tDCS, rTMS and DBS in animal models of normal and pathological behavior – a comparative approach
Background and aims
Non-invasive tDCS and rTMS as well as invasive DBS of the prefrontal cortex (PFC) constitute three brain stimulation (BS) approaches that affect dysfunctional PFC-associated neural networks, i.e. specific neurobiological states that underlie the behavioral manifestation of psychiatric syndromes. The mechanisms by which these neurobiological states are affected are necessarily complex, plausibly including local and remote excitation of fibers, neurons, interneurons and microglia, each of it affecting neurobiological parameters which themselves are differentially altered in specific neurobiological states, i.e. neurotransmission, expression of neural activity and neurotrophic factors, synaptic transmission and network physiology. Thus, the putative ability of BS approaches to affect these neurobiological parameters will determine clinical outcomes. As the majority of BS interventions were applied to humans without systematic or even comparative research on different BS methods in animal models, albeit they represent an ideal approach for investigating neurobiological mechanisms of action, state dependency of BS effects and avenues for future methodological development we propose this animal experimental WP. As such, we will use different rat pathology models in parallel, representing intermediate behavioral phenotypes related to a larger spectrum of psychiatric syndromes (transdiagnostic approach). In a first step, we will characterize neurobiological substrates associated with specific symptom profiles that are relevant for BS (see above). In a second step, we will differentially target PFC-associated neural networks using prefrontal theta burst rTMS (TBrTMS), medial prefrontal tDCS and ventromedial prefrontal DBS to affect pre-defined neurobiological states and describe how neurobiological effects translate into behavior. This will allow us to delineate the causal relation between the clinical outcome of BS and its ability to modulate specific neurobiological states. The project aims at promoting a neurobiological basis for identifying optimal BS approaches in the treatment of symptom profiles (forward translation to WP2-5).
Animal studies using different pathology models in parallel allow delineating causal relations between neurobiological and behavioral states. Thus, behavioral outcome of a therapeutic intervention can be explained by its ability to modulate neurobiological substrates of symptom profiles. This promotes a neurobiological rationale for defining optimal, i.e. the safest, most effective and least invasive stimulation approaches in the treatment of psychiatric conditions that can be recommended for clinical testing.
- Do specific neurobiological states within the PFC-associated neural network translate to specific behavioral profiles?
- Does targeted activity modulation in PFC subregions affect neurobiological parameters in associated neural networks?
- Do neurobiological changes translate into behavior?
- Do neurobiological and behavioral effects of PFC-stimulation depend on the particular pathological state and/or the specificity of the stimulation approach to affect PFC-associated neural networks?
- While delineating the causal relation between clinical outcome of a BS approach and its modulation of neurobiological states, can we establish a rationale driven protocol for the treatment of specific symptom profiles?