The Wernicke conundrum revisited: evidence from connectome-based lesion-symptom mapping

Wernicke's area has been assumed since the 1800s to be the primary region supporting word and sentence comprehension. However, in 2015 and 2019, Mesulam and colleagues raised what they termed the 'Wernicke conundrum', noting widespread variability in the anatomical definition of this area and presenting data from primary progressive aphasia that challenged this classical assumption. To resolve the conundrum, they posited a 'double disconnection' hypothesis: that word and sentence comprehension deficits in stroke-based aphasia result from disconnection of anterior temporal and inferior frontal regions from other parts of the brain due to white matter damage, rather than dysfunction of Wernicke's area itself. To test this hypothesis, we performed lesion-deficit correlations, including connectome-based lesion-symptom mapping, in four large, partially overlapping groups of English-speaking chronic left hemisphere stroke survivors. After removing variance due to object recognition and associative semantic processing, the same middle and posterior temporal lobe regions were implicated in both word comprehension deficits and complex non-canonical sentence comprehension deficits. Connectome lesion-symptom mapping revealed similar temporal-occipital white matter disconnections for impaired word and non-canonical sentence comprehension, including the temporal pole. We found an additional significant temporal-parietal disconnection for non-canonical sentence comprehension deficits, which may indicate a role for phonological working memory in processing complex syntax, but no significant frontal disconnections. Moreover, damage to these middle-posterior temporal lobe regions was associated with both word and non-canonical sentence comprehension deficits even when accounting for variance due to the strongest anterior temporal and inferior frontal white matter disconnections, respectively. Our results largely agree with the classical notion that Wernicke's area, defined here as middle superior temporal gyrus and middle-posterior superior temporal sulcus, supports both word and sentence comprehension, suggest a supporting role for temporal pole in both word and sentence comprehension, and speak against the hypothesis that comprehension deficits in Wernicke's aphasia result from double disconnection.