Balance between excitation (E) and inhibition (I) is a key principle for neuronal network organization and information processing. Consistent with this notion, excitation-inhibition imbalances are considered a pathophysiological mechanism in many brain disorders including autism spectrum disorder (ASD). However, methods to measure E/I ratios in human brain networks are lacking. Here, we present a method to quantify a functional E/I ratio (fE/I) from neuronal oscillations, and validate it in healthy subjects and children with ASD. We define structural E/I ratio in an in silico neuronal network, investigate how it relates to power and long-range temporal correlations (LRTC) of the network's activity, and use these relationships to design the fE/I algorithm. Application of this algorithm to the eeGs of healthy adults showed that fE/I is balanced at the population level and is decreased through GABAergic enforcement. In children with ASD, we observed larger fE/I variability and stronger LRTC compared to typically developing children (TDC). Interestingly, visual grading for EEG abnormalities that are thought to reflect E/I imbalances revealed elevated fE/I and LRTC in ASD children with normal EEG compared to TDC or ASD with abnormal EEG. We speculate that our approach will help understand physiological heterogeneity also in other brain disorders. Excitatory (E) and inhibitory (I) systems are critical for regulating the flow of information in the brain. Without narrow control over the E/I ratio, runaway excitation or quiescence would occur, impeding adequate information processing 1,2. In clinical terms, disruption of E/I balance has become a dominant theory on the pathogenesis of various neurodevelopmental disorders, and perhaps most explicitly in autism spectrum disorder (ASD) 3-6. The nature, however, of implicated E/I imbalances on ASD is diverse, ranging from molecular changes to altered neuronal circuits 3,7,8 and has been hypothesized to explain some of the variability in treatment responses 7. E/I ratio may be regulated at the level of synaptic currents and network connectivity 2,4,9,10 and both levels affect the dynamics of ongoing network activity 11-16. Thus, it may be possible to derive a quantitative measure of E/I ratio from ongoing brain activity, e.g., as measured with electroencephalography (EEG). Such a measure would allow testing hypotheses about the functional role of E/I ratio 8 , could enable physiological stratification within neurodevelopmental disorders and facilitate personalized application of E/I-modulating therapies 3,7,17 .

Our focus of attention naturally fluctuates between different sources of information even when we desire to focus on a single object. Focused attention (FA) meditation is associated with greater control over this process, yet the neuronal mechanisms underlying this ability are not entirely understood. Here, we hypothesize that the capacity of attention to transiently focus and swiftly change relates to the critical dynamics emerging when neuronal systems balance at a point of instability between order and disorder. In FA meditation, however, the ability to stay focused is trained, which may be associated with a more homogeneous brain state. To test this hypothesis, we applied analytical tools from criticality theory to EEG in meditation practitioners and meditation-naïve participants from two independent labs. We show that in practitioners-but not in controls-FA meditation strongly suppressed long-range temporal correlations (LRTC) of neuronal oscillations relative to eyes-closed rest with remarkable consistency across frequency bands and scalp locations. The ability to reduce LRTC during meditation increased after one year of additional training and was associated with the subjective experience of fully engaging one's attentional resources, also known as absorption. Sustained practice also affected normal waking brain dynamics as reflected in increased LRTC during an eyes-closed rest state, indicating that brain dynamics are altered beyond the meditative state. Taken together, our findings suggest that the framework of critical brain dynamics is promising for understanding neuronal mechanisms of meditative states and, specifically, we have identified a clear electrophysiological correlate of the FA meditation state. K E Y W O R D Sabsorption, criticality, long-range temporal correlations, meditation

STXBP1 syndrome is a rare neurodevelopmental disorder caused by heterozygous variants in the STXBP1 gene and is characterized by psychomotor delay, early-onset developmental delay, and epileptic encephalopathy. Pathogenic STXBP1 variants are thought to alter excitation-inhibition (E/I) balance at the synaptic level, which could impact neuronal network dynamics; however, this has not been investigated yet. Here, we present the first EEG study of patients with STXBP1 syndrome to quantify the impact of the synaptic E/I dysregulation on ongoing brain activity. We used high-frequency-resolution analyses of classical and recently developed methods known to be sensitive to E/I balance. EEG was recorded during eyes-open rest in children with STXBP1 syndrome (n = 14) and age-matched typically developing children (n = 50). Brain-wide abnormalities were observed in each of the four resting-state measures assessed here: (i) slowing of activity and increased low-frequency power in the range 1.75–4.63 Hz, (ii) increased long-range temporal correlations in the 11–18 Hz range, (iii) a decrease of our recently introduced measure of functional E/I ratio in a similar frequency range (12–24 Hz), and (iv) a larger exponent of the 1/f-like aperiodic component of the power spectrum. Overall, these findings indicate that large-scale brain activity in STXBP1 syndrome exhibits inhibition-dominated dynamics, which may be compensatory to counteract local circuitry imbalances expected to shift E/I balance toward excitation, as observed in preclinical models. We argue that quantitative EEG investigations in STXBP1 and other neurodevelopmental disorders are a crucial step to understand large-scale functional consequences of synaptic E/I perturbations.

No abstract