhibitory neurotransmitter and is an important factor in both normal cognitive function and the sequelae of traumatic brain injury. While spectroscopy has now been widely applied in traumatic brain injury, primarily to look for markers of neuronal loss before the development of DTI, to the best of our knowledge, no study to date has evaluated changes in GABA. Relative to structural markers of injury (e.g., N-acetylaspartate and choline-containing compounds), GABA is unique in that levels have been shown to be associated with cognitive functioning. For example, correlation of magnetoencephalographymeasures of gamma band activity (likely mediated by GABAa), fMRI, and GABA was demonstrated in the visual cortex in response to a visual discrimination tasks. Similar findings have been found for motor control and GABA in the supplementary motor area, tactile discrimination and GABA in the sensorimotor cortex, and gaze shifting and GABA levels in the frontal eye fields. In 2 of these studies, control regions, chosen to assess cortical GABA levels remote from the site of interest, demonstrated no concordance to performance.  Although GABA level changes do no incorporate measurement of other factors (e.g., receptor density changes, enzyme alterations), the concordance between GABA and discrete task performance supports the need to evaluate this biomarker in conditions in which structural changes may be difficult to characterize.

Evidence on a cellular level also supports that GABA may be a particularly important marker of injury and recovery in concussion. Alterations in GABA, especially GABA transport, have been seen in trauma models, both fluid percussion injury and shear injury to the developing brain. GABA-mediated inhibition can increase after injury such as stroke in response to transport and receptor dysregulation, and the corresponding increase in tonic inhibition may be deleterious to recovery from injury. Intervention, by pharmacologic inhibition of specific GABA subunits, improved motor function recovery in an animal model. This is a proposed mechanism for impaired recovery after cortical injury, with pharmacologic interventions potentially available to reverse this process. GABA changes may alter postconcussive motor plasticity. However, excessive impairment in GABA can also lead to deleterious effects such as seizures, and the understanding of the complexities of GABA after injury is critical to guiding future interventions. It is plausible that our finding of elevated GABA is imaging evidence of changes known to occur with cellular injury. The selective change in the frontal lobe would be consistent with the increased vulnerability of this region to traumatic injury.

The potential that GABA provides a protective effect or corresponds to the postconcussive cognitive symptoms or impairment often observed remains unresolved from this work. While no child in the study was experiencing headaches that would be classified as migraines, literature supporting GABA elevations in this condition provides interesting fodder for consideration. If elevated GABA occurs as a byproduct of injury, it could be envisioned to influence local activity. In general, elevated GABA is associated with improved tuning and performance, suggesting that GABA elevation could be the result of recovery attempts or possibly increased cognitive effort to perform the task as well as healthy controls. Somewhat concordant with this idea, increased activation in the frontal lobe has been described after injury or in impaired states. The correlation between GABA and fMRI activation has been studied, with how well abnormal tissue fits these associations not known. Our GABA voxels included areas outside the strongest activation, but we did find a GABA/fMRI ratio in the frontal lobe that was consistent across the healthy control sample and much higher, and varied, in the concussion group. Elevated GABA was not seen in the other area studied, the medial parietal lobe. Thus, there is some selectivity to the GABA elevation, suggesting that it is related to the function of this brain region or perhaps the task load being applied. This seems possible but, without differences in behavioral performance between groups, premature to conclude. Whether the GABA elevation is causal or only indirectly associated with postconcussive symptoms, it may provide an objective measure for following disease progression and offering a target for modulation.

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