2025 American Academy of Neurology Abstract Website

Anna Bonkhoff¹, Frederic Schaper², Shan Siddiqi², Alexander Cohen², William Drew², Michael Ferguson², Christopher Lin², Anne-Katrin Giese³, Robert Regenhardt⁴, Markus Schirmer⁴, Christina Jern⁵, Arne Lindgren⁶, Jane Maguire⁷, Ona Wu⁸, Sahar Zafar⁴, John Rhee⁹, Eyal Kimchi¹⁰, Andrew Naidech¹¹, Amy Brodtmann¹², Natalia Egorova¹³, Sophia Gozzi¹², Thanh Phan¹⁴, Maurizio Corbetta¹⁵, Jordan Grafman¹⁰, Natalia Rost⁴, Michael Fox¹⁶
¹Mass General Brigham, ²Brigham and Women's Hospital, ³University Medical Center Hamburg-Eppendorf, ⁴Massachusetts General Hospital, ⁵University of Gothenburg, ⁶Lund University, ⁷University of Technology Sydney, ⁸MGH Stroke Research Center, ⁹Dana Farber Cancer Institute, ¹⁰Northwestern University, ¹¹Department of Neurology, ¹²Monash University, ¹³University of Melbourne, ¹⁴Mayo Clinic, ¹⁵University of Padova, ¹⁶Brigham and Women's Hospital / Harvard Medical School

Objective:

To evaluate whether sex-specific functional connectivity mapping explains observed sex differences in depression post-stroke.

Background:

Depression post-stroke is associated with a substantially higher burden of disease, as exemplified by less favorable recovery courses and higher mortality. Female patients are reported to experience depression post-stroke more frequently than male patients. The biological underpinnings of this epidemiological observation are currently not well understood.

Design/Methods:

We utilized three independent, large single- and multi-center datasets of patients with stroke to investigate associations between sex-specific MRI-based lesion connectivity and established brain circuits of depression (N₁=214, derivation cohort; N₂=638 and N₃=1075, validation cohorts). The functional disconnection elicited by each stroke patient’s lesion was estimated in two ways, based on a female- and male-specific connectome (N=354 each). Sex-specific lesion connectivity effects, both general in nature and specific to previously established connectivity profiles of depression, were evaluated on a whole-brain, voxel-wise basis via Permutation Analysis of Linear Models (PALM).

Results:

The evaluation of sex-specific lesion connectivity resulted in broad differences in connectivity strengths: female-specific connectivity was significantly more pronounced, particularly relating to motor cortices (more positive connectivity) and the default mode network (more negative connectivity). In all cohorts, female-specific lesion connectivity was consistently more strongly correlated to connectivity characteristics related to depression than male-specific connectivity (p<0.001).

Conclusions:

Female-specific functional lesion connectivity is more closely linked to connectivity characteristics related to depression, potentially indicating a female-specific more innate tendency to develop depressive symptoms after stroke. These results motivate taking biological sex into account when evaluating new therapeutic regimens of post-stroke depression.