Circadian dynamics in measures of cortical excitation and inhibition balance

Several neuropsychiatric and neurological disorders have recently been characterized as dysfunctions arising from a ‘final common pathway’ of imbalanced excitation to inhibition within cortical networks. How the regulation of a cortical E/I ratio is affected by sleep and the circadian rhythm however, remains to be established. Here we addressed this issue through the analyses of TMS-evoked responses recorded over a 29h sleep deprivation protocol conducted in young and healthy volunteers. Spectral analyses of TMS-evoked responses in frontal cortex revealed non-linear changes in gamma band evoked oscillations, compatible with an influence of circadian timing on inhibitory interneuron activity. In silico inferences of cell-to-cell excitatory and inhibitory connectivity and GABA/Glutamate receptor time constant based on neural mass modeling within the Dynamic causal modeling framework, further suggested excitation/inhibition balance was under a strong circadian influence. These results indicate that circadian changes in EEG spectral properties, in measure of excitatory/inhibitory connectivity and in GABA/glutamate receptor function could support the maintenance of cognitive performance during a normal waking day, but also during overnight wakefulness. More generally, these findings demonstrate a slow daily regulation of cortical excitation/inhibition balance, which depends on circadian-timing and prior sleep-wake history

Rapid-acting antidepressants and the regulation of TrkB neurotrophic signalling-Insights from ketamine, nitrous oxide, seizures and anaesthesia

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain-derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant-induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up-regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid-acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow-wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.Peer reviewe

Circadian regulation of human cortical excitability

Prolonged wakefulness alters cortical excitability, which is essential for proper brain function and cognition. However, besides prior wakefulness, brain function and cognition are also affected by circadian rhythmicity. Whether the regulation of cognition involves a circadian impact on cortical excitability is unknown. Here, we assessed cortical excitability from scalp EEG-responses to transcranial magnetic stimulation in 22 participants during 29-h of wakefulness under constant conditions. Data reveal robust circadian dynamics of cortical excitability that were strongest in those individuals with highest endocrine markers of circadian amplitude. In addition, the time course of cortical excitability correlated with changes in EEG synchronization and cognitive performance. These results demonstrate that the crucial factor for cortical excitability, and basic brain function in general, is the balance between circadian rhythmicity and sleep need, rather than sleep homeostasis alone. These findings have implications for clinical applications such as noninvasive brain stimulation in neurorehabilitation