Narrowing the mechanistic gap for anterior prefrontal cortex function

PROJECT SUMMARY Prefrontal cortex (PFC) is a large and heterogeneous brain area comprising the front third of the human brain that has been implicated in numerous mental health disorders. One of the least-studied subregions of PFC is anterior lateral PFC (aLPFC). This region, whose functioning is impacted in disorders like schizophrenia, has been implicated in reasoning, multi-tasking, planning, memory monitoring, decision-making, and more. It behooves us to reach a mechanistic understanding of the fundamental processes subserved by this region; however, there are numerous challenges, including the absence of a precise animal model, inconsistencies regarding terminology and anatomical boundaries, lack of attention to individual variability in anatomy, lack of high-resolution imaging in living participants, and limited evaluation of the generalizability of its function. In response to these challenges, we seek to do a deep dive on its anatomy and function at the individual level in neurotypical adults, using cutting-edge MRI technology. Leading theories presuppose that aLPFC has a domain-general function, processing abstracted representations that are far removed from initial inputs to the brain. However, this assumption has yet to be carefully tested. Here, we capitalize on a body of work implicating a portion of aLPFC in relational reasoning, or the ability to reason about information by jointly consider several sets of mental representations. First, we seek to evaluate the claim of domain-generality by assessing aLPFC's activation and interactions with other brain regions during performance of four relational reasoning tasks; these tasks involve both visual and—for the first time—auditory domains, as well as visuospatial and semantic (or "where" and "what") stimuli processed by different posterior brain regions. Second, to better localize aLPFC activation during reasoning at the single subject level, we seek to assess whether small sulci (grooves) serve as functional landmarks, predicting the location of this functionally defined region. Third, we seek to leverage the exquisite spatial resolution of our NexGen 7 Tesla MR scanner and a combination of two fMRI methods to test whether aLPFC activation during reasoning is predominantly localized to superficial cortical layers, consistent with involvement in local recurrent connectivity that supports integration of high-level mental representations. Fourth, theories of PFC organization either presuppose that aLPFC receives inputs exclusively from other PFC regions or that it also has long-range connections to more domain- sensitive regions in parietal and temporal cortices. Thus, we seek to use high-resolution diffusion-weighted imaging at 7 Tesla to shed light on the provenance of inputs to aLPFC. With strong expertise in PFC function, neuroanatomy, high-field MR imaging technology, and MRI analytic approaches, our team is poised to yield novel insights about PFC function. This study is both theoretically and technologically innovative and will yield a valuable shared dataset. Better characterizing aLPFC structure and function could yield insights for early identification of disordered thinking in neurodevelopmental conditions such as schizophrenia.