Encoding and Retrieval Dynamics During Frontal-Hippocampal Learning: Causal Modeling of Brain Networks in...

Hippocampal-based associative learning is a cornerstone of human behavior and is compromised in schizophrenia. Learning is subserved by time-driven brain network dynamics during encoding and retrieval of associations, but the impact of these dynamics on effective connectivity (EC) is unclear. We used Dynamic Causal Modeling (DCM) to investigate (a) patient-control differences in connectivity, (b) time-related impacts on connectivity, and (c) the interaction between group and time. We investigated a closed network of regions including the prefrontal and anterior cingulate cortices, the hippocampus, and regions in the magno- and parvo-cellular visual pathways. fMRI data (3 T Siemens Verio) were collected in 90 participants (52 stable schizophrenia patients) using an object-location associative learning paradigm with conditions for (a) Encoding (encoding what goes where) and (b) Retrieval (retrieving what was in the cued location). Competing network architectures were evaluated using DCM. We analyzed DCM-derived EC estimates of the contextual modulation of pathways by task condition and time, with a focus on inter-group differences and interactions with time. The winning model architecture revealed contextual modulation of bottom-up but not top-down pathways. In SCZ, encoding resulted in reduced contextual modulation of hippocampal ➔dACC and the dlPFC ➔ dACC pathways (emphasizing the importance of this triumvirate of regions). In SCZ, retrieval resulted in reduced modulation of the dlPFC ➔ dACC pathway. We observed widespread evidence for the plasticity of connection strengths over time (independent of Group). Finally, retrieval evoked an interaction in the contextual modulation of the inferior temporal ➔ hippocampus pathway (decreased modulation over time in HC, but increased modulation in SCZ). Our DCM-based investigation re-affirms the important role of frontal-hippocampal pathways in memory encoding and retrieval, elucidates the nature of memory dynamics, and reveals task-evoked disruption of network function in schizophrenia.