Unravelling the Neural Basis of Spatial Delusions After Stroke.

OBJECTIVE: Knowing explicitly where we are is an interpretation of our spatial representations. Reduplicative paramnesia is a disrupting syndrome in which patients present a firm belief of spatial mislocation. Here, we studied the largest sample of patients with delusional misidentifications of space (ie, reduplicative paramnesia) after stroke to shed light on their neurobiology. METHODS: In a prospective, cumulative, case-control study, we screened 400 patients with acute right-hemispheric stroke. We included 64 cases and 233 controls. First, lesions were delimited and normalized. Then, we computed structural and functional disconnection maps using methods of lesion-track and network-mapping. The maps were compared, controlling for confounders. Second, we built a multivariate logistic model, including clinical, behavioral, and neuroimaging data. Finally, we performed a nested cross-validation of the model with a support-vector machine analysis. RESULTS: The most frequent misidentification subtype was confabulatory mislocation (56%), followed by place reduplication (19%), and chimeric assimilation (13%). Our results indicate that structural disconnection is the strongest predictor of the syndrome and included 2 distinct streams, connecting right fronto-thalamic and right occipitotemporal structures. In the multivariate model, the independent predictors of reduplicative paramnesia were the structural disconnection map, lesion sparing of right dorsal fronto-parietal regions, age, and anosognosia. Good discrimination accuracy was demonstrated (area under the curve = 0.80 [0.75-0.85]). INTERPRETATION: Our results localize the anatomic circuits that may have a role in the abnormal spatial-emotional binding and in the defective updating of spatial representations underlying reduplicative paramnesia. This novel data may contribute to better understand the pathophysiology of delusional syndromes after stroke. ANN NEUROL 2021;89:1181-1194.

Network localization of heterogeneous neuroimaging findings.

Studies of the same disease often implicate different brain regions, contributing to a perceived reproducibility crisis in neuroimaging. Here, we leverage the normative human brain connectome to test whether seemingly heterogeneous neuroimaging findings localize to connected brain networks. We use neurodegenerative disease, and specifically Alzheimer's disease, as our example as it is one of the diseases that has been studied the most using neuroimaging. First, we show that neuroimaging findings in Alzheimer's disease occur in different brain regions across different studies but localize to the same functionally connected brain network. Second, we show that neuroimaging findings across different neurodegenerative diseases (Alzheimer's disease, frontotemporal dementia, corticobasal syndrome, and progressive non-fluent aphasia) localize to different disease-specific brain networks. Finally, we show that neuroimaging findings for a specific symptom within a disease (delusions in Alzheimer's disease) localize to a symptom-specific brain network. Our results suggest that neuroimaging studies that appear poorly reproducible may identify different regions within the same connected brain network. Human connectome data can be used to link heterogeneous neuroimaging findings to common neuroanatomy, improving localization of neuropsychiatric diseases and symptoms.

Aberrant myelination of the cingulum and Schneiderian delusions in schizophrenia: a 7T magnetization transfer study.

BACKGROUND: The structural integrity of the anterior cingulum has been repeatedly observed to be abnormal in patients with schizophrenia. More recently, aberrant myelination of frontal fasciculi, especially, cingulum has been proposed to underlie delayed corollary discharges that can affect sense of agency and contribute to delusions of control (Schneiderian delusions). Using the magnetization transfer phenomenon at an ultra-high field 7T MRI, we investigated the putative myelin content of cingulum bundle in patients with schizophrenia. METHODS: Seventeen clinically stable patients with schizophrenia and 20 controls were recruited for this 7T MRI study. We used a region-of-interest method and extracted magnetization transfer ratio (MTR) from left and right dorsal cingulum bundles and estimated patients v. controls differences. We also related the cingulum MTR values to the severity of Schneiderian delusions. RESULTS: Patients had a significant reduction in the MTR, indicating reduced myelin content, in the cingulum bundle (right cingulum Hedges' g = 0.91; left cingulum g = 0.03). The reduced MTR of left cingulum was associated with higher severity of Schneiderian delusions (τ = -0.45, p = 0.026) but no such relationship was seen for the right cingulum MTR (τ = -0.136, p = 0.50) among patients. The association between the left cingulum MTR and Schneiderian delusions was not explained by the presence of other delusions, hallucinations, disorganization or negative symptoms. CONCLUSIONS: Dysmyelination of the cingulum bundle is seen in a subgroup of patients with schizophrenia and may be involved in the mechanism of Schneiderian delusions.

Gray Matter Changes Associated With the Development of Delusions in Alzheimer Disease.

OBJECTIVE: Delusions affect approximately a third of Alzheimer disease (AD) patients and are associated with poor outcomes. Previous studies investigating the neuroanatomic correlates of delusions have yet to reach a consensus, with findings of reduced volume across all lobes, particularly in frontal regions. The current study examined the gray matter (GM) differences associated with delusions in AD. METHODS: Using voxel-based morphometry, we assessed GM in 23 AD patients who developed delusions (AD+D) and 36 comparable AD patients who did not (AD-D) at baseline and follow-up. Analysis of variance was used to identify consistent differences between AD+D and AD-D patients across time points (main effect of group), consistent changes from baseline to follow-up (main effect of time), and differential changes between AD+D and AD-D over time (interaction of group and time). All data were obtained from the National Alzheimer's Coordinating Center database. RESULTS: The AD+D group had consistently lower frontal GM volume, although both groups showed decreased GM in frontotemporal brain regions over time. An interaction was observed between delusions and longitudinal change, with AD+D patients having significantly elevated GM in predominantly temporal areas at baseline assessment, becoming significantly lower than the AD-D group at follow-up. CONCLUSION: These findings suggest that, there are specific volumetric markers that distinguish patients with delusions from those without, before, and after the onset of delusions. Specifically, the decline of GM in temporal areas that had elevated levels prior to the onset of delusions may be involved in the manifestation of delusions.

Delusions and visual hallucinations in a patient with Parkinson's disease with dementia showing pronounced Lewy body pathology in the nucleus basalis of Meynert.

We describe an autopsy-proven case of Parkinson's disease with dementia showing early-onset delusions and hallucinations with limbic-type Lewy body pathology. A Japanese man 72 years old at time of death, developed hand tremor at the age of 45. On neurological examination at 47 years of age, parkinsonian symptoms and signs were present. Pergolide mesylate 1000 µg/day improved his motor symptoms. Then, delusional jealousy appeared and he consulted the psychiatric department in our hospital at the age of 50. Pergolide mesylate 2000 µg/day and trihexyphenidyl hydrochloride 6 mg/day were prescribed. His delusional jealousy made him hit his wife at the age of 63, and visual hallucinations were demonstrated. Brain magnetic resonance imaging (MRI) at the age of 65 revealed mild frontal lobe atrophy. At the age of 72, apparent dementia and dysphagia appeared. The total clinical course was 27 years. The brain showed mild frontal atrophy and weighed 1295 g before fixation. Depigmentation of the substantia nigra and locus ceruleus was macroscopically apparent. Neuronal loss with gliosis was noteworthy in the substantia nigra, locus ceruleus, dorsal vagal nucleus, nucleus basalis of Meynert (NBM), and intermediate lateral nuclei; however, cerebral neocortex and limbic systems were relatively preserved. Widespread occurrence of Lewy bodies with a few Lewy neurites were demonstrated (limbic-type). Noticeable Lewy body pathology in the NBM was shown in contrast to that in other limbic system structures, such as the amygdala and parahippocampal gyrus, and cerebral cortex. In vivo structural imaging studies revealed that cholinergic projections from the NBM could be responsible for generation of cholinergic deficiency syndrome, including delusions and hallucinations. Furthermore, basal forebrain volume is reduced in patients with Parkinson's disease showing visual hallucinations. Prominent Lewy body pathology in the NBM could be related to not only visual hallucinations but also delusions.

Reduced parahippocampal volume and psychosis symptoms in Alzheimer's disease.

OBJECTIVE: Establishing structural imaging correlates of psychosis symptoms in Alzheimer's disease (AD) could localise pathology and target symptomatic treatment. This study investigated whether psychosis symptoms are associated with visuoperceptual or frontal networks, and whether regional brain volume differences could be linked with the paranoid (persecutory delusions) or misidentification (misidentification phenomena and/or hallucinations) subtypes. METHODS: A total of 104 patients with probable AD (AddNeuroMed; 47 psychotic, 57 non-psychotic), followed up for at least one year with structural MRI at baseline. Presence and subtype of psychosis symptoms were established using the Neuropsychiatric Inventory. Volume and cortical thickness measures in visuoperceptual and frontal networks were explored using multivariate analyses to compare with both a global (psychotic versus not) and subtype-specific approach, adjusting for potential confounding factors. RESULTS: There was a significant main effect of psychosis subtypes on the ventral visual stream region of interest (F30,264  = 1.65, p = 0.021, np2  = 0.16). This was explained by reduced left parahippocampal gyrus volume (F1,97  = 11.1, p = 0.001, np2  = 0.10). When comparisons were made across psychosis subtypes, left parahippocampal volume reduction remained significant (F7,95  = 3.94, p = 0.011, np2  = 0.11) and was greatest for the misidentification and mixed subtypes compared to paranoid and non-psychotic groups. CONCLUSIONS: These findings implicate the ventral visual stream in psychosis in AD, consistent with integrative theories regarding origins of psychosis, and provide further evidence for a role in the misidentification subtype. Specifically, reduced volume in the parahippocampal gyrus is implicated in misidentification delusion formation, which we hypothesise is due to its role in context attribution. Copyright © 2017 John Wiley & Sons, Ltd.

Lesion-Related Delusional Misidentification Syndromes: A Comprehensive Review of Reported Cases.

Delusional misidentification syndromes (DMSs) are persistent delusions of hyper- or hypofamiliarity for meaningful persons and places in one's environment. This study set to determine the clinical course, neuroanatomical localization, neuropsychological abnormalities, and delusional content in patients with DMSs occurring after focal neurological injuries. Sixty-one patients were identified: 28 with hypofamiliar delusions, 27 with hyperfamiliar delusions, and, most surprisingly, six patients with both hypo- and hyperfamiliar delusions. Recognition is often delayed by months from the time of injury, and the delusions are self-limited. Patients with DMSs had right hemisphere (92%) injuries (specifically right frontal injuries in 63%), prominent memory impairment (73%), and multiple concurrent DMSs (29%).

Gray matter atrophy in patients with mild cognitive impairment/Alzheimer's disease over the course of developing delusions.

OBJECTIVE: We conducted a neuroimaging analysis to understand the neuroanatomical correlates of gray matter loss in a group of mild cognitive impairment and early Alzheimer's disease patients who developed delusions. METHODS: With data collected as part of the Alzheimer's Disease Neuroimaging Initiative, we conducted voxel-based morphometry to determine areas of gray matter change in the same Alzheimer's Disease Neuroimaging Initiative participants, before and after they developed delusions. RESULTS: We identified 14 voxel clusters with significant gray matter decrease in patient scans post-delusional onset, correcting for multiple comparisons (false discovery rate, p < 0.05). Major areas of difference included the right and left insulae, left precuneus, the right and left cerebellar culmen, the left superior temporal gyrus, the right posterior cingulate, the right thalamus, and the left parahippocampal gyrus. CONCLUSIONS: Although contrary to our initial predictions of enhanced right frontal atrophy, our preliminary work identifies several neuroanatomical areas, including the cerebellum and left posterior hemisphere, which may be involved in delusional development in these patients.

"Crossed" somatoparaphrenia: an unusual new case and a review of the literature.

Somatoparaphrenia is a delusional misidentification and confabulation of body parts, usually arm or hand, opposite to a cerebral lesion, generally of the "minor" right hemisphere. There is some controversy concerning lesion site (fronto-parietal; parieto-temporal; posterior insula, additional subcortical nuclei) or necessary associated symptoms (hemiparesis/plegia, anosognosia, neglect, position sense deficit). We here present a patient who is unusual in many respects, that is: (1) he is a right-hander with somatoparaphrenia after a "dominant" left-hemisphere lesion associated with aphasia and ideo-motor apraxia, but also with right hemineglect. He thus has "crossed" somatoparaphrenia; (2) his delusional misidentification concerned the right leg and not the arm or hand; (3) he has no anosognosia; (4) his proprioception is disturbed for the leg only; and (5) the lesion site is very posterior, a left occipito-parietal haemorrhage without involvement of the frontal lobe or the posterior insula. We present this case together with the seven other cases of "crossed somatoparaphrenia" with and without aphasia we found since 1935 in the literature and discuss their relevance in relation to the above controversies.

Clinicopathological Study of Patients With C9ORF72-Associated Frontotemporal Dementia Presenting With Delusions.

BACKGROUND: Several clinical studies point to a high prevalence of psychotic symptoms in frontotemporal dementia associated with C9ORF72 mutations, but clinicopathological studies addressing the association between C9ORF72 mutations and delusions are lacking. METHOD: Seventeen patients with pathologically proven frontotemporal lobar degeneration (FTLD) associated with C9ORF72 mutations were identified from Neurodegenerative Disease Brain Bank. Of the 17 cases with C9ORF72 mutation, 4 exhibited well-defined delusions. The clinical history, neurological examination, neuropsychological testing, neuroimaging analysis, and postmortem assessment of the patients with delusions were evaluated and compared with the other cases. RESULT: The content of the delusions was mixed including persecution, infidelity, and grandiosity. All cases showed parkinsonism; voxel-based morphometry analysis showed greater precuneus atrophy in patients with delusions than those without delusions. All 4 had unclassifiable FTLD with TAR DNA-binding protein inclusions, with characteristics of both type A and type B. Three cases had additional τ pathology and another had α-synuclein pathology. CONCLUSION: C9ORF72 carriers with well-defined delusions likely associated with additional pathologies and parietal atrophy in neuroimaging. Patients presenting with middle-aged onset of delusions should be screened for C9ORF72 mutations, especially if family history and parkinsonism are present.

Peculiar body representation alterations in hemineglect: a case report.

We report the case of FP affected by personal and extrapersonal neglect and a body representation deficit characterized by delusional ideas. When FP performed the human figure, he placed body parts to the left, despite his extrapersonal neglect. Differently, when he performed the car figure, he placed all parts to the right, in line with his deficit. Comparing FP with a small patient group with the same clinical features without delusional ideas about body emerged that he was the only one to suffer from a specific body representation deficit characterized by a lack of body ownership sense.

Correlation between right medial temporal lobe atrophy and persecutory delusions in patients with dementia of the Alzheimer's type demonstrated on VSRAD advance.

BACKGROUND: The relationship between focal brain atrophy and delusions in patients with Dementia of the Alzheimer's Type (DAT) is not well understood. Few studies have been reported on the association between medial temporal atrophy (MTA) and persecutory delusions in patients with DAT. We investigated the relationship between MTA and persecutory delusions in patients with DAT using voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) advance software, which allows us to quantify the laterality and the degree of MTA on magnetic resonance imaging (MRI) scans. METHODS: Thirty-one patients diagnosed with DAT were recruited and scanned with a 1.5 tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z score (Z-score) on the target VOI, with higher scores indicating more severe. These DAT patients were divided into a group with (D group: n = 13) and without (ND group: n = 18) persecutory delusions. RESULTS: In the D group, the mean the bilateral, right, and left Z-scores were 2.45, 2.69, and 2.19, respectively. These mean Z-scores of the ND group were 2.00, 2.00, and 1.95, respectively. The right Z-scores for the D group were significantly higher than those for the ND group (p < 0.05). CONCLUSIONS: These findings suggest that right MTA could contribute to the development of persecutory delusions in patients with DAT.

The application of nonlinear Dynamic Causal Modelling for fMRI in subjects at high genetic risk of schizophrenia.

Nonlinear Dynamic Causal Modelling (DCM) for fMRI provides computational modelling of gating mechanisms at the neuronal population level. It allows for estimations of connection strengths with nonlinear modulation within task-dependent networks. This paper presents an application of nonlinear DCM in subjects at high familial risk of schizophrenia performing the Hayling Sentence Completion Task (HSCT). We analysed scans of 19 healthy controls and 46 subjects at high familial risk of schizophrenia, which included 26 high risk subjects without psychotic symptoms and 20 subjects with psychotic symptoms. The activity-dependent network consists of the intra parietal cortex (IPS), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus. The connections between the MD thalamus and the IFG were gated by the MD thalamus. We used DCM to investigate altered connection strength of these connections. Bayesian Model Selection (BMS) at the group and family level was used to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging (BMA) was used to assess the connection strengths with the gating from the MD thalamus and the IFG. The nonlinear models provided the better explanation of the data. Furthermore, the BMA analysis showed significantly lower connection strength of the thalamocortical connection with nonlinear modulation from the MD thalamus in high risk subjects with psychotic symptoms and those who subsequently developed schizophrenia. These findings demonstrate that nonlinear DCM provides a method to investigate altered connectivity at the level of neural circuits. The reduced connection strength with thalamic gating may be a neurobiomarker implicated in the development of psychotic symptoms. This study suggests that nonlinear DCM could lead to new insights into functional and effective dysconnection at the network level in subjects at high familial risk.

The clinical significance of bilateral basal ganglia calcification presenting with mania and delusions.

The authors present the case of a 37-year-old man who developed a psychotic manic episode and was found to have bilateral basal ganglia calcification (BGC). The authors present this case report along with a discussion of the literature on the neuropsychiatry of BGC.

[Delusional disorder, autoaggression und suicide]. / Wahnerkrankung, Autoaggression und Suizid.

The authors report on the suicide of a 27-year-old woman with extreme self-inflicted injuries. The victim suffered from schizophrenic psychosis with several stays in mental institutions and one previous suicide attempt. Autopsy revealed multiple cut and stab injuries in various body regions (51 stabs to the chest, cutting off parts of ears and nose, stab to the eye and transection of the scalp). Death was caused by exsanguination.

Delusions of death in a patient with right hemisphere infarction.

Although a role for right hemisphere dysfunction has been hypothesized in Cotard delusion, it remains unclear which functions are disturbed. We report here the first known patient with unilateral right hemisphere lesions and delusions of death (1 of the 2 types of Cotard delusion). This man began to believe that he was dead after suffering a right hemisphere infarction involving the frontal, temporal, and parietal lobes, as well as the thalamus. He had delusions of death in the context of both depersonalization/derealization and delusional misidentifications of people and places. Neuropsychological testing revealed left hemispatial neglect and deficits in general attention. The patient's sense of body ownership and face recognition abilities were preserved. This case suggests that abnormal feelings of familiarity, which have been implicated in several delusional misidentification syndromes, contribute significantly to the development of delusions of death. If this is true, affective processes involved in the identification of people and places and in the feeling of being alive may partially overlap, and these affective processes may be supported by the right hemisphere.

Frontotemporal atrophy associated with paranoid delusions in women with Alzheimer's disease.

BACKGROUND: Paranoid delusions are a common and difficult-to-manage feature of Alzheimer's disease (AD). We investigated the neuroanatomical correlates of paranoid delusions in a cohort of AD patients, using magnetic resonance imaging (MRI) to measure regional volume and regional cortical thickness. METHODS: 113 participants with probable AD were assessed for severity of disease, cognitive and functional impairment. Presence and type of delusions were assessed using the Neuropsychiatric Inventory (NPI). Structural MRI images were acquired on a 1.5 T scanner, and were analyzed using an automated analysis pipeline. RESULTS: Paranoid delusions were experienced by 23 (20.4%) of the participants. Female participants with paranoid delusions showed reduced cortical thickness in left medial orbitofrontal and left superior temporal regions, independently of cognitive decline. Male participants with delusions did not show any significant differences compared to males without delusions. An exploratory whole brain analysis of non-hypothesized regions showed reduced cortical thickness in the left insula for female participants only. CONCLUSION: Frontotemporal atrophy is associated with paranoid delusions in females with AD. Evidence of sex differences in the neuroanatomical correlates of delusions as well as differences in regional involvement in different types of delusions may be informative in guiding management and treatment of delusions in AD.

Structural brain and neuropsychometric changes associated with pediatric bipolar disorder with psychosis.

OBJECTIVES: To identify neuropsychological and structural brain changes using a combination of high-resolution structural and diffusion tensor imaging in pediatric bipolar disorder (PBD) with psychosis (presence of delusions and or hallucinations). METHODS: We recruited 15 patients and 20 euthymic age- and gender-matched healthy controls. All subjects underwent high-resolution structural and diffusion tensor imaging. Voxel-based morphometry (VBM), tract-based spatial statistics (TBSS), and probabilistic tractography were used to analyse magnetic resonance imaging data. RESULTS: The PBD subjects had normal overall intelligence with specific impairments in working memory, executive function, language function, and verbal memory. Reduced gray matter (GM) density was found in the left orbitofrontal cortex, left pars triangularis, right premotor cortex, occipital cortex, right occipital fusiform gyrus, and right crus of the cerebellum. TBSS analysis showed reduced fractional anisotropy (FA) in the anterior corpus callosum. Probabilistic tractography from this cluster showed that this region of the corpus callosum is connected with the prefrontal cortices, including those regions whose density is decreased in PBD. In addition, FA change was correlated with verbal memory and working memory, while more widespread reductions in GM density correlated with working memory, executive function, language function, and verbal memory. CONCLUSIONS: The findings suggest widespread cortical changes as well as specific involvement of interhemispheric prefrontal tracts in PBD, which may reflect delayed myelination in these tracts.

Association between subcortical lesions and behavioral and psychological symptoms in patients with Alzheimer's disease.

BACKGROUND/AIMS: The most devastating features of Alz-heimer's disease (AD) are often the behavioral and psychological symptoms in dementia (BPSD). There is controversy as to whether subcortical lesions contribute to BPSD. The aim of this study was to examine the relationship between BPSD and subcortical lesions (white-matter lesions and lacunes) in AD. METHODS: CT or MRI from 259 patients with mild-to-moderate AD were assessed with the Age-Related White Matter Changes scale. Linear measures of global and temporal atrophy and Mini-Mental State Examination scores were used to adjust for AD pathology and disease severity in logistic regression models with the BPSD items delusions, hallucinations, agitation, depression, anxiety, apathy and irritability. RESULTS: Lacunes in the left basal ganglia were associated with delusions (OR 2.57, 95% CI 1.21-5.48) and hallucinations (OR 3.33, 95% CI 1.38-8.01) and lacunes in the right basal ganglia were associated with depression (OR 2.13, 95% CI 1.01-4.51). CONCLUSION: Lacunes in the basal ganglia resulted in a 2- to 3-fold increased risk of delusions, hallucinations and depression, when adjusting for cognition and atrophy. This suggests that basal ganglia lesions can contribute to BPSD in patients with AD, independently of the AD process.