scholarly journals Salience network atrophy links neuron type-specific pathobiology to loss of empathy in frontotemporal dementia

2019 ◽  
Author(s):  
Lorenzo Pasquini ◽  
Alissa L. Nana ◽  
Gianina Toller ◽  
Jesse Brown ◽  
Jersey Deng ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Large Scale ◽  
Anterior Cingulate ◽  
Projection Neurons ◽  
Salience Network ◽  
Neuron Type ◽  
Social Emotional ◽  
Emotional Empathy ◽  
Emotional Function ◽  
Fork Cells

AbstractEach neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs) and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.

scholarly journals Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia

2020 ◽  
Vol 30 (10) ◽  
pp. 5387-5399 ◽  
Author(s):  
Lorenzo Pasquini ◽  
Alissa L Nana ◽  
Gianina Toller ◽  
Jesse A Brown ◽  
Jersey Deng ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Large Scale ◽  
Anterior Cingulate ◽  
Projection Neurons ◽  
Salience Network ◽  
Neuron Type ◽  
Social Emotional ◽  
Emotional Empathy ◽  
Emotional Function ◽  
Fork Cells

Abstract Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.

scholarly journals Spatiotemporal Integrity and Spontaneous Nonlinear Dynamic Properties of the Salience Network Revealed by Human Intracranial Electrophysiology: A Multicohort Replication

2020 ◽  
Vol 30 (10) ◽  
pp. 5309-5321 ◽  
Author(s):  
Anup Das ◽  
Vinod Menon
Keyword(s):  
Large Scale ◽  
Temporal Dynamics ◽  
Functional Organization ◽  
Dynamic Properties ◽  
Critical Role ◽  
Anterior Cingulate ◽  
Human Cognition ◽  
Salience Network ◽  
Temporal Properties ◽  
Nonlinear Dynamic Properties

Abstract The salience network (SN) plays a critical role in cognitive control and adaptive human behaviors, but its electrophysiological foundations and millisecond timescale dynamic temporal properties are poorly understood. Here, we use invasive intracranial EEG (iEEG) from multiple cohorts to investigate the neurophysiological underpinnings of the SN and identify dynamic temporal properties that distinguish it from the default mode network (DMN) and dorsolateral frontal–parietal network (FPN), two other large-scale brain networks that play important roles in human cognition. iEEG analysis of network interactions revealed that the anterior insula and anterior cingulate cortex, which together anchor the SN, had stronger intranetwork interactions with each other than cross-network interactions with the DMN and FPN. Analysis of directionality of information flow between the SN, DMN, and FPN revealed causal outflow hubs in the SN consistent with its role in fast temporal switching of network interactions. Analysis of regional iEEG temporal fluctuations revealed faster temporal dynamics and higher entropy of neural activity within the SN, compared to the DMN and FPN. Critically, these results were replicated across multiple cohorts. Our findings provide new insights into the neurophysiological basis of the SN, and more broadly, foundational mechanisms underlying the large-scale functional organization of the human brain.

scholarly journals Anatomical and functional connectivity support the existence of a salience network node within the caudal ventrolateral prefrontal cortex

2021 ◽  
Author(s):  
Lucas R. Trambaiolli ◽  
Xiaolong Peng ◽  
Julia F. Lehman ◽  
Hesheng Liu ◽  
Suzanne N. Haber
Keyword(s):  
Prefrontal Cortex ◽  
Functional Connectivity ◽  
Large Scale ◽  
Cognitive Networks ◽  
Anterior Cingulate ◽  
Salience Network ◽  
Subcortical Structures ◽  
Dorsal Anterior Cingulate Cortex ◽  
Ventrolateral Prefrontal Cortex ◽  
Caudal Area

AbstractThree large-scale brain networks are considered essential to cognitive flexibility: the ventral and dorsal attention (VAN and DAN) and salience (SN) networks. The ventrolateral prefrontal cortex (vlPFC) is a known component of the VAN and DAN, but its role in the SN is controversial. In this study, we used a translational and multimodal approach to demonstrate the existence of a SN node within the vlPFC. First, we used tract-tracing methods in non-human primates (NHP) to quantify the anatomic connectivity strength between the different vlPFC areas and the frontal and insular cortices. The strongest connections with the dorsal anterior cingulate cortex (dACC) and anterior insula (AI) locations comprising the two main cortical SN nodes were derived from the caudal area 47/12. This location also has strong axonal projections to subcortical structures of the salience network, including the dorsomedial thalamus, hypothalamus, sublenticular extended amygdala, and periaqueductal gray. Second, we used a seed-based functional connectivity analysis in NHP resting-state functional MRI (rsfMRI) data to validate the caudal area 47/12 as an SN node. Third, we used the same approach in human rsfMRI data to identify a homologous structure in caudal area 47/12, also showing strong connections with the SN cortical nodes, thus confirming the caudal area 47/12 as the SN node in the vlPFC. Taken together, the vlPFC contains nodes for all three cognitive networks, the VAN, DAN, and SN. Thus, the vlPFC is in a position to switch between these three cognitive networks, suggesting a key role as an attentional hub. Its tight additional connections to the orbitofrontal, dorsolateral, and ventral premotor cortices, places the vlPFC at the center for switching behaviors based on environmental stimuli, computing value and cognitive control.

The parent-offspring microbiome and neurobehavioral development

2019 ◽  
Vol 42 ◽  
Author(s):  
Jeffrey R. Alberts ◽  
Christopher Harshaw ◽  
Gregory E. Demas ◽  
Cara L. Wellman ◽  
Ardythe L. Morrow
Keyword(s):  
Mammalian Species ◽  
Social Emotional ◽  
Behavioral Measures ◽  
Neurobehavioral Development ◽  
Emotional Function ◽  
Neurobehavioral Outcomes ◽  
Methodological Approaches ◽  
And Behavior

Abstract We identify the significance and typical requirements of developmental analyses of the microbiome-gut-brain (MGB) in parents, offspring, and parent-offspring relations, which have particular importance for neurobehavioral outcomes in mammalian species, including humans. We call for a focus on behavioral measures of social-emotional function. Methodological approaches to interpreting relations between the microbiota and behavior are discussed.

scholarly journals Genetic factors influencing a neurobiological substrate for psychiatric disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Till F. M. Andlauer ◽  
Thomas W. Mühleisen ◽  
Felix Hoffstaedter ◽  
Alexander Teumer ◽  
Katharina Wittfeld ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Risk ◽  
Meta Analysis ◽  
Anterior Cingulate ◽  
Psychiatric Disease ◽  
Salience Network ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Common Substrate ◽  
The Common

AbstractA retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex—areas that constitute hub nodes of the salience network—represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.

scholarly journals Distinct network topology in Alzheimer’s disease and behavioral variant frontotemporal dementia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Adeline Su Lyn Ng ◽  
Juan Wang ◽  
Kwun Kei Ng ◽  
Joanna Su Xian Chong ◽  
Xing Qian ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontotemporal Dementia ◽  
Network Topology ◽  
Neuropsychiatric Symptoms ◽  
Brain Network ◽  
Salience Network ◽  
Behavioral Variant Frontotemporal Dementia ◽  
Control Networks ◽  
And Control

Abstract Background Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social–emotional functional deficits. Methods In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. Results Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. Conclusions Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

scholarly journals Robust information routing by dorsal subiculum neurons

2021 ◽  
Vol 7 (11) ◽  
pp. eabf1913
Author(s):  
Takuma Kitanishi ◽  
Ryoko Umaba ◽  
Kenji Mizuseki
Keyword(s):  
Nucleus Accumbens ◽  
Large Scale ◽  
Dorsal Hippocampus ◽  
Retrosplenial Cortex ◽  
Projection Neurons ◽  
Target Region ◽  
Ca1 Neurons ◽  
Axonal Projections ◽  
Output Structure ◽  
Hippocampal Ca1

The dorsal hippocampus conveys various information associated with spatial navigation; however, how the information is distributed to multiple downstream areas remains unknown. We investigated this by identifying axonal projections using optogenetics during large-scale recordings from the rat subiculum, the major hippocampal output structure. Subicular neurons demonstrated a noise-resistant representation of place, speed, and trajectory, which was as accurate as or even more accurate than that of hippocampal CA1 neurons. Speed- and trajectory-dependent firings were most prominent in neurons projecting to the retrosplenial cortex and nucleus accumbens, respectively. Place-related firing was uniformly observed in neurons targeting the retrosplenial cortex, nucleus accumbens, anteroventral thalamus, and medial mammillary body. Theta oscillations and sharp-wave/ripples tightly controlled the firing of projection neurons in a target region–specific manner. In conclusion, the dorsal subiculum robustly routes diverse navigation-associated information to downstream areas.

Differential engagement of anterior cingulate cortex subdivisions for cognitive and emotional function

2007 ◽  
Vol 44 (3) ◽  
pp. 343-351 ◽  
Author(s):  
Aprajita Mohanty ◽  
Anna S. Engels ◽  
John D. Herrington ◽  
Wendy Heller ◽  
Moon-Ho Ringo Ho ◽  
...  
Keyword(s):  
Anterior Cingulate Cortex ◽  
Cingulate Cortex ◽  
Anterior Cingulate ◽  
Emotional Function

scholarly journals Relationship Turmoil and Emotional Empathy in Frontotemporal Dementia

2019 ◽  
Vol 33 (3) ◽  
pp. 260-265 ◽  
Author(s):  
Akitoshi Takeda ◽  
Virginia E. Sturm ◽  
Katherine P. Rankin ◽  
Robin Ketelle ◽  
Bruce L. Miller ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Emotional Empathy

scholarly journals Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study

Brain ◽  
2019 ◽  
Vol 142 (4) ◽  
pp. 1108-1120 ◽  
Author(s):  
Henri J M M Mutsaerts ◽  
Saira S Mirza ◽  
Jan Petr ◽  
David L Thomas ◽  
David M Cash ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Frontotemporal Dementia ◽  
Symptom Onset ◽  
Arterial Spin Labelling ◽  
Anterior Cingulate ◽  
Middle Temporal Gyrus ◽  
Inverse Association ◽  
Mutation Carriers ◽  
Spin Labelling

Abstract Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

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