PZ5 Flexible Amplifiers

One of the most distinctive features of the mammalian cerebral cortex is its laminar structure. Of all cortical layers, layer 6b (L6b) is by far the least studied, despite exhibiting direct sensitivity to orexin and having widespread connectivity, suggesting an important role in regulating cortical oscillations and brain state. We performed chronic electroencephalogram (EEG) recordings in mice in which a subset of L6b neurons was conditionally ‘silenced’, during undisturbed conditions, after sleep deprivation (SD), and after intracerebroventricular (ICV) administration of orexin. While the total amount of waking and sleep or the response to SD were not altered, L6b-silenced mice showed a slowing of theta frequency (6–9 Hz) during wake and rapid eye movement (REM) sleep, and a marked reduction of total EEG power, especially in non-rapid eye movement (NREM) sleep. The infusion of orexin A increased wakefulness in both genotypes, but subsequent levels of EEG slow-wave activity during NREM sleep were lower in L6b-silenced animals in the occipital derivation. In summary, these results demonstrate a role for cortical L6b in state-dependent brain oscillations and in the response to orexinergic neurotransmission. Our findings provide new insights in functions of L6b neurons and could inform the understanding of abnormal regulation of brain states in neurodevelopmental and psychiatric disorders.

Neuromodulation is widely employed to enhance neural activity and restore impaired circuitry, yet current methods suffer from invasiveness, limited depth, or poor spatial resolution. Temporal interference stimulation (TIS) has emerged as a non-invasive approach to modulate deep brain regions via interference of high-frequency electric fields, achieving spatial selectivity. Despite its potential, the physiological effects remain unexplored. Here, we present a customized liquid metal-based neural interface to record electrophysiological responses to TIS across diverse neural tissues, from brain organoids to mouse brains. The softness of the interface minimizes invasiveness while ensuring stable access to deep neural regions. Electrophysiological analyses reveal TIS-induced dynamics in neurodevelopment and functional connectivity. Furthermore, we investigated latent neural dynamics, presenting population-level neural activity, to compare responses across models of differing complexity and maturity. By combining soft neural interfaces with multi-scale analyses, this study uncovers how neuromodulation shapes neural dynamics and supports the development of future therapeutic strategies.

Current disease-sensing devices primarily focus on distinguishing between healthy and diseased states, effective for diagnosis but limited in guiding optimal intervention timing for prevention. We developed a tripartite framework identifying pre-disease state in depression, a reversible phase preceding irreversible onset. Using complex systems theory, we analyzed early-warning signals emerging as biological systems approach critical transitions. Continuous monitoring of nine multimodal biomarkers—spanning electrophysiological, behavioral, and biological—enabled classification into normal, pre-disease, and disease states by quantitatively defining critical points. An artificial intelligence agent classified disease states with 95.2% accuracy using multimodal data, enabled by ultrasoft neural probes for stable, low-damage recordings. Therapeutic validation with a skin-attachable wireless vagus nerve stimulator integrating soft three-dimensional electrodes demonstrated superior efficacy during pre-disease states. Subjects treated during pre-disease showed faster recovery and greater therapeutic responses, while those treated after disease onset failed to achieve full recovery. This framework provides evidence-based rationale for early intervention.