Clinical NeuroanatomyWhite matter abnormalities of right hemisphere attention networks contribute to visual hallucinations in dementia with Lewy bodies
Introduction
Visual hallucinations (VH) are visual experiences not elicited by external stimuli. They are common in numerous pathological conditions, including: ocular diseases (ffytche & Howard, 1999; ffytche, 2009; Schadlu, et al., 2009); epilepsy (Duarte Mangas, et al., 2017; Panayiotopoulos, 1999; Saha et al., 2016); primary psychiatric disorders with psychosis (Baethge et al., 2005; Bracha et al., 1989; Goodwin et al., 1971); and neurodegenerative diseases (Cagnin et al., 2013; Diederich et al., 2009; Fenelon et al., 2000; Urwyler et al., 2016; Williams et al., 2008).
As reviewed by ffytche (ffytche 2008), the literature on VH originally focused on the abnormal functioning of specific brain regions, such as the occipital lobe, and the role of topological hyperfunction (Holroyd et al., 2000; Panayiotopoulos 1999). There is plenty of evidence of VH being associated with transient increases in activity in localized cortical regions, and the specialization of the regions affected decides the content of the VH. Indirect evidence comes from patients experiencing types of VH that relate to their abilities that are still intact, not to those they have lost (ffytche et al., 2004; Hubl et al., 2007). In many brain diseases, VH are characterized mainly by recurrent complex visions (seeing objects, animals and human beings, for instance), rather than simple VH such as seeing dots, lines, flashes, and amorphous shapes (Collerton et al., 2005). A topology-based approach seems unable to explain the complexity of the symptoms adequately, so a functional model has been proposed that emphasizes the altered integration and segregation of information, and the neural activity involved in promoting efficient information processing (Park & Friston, 2013). This “hodological” view has been applied to neuropsychological theories of VH, according to which they would result from: an abnormal processing of visual information combined with an impaired top-down monitoring of visual attention (Collerton et al., 2005); or from an imbalance between the dorsal and ventral attention networks (Shine et al., 2011; O'Brien et al., 2020). In the last two decades, attention and visual perception networks have been elucidated both anatomically and functionally, and the activity and interaction between networks have been investigated (Corbetta & Shulman, 2011; Thiebaut de Schotten, Dell'Acqua, et al., 2011; Bartolomeo et al., 2012). It has emerged that dorsal and ventral attention networks have different functions, and functional localizations. The dorsal attention network has a bilateral organization, and is involved in representing contralateral spatial information, and in shifting attention and eye movements. The ventral attention network has a right-hemisphere dominance and is involved in vigilance, in re-orienting attention to sensory-driven or behaviorally-relevant stimuli, and in task resetting (Corbetta & Shulman, 2002; He, Snyder, et al., 2007).
As concerns structural connectivity, the inferior longitudinal fasciculus (ILF) bi-directionally connects the occipital regions to the medial and lateral anterior temporal lobes. It is involved in processing visual emotion and visual memory information (Latini et al., 2017). The inferior fronto-occipital fasciculus (IFOF) connects regions of the occipital and ventral frontal lobes. Connections between the visual part of the parietal lobe and the frontal cortex are via the superior longitudinal fasciculus (SLF), while those between the occipital and limbic cortex are via the cingulum and the ILF. The SLF and IFOF contain projections of neuronal networks involved in processing visual attention, visual working memory, visual praxis, visuo-vestibular function, and eye movement control (ffytche et al., 2010).
Recurrent complex VH are a core feature pointing to the diagnosis of dementia with Lewy bodies (DLB) (McKeith et al., 2017). They occur in about 60% of suspected cases of DLB (Aarsland et al., 2001), and are considered a strong predictor of this condition (Tiraboschi et al., 2006). Patients with DLB show occipital hypometabolism, one of the neuroimaging hallmarks of the disease, that has revealed no clear relationship with VH (Delli Pizzi et al., 2014; Firbank et al., 2016; Taylor et al., 2012). DLB is consequently an attractive model for investigating the neural mechanisms behind VH.
Some studies have focused on white matter connectivity in subjects with DLB and VH, finding changes in the level of diffusivity in temporo-occipital connections, especially in the right hemisphere (Kantarci et al., 2010; Delli Pizzi, Franciotti, Taylor, Esposito, et al., 2015). Previous association between long white matter tracts and functional brain networks have been reported (Thiebaut de Schotten, Dell'Acqua, et al., 2011; Parlatini et al., 2017), but no multimodal studies to date have assessed the combined interaction of structural and functional changes in cases of DLB-related VH. Here, we use diffusion tensor imaging tractography to examine the involvement of white matter tracts connecting the visual cortex to regions of the attention networks in patients with DLB with and without VH. We also explore: whether changes in the white matter bundles of subjects who experience VH lead to a reduction in cortical thickness; and whether functional changes in the attention and visual networks are detectable on resting-state functional MRI images (rs-fMRI).
Section snippets
Patients
Thirty patients with a diagnosis of probable DLB according to McKeith criteria (McKeith et al., 2017) and 13 age-matched healthy controls were enrolled in the study at the Memory Clinic of the Department of Neurosciences at Padua University (Italy). Among the patients with DLB, 7/30 were not considered in subsequent imaging analyses due to movement artifacts. The final sample thus consisted of: 23 patients with DLB, 10 of whom experienced VH (the VH subgroup), and 13 who never experienced VH
Demographic and clinical features
The sample's demographic and clinical data are summarized in Table 1. The groups of patients with DLB and controls matched for age and education level. The VH subgroup had symptoms of RBD more frequently than the no-VH subgroup. No significant differences emerged for duration of the disease, cognitive fluctuations, severity of parkinsonism, degree of cognitive impairment or burden of behavioral disturbances (excluding the scores obtained from the NPI sub-item of VH burden). Patients in the
Discussion
This multimodal MRI study examined structural and functional connectivity abnormalities in patients with DLB and visual hallucinations (VH). Four findings are worth noting. First, whole-brain tractography analysis showed damage to white matter tracts in patients with VH, especially in the right hemisphere: FA was decreased in the right ILF and SLF3, and MD was increased in the right ILF, SLF3, IFOF, and left UNC. Second, cortical thickness in regions connected through the right SLF3 was reduced
Funding
MTS funding comes from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 81852).
CB received a grant by the Associazione Italiana Ricerca Alzheimer Onlus (AIRAlzh) funded by Consorzio Nazionale delle Cooperative di Consumatori (COOP ITALIA S.C.)
MC funding comes from FLAG-ERA JTC 2017; Dipartimento Eccellenza del MIUR Neuro-DiP; Progetto Strategico UniPD.
No part of the study procedures was pre-registered prior to the
Declaration of competing interest
The authors have no competing interests to disclose.
References (90)
- et al.
A reproducible evaluation of ANTs similarity metric performance in brain image registration
Neuroimage
(2011) - et al.
Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in an aging and dementia cohort
Sleep Medicine
(2011) - et al.
The reorienting system of the human brain: From environment to theory of mind
Neuron
(2008) - et al.
Registration based cortical thickness measurement
Neuroimage
(2009) The hodology of hallucinations
Cortex; a Journal Devoted To the Study of the Nervous System and Behavior
(2008)- et al.
Mini-mental state". A practical method for grading the cognitive state of patients for the clinician
Journal of Psychiatric Research
(1975) - et al.
Damage to the shortest structural paths between brain regions is associated with disruptions of resting-state functional connectivity after stroke
Neuroimage
(2020) - et al.
Structural connectivity in a single case of progressive prosopagnosia: The role of the right inferior longitudinal fasciculus
Cortex; a Journal Devoted To the Study of the Nervous System and Behavior
(2014) - et al.
Disconnection and hyper-connectivity underlie reorganization after tbi: A rodent functional connectomic analysis
Experimental Neurology
(2016) - et al.
Breakdown of functional connectivity in frontoparietal networks underlies behavioral deficits in spatial neglect
Neuron
(2007)
Hearing dysphasic voices
Lancet
Improved optimization for the robust and accurate linear registration and motion correction of brain images
Neuroimage
Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration
Neuroimage
Divergent functional connectivity during attentional processing in Lewy body dementia and Alzheimer's disease
Cortex; a Journal Devoted To the Study of the Nervous System and Behavior
Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study
Brain Research
Individual differences in structural and functional connectivity predict speed of emotion discrimination
Cortex; a Journal Devoted To the Study of the Nervous System and Behavior
Cooperative and competitive spreading dynamics on the human connectome
Neuron
Functional segregation and integration within fronto-parietal networks
Neuroimage
Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data
Neuroimage
Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography
Neuroimage
'What' and 'where' in the human brain
Current Opinion in Neurobiology
Visual hallucinations in eye disease and Lewy body disease
The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry
Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers
Neuroimage
Bayesian analysis of neuroimaging data in FSL
Neuroimage
A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia
Int J Geriatr Psychiatry
An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance
Annual Review of Neuroscience
Hallucinations in bipolar disorder: Characteristics and comparison to unipolar depression and schizophrenia
Bipolar Disorders
Brain networks of visuospatial attention and their disruption in visual neglect
Front Hum Neurosci
High prevalence of visual hallucinations in research subjects with chronic schizophrenia
The American Journal of Psychiatry
Rey-osterrieth complex figure: Normative values in an Italian population sample
Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Clinical and cognitive correlates of visual hallucinations in dementia with Lewy bodies
Neurologia I Neurochirurgia Polska
Principles and limitations of computational algorithms in clinical diffusion tensor MR tractography
AJNR. American Journal of Neuroradiology
Why people see things that are not there: A novel perception and attention deficit model for recurrent complex visual hallucinations
The Behavioral and Brain Sciences
Control of goal-directed and stimulus-driven attention in the brain
Nature Reviews. Neuroscience
Spatial neglect and attention networks
Annual Review of Neuroscience
The neuropsychiatric inventory: Comprehensive assessment of psychopathology in dementia
Neurology
Structural alteration of the dorsal visual network in DLB patients with visual hallucinations: A cortical thickness MRI study
Plos One
Structural connectivity is differently altered in dementia with Lewy body and alzheimer's disease
Front Aging Neurosci
Thalamic involvement in fluctuating cognition in dementia with Lewy bodies: Magnetic resonance evidences
Cerebral Cortex
Hallucinations in Parkinson disease
Nature Reviews. Neurology
Misdiagnoses of epilepsy as ekbom syndrome, mood instability, and nocturnal visual hallucinations
Case Rep Psychiatry
Hallucinations in Parkinson's disease: Prevalence, phenomenology and risk factors
Brain: a Journal of Neurology
DLB fluctuations: Specific features that reliably differentiate DLB from AD and normal aging
Neurology
The perceptual consequences of visual loss: 'positive' pathologies of vision
Brain: a Journal of Neurology
Visual command hallucinations in a patient with pure alexia
Neurologia I Neurochirurgia Polska
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2022, NeuroImage: ClinicalCitation Excerpt :Hypotheses regarding the etiology of VH in neurodegenerative disease involve altered connections between visual regions (Esmaeeli et al., 2019; Tsukada et al., 2015; Shine et al., 2011). Supporting these hypotheses, alterations in white matter tracts, including the inferior and superior longitudinal fasciculus (which connect parieto-occipital cortex with anterior temporal and frontal cortices respectively) have been reported in Lewy body dementia patients with complex VH (Zorzi et al., 2021; Zarkali et al., 2020; Yuki et al., 2020). The cholinergic system has also been implicated in the etiology of complex VH in neurodegenerative disease (O'Brien et al., 2020), with the main cortical innervation being from the nucleus basalis of Meynert (nbM).
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