Neurotransmitter imbalance dysregulates brain dynamic fluidity in frontotemporal degeneration

Frontotemporal degeneration (FTD) is characterized by reduced global brain flexibility along with GABAergic/glutamatergic neurotransmitter deficits. We aimed to assess the relationship between dynamical properties of time-varying whole-brain network connectivity as well as static large-scale networks and neurotransmitter imbalance using resting-state functional MRI and transcranial magnetic stimulation (TMS) in sixty-six patients with FTD. We assessed GABAergic and glutamatergic neurotransmission by TMS, considering short- and long-interval intracortical inhibition and intracortical facilitation, and large-scale networks connectivity as well as four indexes of meta-state dynamic fluidity: (1) number of distinct meta-states, (2) number of switches from one meta-state to another, (3) span of the realized meta-states, and (4) total distance traveled in the state space. No significant correlations between TMS parameters and large-scale networks connectivity were observed. However, we observed a significant correlation between short-interval intracortical inhibition–intracortical facilitation and four meta-states (all indexes p < 0.02, false discovery rate-corrected). This study suggests that neurotransmitter imbalance dysregulates brain dynamic fluidity, linking microscopic and macroscopic changes in FTD.