GABA_A binding correlates with high-frequency EEG: a possible proxy for depolarization in traumatic brain injury

Traumatic brain injury (TBI) frequently results in long-term cognitive and functional deficits, yet routine diagnostic tools often fail to capture the diffuse network dysfunction and underlying neurochemical changes that contribute to poor recovery. Resting-state EEG is sensitive to injury-related abnormalities in neural oscillations, while [¹¹C]flumazenil PET quantifies gamma-aminobutyric acid (GABA_A) receptor availability-a key determinant of inhibitory tone and cortical synchronization-but these modalities are rarely integrated. Linking EEG spectral features to molecular measures of GABA_A function may provide translational biomarkers that bridge non-invasive neurophysiological findings with underlying neurochemical status. The primary aim of this study was to determine whether resting-state EEG spectral features, particularly in the high-frequency beta and gamma bands, track longitudinal changes in GABA_A receptor availability measured with [¹¹C]flumazenil PET in individuals recovering from TBI. A secondary aim was to characterize the persistence of low-frequency abnormalities (increased delta, reduced alpha) over the first year of recovery and explore their potential relevance as non-invasive markers of network dysfunction. We analysed EEG data from 68 subjects with TBI and 75 non-brain-injured controls; longitudinal follow-up EEG data were available for 37 TBI participants and 20 non-brain-injured controls. We found that the TBI subjects exhibited significantly higher delta power and lower alpha power; this remained at the chronic visit. Among the longitudinally studied subjects, a subset of seven TBI participants and six non-brain-injured controls were studied with [¹¹C]flumazenil PET data. We found strong positive correlations between longitudinal changes in [¹¹C]flumazenil PET measured GABA_A receptor availability and concurrent changes in EEG high beta (r ² = 0.79, P < 0.01) as well as low and high gamma power (r ² = 0.71, P < 0.05; r ² = 0.77, P < 0.01) in TBI subjects for the 'eyes-open' condition. These exploratory findings provide preliminary evidence that GABA_A receptor availability, measured via [¹¹C] flumazenil PET, is associated with high-frequency EEG power in TBI. This PET-EEG coupling may reflect underlying changes in excitatory-inhibitory network balance consistent with restoration of fronto-striatal arousal and neuronal membrane 'tone' under the mesocircuit model, although the small sample size of the cohort with multimodal measurements warrants cautious interpretation and further replication. Nonetheless, the observations in this cohort are consistent with a key role of increasing inhibitory activity across fronto-striatal neurons and networks in recovery from TBI.