Finding the imposter: brain connectivity of lesions causing delusional misidentifications

Abstract

SEE MCKAY AND FURL DOI101093/AWW323 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome). How a single brain lesion could cause such a complex disorder is unclear, leading many to speculate that concurrent delirium, psychiatric disease, dementia, or a second lesion is required. Here we instead propose that Capgras and other delusional misidentification syndromes arise from single lesions at unique locations within the human brain connectome. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. First, 17 cases of lesion-induced delusional misidentifications were identified and lesion locations were mapped to a common brain atlas. Second, lesion network mapping was used to identify brain regions functionally connected to the lesion locations. Third, regions involved in familiarity perception and belief evaluation, two processes thought to be abnormal in delusional misidentifications, were identified using meta-analyses of previous functional magnetic resonance imaging studies. We found that all 17 lesion locations were functionally connected to the left retrosplenial cortex, the region most activated in functional magnetic resonance imaging studies of familiarity. Similarly, 16 of 17 lesion locations were functionally connected to the right frontal cortex, the region most activated in functional magnetic resonance imaging studies of expectation violation, a component of belief evaluation. This connectivity pattern was highly specific for delusional misidentifications compared to four other lesion-induced neurological syndromes (P < 0.0001). Finally, 15 lesions causing other types of delusions were connected to expectation violation (P < 0.0001) but not familiarity regions, demonstrating specificity for delusion content. Our results provide potential neuroanatomical correlates for impaired familiarity perception and belief evaluation in patients with delusional misidentifications. More generally, we demonstrate a mechanism by which a single lesion can cause a complex neuropsychiatric syndrome based on that lesion's unique pattern of functional connectivity, without the need for pre-existing or hidden pathology.

Keywords: Capgras; connectivity; delusional misidentifications; delusions; fregoli.

© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Lesions causing delusional misidentifications. Each lesion, numbered 1 through 17, was identified from a literature search or from cases seen by the authors and manually traced onto a common brain atlas (MNI).

Figure 2

Lesion network mapping technique. (A) Lesions traced onto a standardized MNI brain template. (B) Brain regions functionally connected to each lesion location based on a large resting state functional connectivity database. (C) Overlap in the functional connectivity maps from each lesion identifies brain regions functionally connected to the greatest number of lesion locations.

Figure 3

Network mapping of delusional misidentification lesions overlaps with regions involved in familiarity detection. (A) Regions functionally connected to lesion locations causing delusional misidentifications (negative correlations). Colour scale reflects the number of lesion locations with significant connectivity to each voxel. Peak coordinate: x = −6, y = −56, z = 12. (B) Regions most activated by familiar versus unfamiliar stimuli. Colour scale reflects the probability that a voxel is activated in neuroimaging studies of familiarity. Peak coordinate: x = −4, y = −56, z = 20. (C) Overlap image showing regions within the familiarity meta-analysis significantly connected to at least 15 of 17 lesions. Displayed brain slices from left to right are x = −4, z = 30, y = −62.

Figure 4

Network mapping of delusional misidentification lesions overlaps with regions involved in expectation violation. (A) Regions functionally connected to lesion locations causing delusional misidentifications (positive correlations). Colour scale reflects the number of lesion locations with significant connectivity to each voxel. Peak coordinate: x = 54, y = 14, z = −10. (B) Regions most activated by detection of invalid or unexpected stimuli in the Posner Paradigm. Colour scale reflects the probability that a voxel is activated in neuroimaging studies of invalid cues. Peak coordinate: x = 38, y = 20, z = 2. (C) Overlap image showing regions within the violation of expectation meta-analysis significantly connected to at least 14 of 17 lesions. Displayed brain slices from left to right are x = 42, z = 22, y = 0.

Figure 5

Lesions causing delusional misidentifications are functionally connected to brain regions involved in familiarity detection and violation of expectation. The temporal correlation in spontaneous functional MRI activity between lesion locations and regions identified in our familiarity meta-analyses (A) or violation of expectation meta-analysis (B) were computed using a cohort of healthy subjects. Correlations were averaged across our 17 lesion locations causing delusional misidentifications (blue) and compared to 77 lesions causing other neurological syndromes (control syndromes, red). *P < 0.0005. ** P < 0.0001.

Figure 6

Lesions causing other delusions are functionally connected to brain regions involved in violation of expectation but not familiarity detection. The temporal correlation in spontaneous functional MRI activity between lesion locations and regions identified in our familiarity meta-analyses (A) or violation of expectation meta-analysis (B) were computed using a cohort of healthy subjects. Correlations were averaged across our 15 lesion locations causing other delusions (blue) and compared to lesions causing other neurological syndromes (red). *P < 0.01. **P < 0.0001.