Dissociation of Striosome and Matrix Activation in the Human Striatum During the Cue and Execution Phases of Working Memory

The striatum comprises two neurochemically and anatomically distinct tissue compartments, the striosome and matrix, that are hypothesized to support different aspects of cognition and action. In animal studies, the striosome has been linked to reward evaluation, emotional learning, and decision-making under conflict, whereas the matrix is more closely associated with sensorimotor integration and task execution. However, evidence for compartment-specific function in humans is limited and indirect. Using probabilistic tractography, we identified voxels with striosome-like and matrix-like patterns of structural connectivity in healthy adults. We then examined how these compartment-like voxels responded to task demands during an fMRI n-back working-memory paradigm that visually presented four stimulus categories (body part, face, place, or tool). We assessed activation in a low-load condition (0-back, remembering a just-viewed stimulus) vs. a high-load condition (2-back, remembering a stimulus viewed two prior). Functional activation was temporally segregated and matched our prior findings in motor tasks: striosome-like voxels were preferentially engaged during the cue and initial preparation phases, whereas matrix-like voxels dominated during task execution. Trial accuracy strongly modulated striatal activation, with both compartments showing significantly greater responses during "correct" than in "error" trials. Notably, the accuracy-related increase in activation was larger in striosome-like voxels, consistent with a prominent role for striosomal processing in performance evaluation. Both striosome- and matrix-like voxels significantly increased activation from 0-back to 2-back, indicating sensitivity to working-memory load, with larger increases for matrix-like than for striosome-like voxels. Category-selective responses also differed by compartment and cognitive load. Under low working-memory load (0-back), stimulus-category effects were modest and broadly similar between compartments. Under higher load (2-back), activation in striosome-like voxels remained selective for specific stimulus categories, while matrix-like voxels lost category specificity. Together, these findings suggest that the striosome-matrix distinction generalizes from motor to cognitive domains, reflecting a conserved division between preparatory and execution-related processes that varies systematically with task demands, memory category, and performance accuracy. This convergence of compartment-specific responses across domains points to a core organizational principle of the human striatum with potential implications for neuropsychiatric diseases. Key PointsO_LIStriatal medium spiny neurons are organized into two interdigitated compartments, the striosome and matrix, which are embryologically, pharmacologically, and anatomically distinct. Compartment-specific functions have been demonstrated in animals, but their roles in human cognition are unexplored. C_LIO_LIWe found that in humans, striosome-like voxels preferentially activated during memory cues, while matrix-like voxels preferentially activated during recall and memory maintenance. In both compartments, activation scaled with task difficulty. C_LIO_LIActivation in striosome-like voxels scaled more strongly with task accuracy and difficulty, suggesting a striosome-selective role in vigilance and/or motivation. C_LI