Educational Course - Full Day (8 hours)
The prefrontal cortex (PFC) is critically important for higher-order cognition in humans, playing a central role in cognitive control and goal-directed behavior (Miller & Cohen, 2001). Patients with damage to the PFC show deficits ranging from working memory and attention problems, to issues with motivation, response inhibition, and language (Szczepanski & Knight, 2014). How are such a vast array of cognitive processes orchestrated by a few cubic centimeters of cortical tissue? Classic proposals posit that the unique anatomical and functional properties of association cortex circuits, such as in PFC, can account for this remarkable flexibility of human cognition (Sanides, 1964). As the tools of modern neuroimaging advance, we are now more suited than ever to test these foundational frameworks. In this talk, I will share how a precision neuroimaging approach, with careful focus on neuroanatomical properties, can reveal fundamental principles of PFC functioning across studies, methods, and species.
First, I will show how structures known as tertiary sulci - the smallest and shallowest of sulcal indentations - offer insights into PFC functioning that bridge spatial scales (microns to networks), modalities (functional connectivity to behavior), and species. These tertiary sulcal structures are prominent within individual brains but are often smaller or completely missing from average cortical templates commonly used in human neuroimaging (Miller et al., 2021a). In these cases, the map of tertiary sulci within each individual participant may serve as a coordinate system specific to that individual on which functions may be further mapped. Using manual or semi-automated neuroanatomical labeling of PFC morphology within individuals can enable the characterization of structural-functional relationships in PFC that are more difficult to obtain when averaging across individual brains (Lyu et al., 2021; Miller et al., 2021b). For example, the morphology and depth of tertiary sulci co-varies with working memory and reasoning skills across development (Voorhies et al., Nat Comms, 2021; Yao et al., Cereb Cortex, 2022). I will then lay out how our field can apply lessons from precision neuroanatomical approaches to a wider array of neuroimaging studies and questions.
Second, I will demonstrate how dense, longitudinal sampling paradigms can reveal within-individual functional organization across different areas of human PFC. Specifically, I will use the example of gradients of working memory representations in PFC that are transformed over long-term learning (Miller et al., Neuron, 2022). Three human participants each completed over 20 sessions of functional MRI (fMRI) along with at-home training across three months. During this time, participants repeatedly performed a delayed recognition working memory task and a sequence learning task, which both employed a set of novel fractal stimuli that were unique to each participant. Across the course of training, working memory representations were transformed along a general rostral-caudal anatomical and functional organization in PFC: stimulus-specific working memory representations emerged in mid-lateral PFC and categorical representations in caudal PFC areas. A host of neuroanatomical properties are thought to endow the PFC with a propensity for this kind of plasticity and make it well-suited to serve as an integrative hub for learning effects across timescales (Miller & Constantinidis, 2024). These functional and neuroanatomical organizations may be best captured by densely sampling PFC activity patterns over time within individuals, and I will share the principles and advantages of such study designs.
Finally, I will dive below the level of voxels into microscale organization and show how working memory circuitry operates at different spatial scales in PFC circuits. Traditionally, many neuronal activity patterns in PFC are thought to be inaccessible to voxel-level sampling because of the spatial intermixing of neurons in close anatomical proximity with different functional tuning. However, several new studies recording from PFC in NHPs reveal a micro- to macro-scale organization of neuronal coding that can help bridge across spatial scales of functioning in PFC (Sun et al., 2024; Xiang et al., 2024). I will highlight these findings and their important conclusions for neuroimaging studies of human PFC: can we observe a “cognitive globe” of functioning mirrored at the micro- and meso-scale levels in PFC?
Collectively, in this course I will demonstrate how the tools and lessons of individual-level neuroanatomy and functioning allow us to better characterize robust brain-behavior relationships and advance our understanding of working memory and related cognitive processes in the PFC.