Author(s): Alves, Pedro Nascimento
Date: 2022
Persistent ID: http://hdl.handle.net/10451/63569
Origin: Repositório da Universidade de Lisboa
Subject(s): orientação espacial; delírio; AVC; conectividade; spatial orientation; delusions; stroke; connectivity
Orientation in space is an important determinant of human behaviour. Spatial delusions are a disrupting form of spatial disorientation characterized by a firm conviction of place mislocation. Patients believe they are in a reduplicated, transformed or dislocated place and are rather insensitive to surrounding incongruences. Spatial delusions are frequent after right hemispheric lesions and in neurodegenerative diseases, but empirical evidence about their presentation and pathophysiology is lacking. Here, we aimed to comprehensively study stroke-associated spatial delusions’ clinical features and neural basis. The first study systematically reviewed the reported evidence about lesion-associated spatial delusions. Then, we performed a prospective screening for spatial delusions in right hemisphere acute stroke patients and were able to identify the largest sample of patients with spatial delusion, to our knowledge. The second study described spatial delusions’ clinical and phenomenological features and analysed their neural correlations (n=60). Most places of mislocation were closer to the patient’s home than to the hospital. The duration of the syndrome was short (median: 3 days, interquartile range: 1-7 days) and moderately correlated with structural disruption of left inferior temporal fibres (r=0.39). Each clinical subtype (i.e., place reduplication, transformation or dislocation) had characteristic response patterns, which were reported, and representative examples were provided. In the third study, we performed a case-control analysis of the structural and functional predictors of the syndrome (stroke patients with spatial delusions, n=64; stroke controls, n=233). Spatial delusions were most strongly predicted by the structural disconnection of two distinct streams, connecting right fronto-thalamic and right occipitotemporal structures. The multivariate model also included age, anosognosia and lesion sparing of right dorsal fronto-parietal regions as independent predictors. It was nested cross-validated with a support-vector machine analysis and a good discrimination accuracy was demonstrated (median area under the curve: 0.80, interquartile range: 0.75–0.85). Cognitively, spatial delusions do not seem to be explained by deficits in single cognitive domains but by a dysfunctional combination of multidomain information. The brain’s functional organization comprises multimodal integrative networks, namely the default mode network, and ventral and dorsal attention networks. The neuroimaging study of their anatomy has taken a predominantly corticocentric approach, but clinical, electrophysiological and phylogenetic-derived data suggest that they have essential subcortical components. In the fourth study, we applied neuroimaging methods of functional alignment to healthy subjects’ resting-state functional MRI and demonstrated that the default mode network comprises a subcortical network that matches the anatomical model of the limbic system. Using a similar methodology, the fifth study revealed that the ventral and dorsal attention networks include the pulvinar, the superior colliculi and group brainstem nuclei whose projections are spatially correlated with the acetylcholine nicotinic receptor and dopamine transporter systems. The sixth study explored the relationship between spatial delusions and acute stroke treatment modalities. We performed a subanalysis of the ischemic stroke sample collected for the second and third studies and found an association between endovascular thrombectomy and occurrence of the syndrome (multivariate logistic regression model including age, clinical severity, vascular territory, inter-hospital transfer and endovenous thrombolysis as covariates; odds ratio: 2.46, 95% confidence interval: 1.18 to 5.16). We demonstrated that shared clusters of lesion and structural disconnection, overlapping right thalamo-orbitofrontal fibres and right anterior temporal areas, mediate the association. These regions are irrigated by proximal middle cerebral artery branches, which seem to be particularly prone to ischemia during clot manipulation and extraction. In conclusion, our results provide a broader characterization of stroke-associated spatial delusions’ clinical and phenomenological features, which may support their appropriate diagnosis. They also shed light on the functional and structural predictors of the syndrome and on the subcortical organization of multimodal integrative functional networks. They may contribute to a better understanding of delusional misidentifications and extend our knowledge about the neurobiology of spatial orientation disorders.
