title: 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THIS ARTICLE: Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome).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.
authors.affiliation: Berenson-Allen Center for Non-Invasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA rdarby@bidmc.harvard.edu.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Department of Neurology, McLean Psychiatric Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: R Ryan
authors.initials: RR
authors.lastname: Darby
authors.affiliation: Berenson-Allen Center for Non-Invasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Laganiere
authors.affiliation: Berenson-Allen Center for Non-Invasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual-Leone
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sashank
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Berenson-Allen Center for Non-Invasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Athinoula A. Martinos Centre for Biomedical Imaging, Charlestown, MA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Fox
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D001930:Brain Injuries / Q000150:complications*; D001931:Brain Mapping; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D015201:Meta-Analysis as Topic; D009042:Motivation; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D021641:Recognition, Psychology; D012563:Schizophrenia, Paranoid / Q000175:diagnosis* / Q000209:etiology*
keywords: Capgras; connectivity; delusional misidentifications; delusions; fregoli