Fronto-striatal dysregulation of motivational and cognitive flexibility (completed)

Within the CRC, mechanisms and brain systems mediating volitional control are elucidated, and in particular, the balance between flexibility and stability (shielding-shifting dilemma). Focusing on fronto-striatal brain systems project B3 will investigate the balance between stability and flexibility in both “hot” (e.g. reward and punishment related) motivational and “cold” (e.g. explicit rule-based) cognitive control processes, assuming a dynamic interplay between ventral, limbic-striatal and dorsal, fronto-striatal circuits. Dopaminergic functions follow an inverted U-shaped function such that different dopamine baseline levels can either optimize or overdose functions associated with dorsal and ventral striatal circuits. Parkinson’s disease (PD) is characterized by neurodegenerative processes primarily affecting the nigrostriatal dopaminergic projections and changing dopamine levels over time. Of note, dopamine depletion follows an asymmetric spatio-temporal progression with the dorsal striatal circuits being initially affected, while only later progressing to ventral parts of the striatum. PD probably represents one of the best available human models for fronto-striatal dsyfunctions, also differentiating between dorsal and ventral components in the course of disease. Further, neuropsychiatric symptoms (depression, impulsivity) which are frequent sequelae of PD can, on a neural level, be understood as reflecting an altered balance of dorsal and ventral striatal functionality. In project B3 we will use PD as a model disorder to test the hypothesis that shielding and shifting of motivational and cognitive goals is altered by dopamine depletion. Extending previous research the following research questions will be targeted: a) We will stratify patients according to symptoms of depression and impulsivity to study influences of altered trait affectivity; b) we will employ paradigms simultanously addressing dorsal (cognitive flexibility) and ventral (motivational flexibility) striatal functions, allowing for testing interaction effects within one sample; c) we will conduct a prospective longitudinal design in order to study intraindividual changes in the functional balance between dorsal and ventral striatal circuits in the course of the disease and under medication-on and -off conditions. Using a modified set- switching paradigm (see B1) we will also exploratory test the effects of phasic positive affect induction on cognitive flexibility in PD patients under medication on and off conditions. Starting with a sample of mild PD (Hoehn & Yahr I-II), patients will be followed-up after two years. Established behavioral tasks that have been proven to be feasible in PD patients will provide a basis for comparisons between previous studies and new data using a multilevel approach including pharmacological functional magnetic resonance imaging (fMRI). Results are expected to make an important contribution to better understand the neural underpinnings of volitional control, focusing on fronto-striatal circuit (dys-) functions and relevant modulators such as neuropsychiatric symptoms and disease duration.