For many brain disorders, the progression of pathological changes at the molecular and cellular level poorly correlates with their phenotypic presentation. There are many examples for which behavioral functionality is maintained even following drastic regional neural loss. Neural networks can undergo fundamental changes very early in neurodegenerative, neuro-immunological as well as psychiatric disorders in a disease-transcending manner, even in regions not yet affected by the underlying molecular and cellular pathophysiology. These early changes are often maladaptive and associated with hyperactive neurons, which marks the starting point for activity-dependent neurodegeneration. Networks undergo plastic changes not necessarily aiming at optimizing the phenotypic outcome, but by systems dynamics governed in a stability retaining manner. These states can be formalized as self-balancing attractors, based on systems-theoretical framework. These early neural network changes are a distinct (patho-)physiological entity which offers new therapeutic targets for preventing the manifestation of disease and fostering resilience.

At this early stage, short-term application of mediators can rebalance the network to achieve a physiological state and to counterbalance maladaptation early, preventing or delaying activity-depending neurodegeneration. For a translationally relevant neuromodulation, we explore circuit-wide, long-lasting disinhibitory effect of sub-ablative dose stereotactic radiosurgery to focal brain targets for durable rebalancing of neuronal networks. Not the least, these network states are highly dependent on the internal brain state. We investigate functional brain states – such as the slow wave state and the persistent state – in various conditions of vigilance.

For assessing and manipulating primarily cortico-thalamic network states, we implement all optical and optomagnetic multi-modal imaging approaches in rodents, such as 2-photon Ca2+ imaging, optic-fiber-based Ca2+ recordings, single cell optogenetics, and functional MRI. We e.g. combine optical recordings of slow oscillations with simultaneous fMRI, to attain the brain-wide fMRI signature of neuronal signals-of-interest slow oscillations. We also enhance the temporal resolution of fMRI by implementing fast line-scanning methods. These pipelines are also translationally applicable in human EEG-fMRI recordings.