Brain age revisited: Investigating the state vs. trait hypotheses of EEG-derived brain-age dynamics with deep...

The brain's biological age has been considered as a promising candidate for a neurologically significant biomarker. However, recent results based on longitudinal magnetic resonance imaging (MRI) data have raised questions on its interpretation. A central question is whether an increased biological age of the brain is indicative of brain pathology and if changes in brain age correlate with diagnosed pathology (state hypothesis). Alternatively, could the discrepancy in brain age be a stable characteristic unique to each individual (trait hypothesis)? To address this question, we present a comprehensive study on brain aging based on clinical Electroencephalography (EEG), which is complementary to previous MRI-based investigations. We apply a state-of-the-art temporal convolutional network (TCN) to the task of age regression. We train on recordings of the Temple University Hospital EEG Corpus (TUEG) explicitly labeled as non-pathological and evaluate on recordings of subjects with non-pathological as well as pathological recordings, both with examinations at a single point in time TUH Abnormal EEG Corpus (TUAB) and repeated examinations over time. Therefore, we created four novel subsets of TUEG that include subjects with multiple recordings: repeated non-pathological (RNP): all labeled non-pathological; repeated pathological (RP): all labeled pathological; transition non-patholoigical pathological (TNPP): at least one recording labeled non-pathological followed by at least one recording labeled pathological; and transition pathological non-pathological (TPNP): similar to TNPP but with opposing transition (first pathological and then non-pathological). The results show that our TCN reaches state-of-the-art performance in age decoding on non-pathological subjects of TUAB with a mean absolute error of 6.6 years and an $R^2$ score of 0.73. Our extensive analyses demonstrate that the model underestimates the age of non-pathological and pathological subjects, the latter significantly (-1 and -5 years, paired t-test, $p = 0.18$ and $p = 6.6e-3$ ). Furthermore, there exist significant differences in average brain age gap between non-pathological and pathological subjects both with single examinations (TUAB) and repeated examinations (RNP vs. RP) (-4 and -7.48 years, permutation test, $p = 1.63e-2$ and $p = 1e-5$ ). We find mixed results regarding the significance of pathology classification based on the brain age gap biomarker. While it is indicative of pathological EEG in datasets TUAB and RNP versus RP (61.12% and 60.80% BACC, permutation test, $p = 1.32e-3$ and $p = 1e-5$ ), it is not indicative in TNPP and TPNP (44.74% and 47.79% BACC, permutation test, $p = 0.086$ and $p = 0.483$ ). Additionally, all of these classification scores are clearly inferior to the ones obtained from direct EEG pathology classification at 86% BACC and higher. Furthermore, we could not find evidence that a change of EEG pathology status within subjects relates to a significant change in brain age gap in datasets TNPP and TPNP (0.46 and 1.35 years, permutation test, $p = 0.825$ and $p = 0.43$ ; and Wilcoxon-Mann-Whitney and Brunner-Munzel test, $p = 0.13$ ). Our findings, thus, support the trait rather than the state hypothesis for brain age estimates derived from EEG. In summary, our findings indicate that the neural underpinnings of brain age changes are likely more multifaceted than previously thought, and that taking this into account will benefit the interpretation of empirically observed brain age dynamics.