A Reappraisal of the Role of the Mammillothalamic Tract in Memory Deficits Following Stroke in the Thalamus

The thalamus, traditionally viewed as a sensory relay station, is now recognized for its critical role in higher-order cognitive functions, including memory. While most research has focused on its distinct nuclei, the thalamus also contains crucial white matter tracts, such as the mammillothalamic tract (MTT), part of the Papez circuit. Despite its established role in memory, the MTT remains underappreciated in studies on the cognitive role of the thalamus, increasing the risk of misattributing memory functions to nearby thalamic nuclei. This study investigates the memory impact of thalamic strokes by considering disruption to the MTT. We examined 40 patients with chronic ischemic thalamic lesions and 45 healthy controls using neuropsychological assessments, focusing on the Free and Cued Selective Reminding Test (FCSRT) and high-resolution structural neuroimaging. Advanced imaging techniques, such as symptom mapping and disconnectome analyses, were employed to analyze the relationships between lesion sites, tract disconnections and cognitive outcomes. Additionally, the expression of calbindin-rich matrix cells and parvalbumin-rich core cells was examined to assess how the connectivity property of thalamic cells, and its disruption, can relate to cognitive deficits following a thalamic stroke. Patients with left-sided thalamic lesions, especially those involving the MTT, showed significant memory impairments. Symptom mapping identified a specific cluster of lesioned voxels in the left anterior-lateral thalamus, including the MTT, as being strongly associated with poorer memory performance. Disconnectome analysis confirmed that verbal memory deficits were associated with disruption of the MTT. Furthermore, a striking overlap was observed between the critical regions linked to memory deficits and calbindin-rich thalamic areas. However, this calbindin-rich region was also disrupted in patients without memory impairment, revealing that MTT disruption, and not lesions to this region, induced memory deficits in these patients. The identified FCSRT deficit cluster overlapped with brain regions consistently linked to memory processes following fMRI meta-analytic mapping of memory-related keywords. These findings challenge the traditional focus on thalamic nuclei and connector hubs, indicating a need to reappraise the importance of the MTT in memory impairment after a thalamic stroke. This study advocates for a shift in thalamic research, emphasizing the need to investigate tract-specific contributions and disruptions of the MTT but also of other tracts such as the interthalamic adhesion or amygdalo-fugal pathway, rather than holding only to a "nuclei-centric" view of the thalamus.