RESUMO
Recent studies have shown that white-gray contrast (WGC) of either cortical or subcortical gray matter provides for accurate predictions of age in typically developing (TD) children, and that, at least for the cortex, it changes differently with age in subjects with autism spectrum disorder (ASD) compared to their TD peers. Our previous study showed different patterns of contrast change between ASD and TD in sensorimotor and association cortices. While that study was confined to the cortex, we hypothesized that subcortical structures, particularly the thalamus, were involved in the observed cortical dichotomy between lower and higher processing. The current paper investigates that hypothesis using the WGC measures from the thalamus in addition to those from the cortex. We compared age-related WGC changes in the thalamus to those in the cortex. To capture the simultaneity of this change across the two structures, we devised a metric capturing the co-development of the thalamus and cortex (CoDevTC), proportional to the magnitude of cortical and thalamic age-related WGC change. We calculated this metric for each of the subjects in a large homogeneous sample taken from the Autism Brain Imaging Data Exchange (ABIDE) (N = 434). We used structural MRI data from the largest high-quality cross-sectional sample (NYU) as well as two other large high-quality sites, GU and OHSU, all three using Siemens 3T scanners. We observed that the co-development features in ASD and TD exhibit contrasting patterns; specifically, some higher-order thalamic nuclei, such as the lateral dorsal nucleus, exhibited reduction in codevelopment with most of the cortex in ASD compared to TD. Moreover, this difference in the CoDevTC pattern correlates with a number of behavioral measures across multiple cognitive and physiological domains. The results support previous notions of altered connectivity in autism, but add more specific evidence about the heterogeneity in thalamocortical development that elucidates the mechanisms underlying the clinical features of ASD.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Criança , Humanos , Estudos Transversais , Tálamo , Imageamento por Ressonância MagnéticaRESUMO
Studies have shown that prenatal maternal stress (PNMS) affects brain structure and function in childhood. However, less research has examined whether PNMS effects on brain structure and function extend to young adulthood. We recruited women who were pregnant during or within 3 months following the 1998 Quebec ice storm, assessed their PNMS, and prospectively followed-up their children. T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI were obtained from 19-year-old young adults with (n = 39) and without (n = 65) prenatal exposure to the ice storm. We examined between-group differences in gray matter volume (GMV), surface area (SA), and cortical thickness (CT). We used the brain regions showing between-group GMV differences as seeds to compare between-group functional connectivity. Within the Ice Storm group, we examined (1) associations between PNMS and the atypical GMV, SA, CT, and functional connectivity, and (2) moderation by timing of exposure. Primarily, we found that, compared to Controls, the Ice Storm youth had larger GMV and higher functional connectivity of the anterior cingulate cortex, the precuneus, the left occipital pole, and the right hippocampus; they also had larger CT, but not SA, of the left occipital pole. Within the Ice Storm group, maternal subjective distress during preconception and mid-to-late pregnancy was associated with atypical left occipital pole CT. These results suggest the long-lasting impact of disaster-related PNMS on child brain structure and functional connectivity. Our study also indicates timing-specific effects of the subjective aspect of PNMS on occipital thickness.
RESUMO
Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-ß (Aß) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aß ([18F]AZD4694) and tau ([18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aß-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aß-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aß and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aß and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/patologia , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/líquido cefalorraquidianoRESUMO
Tau is one of several proteins associated with frontotemporal dementia. While knowing which protein is causing a patient's disease is crucial, no biomarker currently exists for identifying tau in vivo in frontotemporal dementia. The objective of this study was to investigate the potential for the promising 18F-MK-6240 PET tracer to bind to tau in vivo in genetic frontotemporal dementia. We enrolled subjects with genetic frontotemporal dementia, who constitute an ideal population for testing because their pathology is already known based on their mutation. Ten participants (three with symptomatic P301L and R406W MAPT mutations expected to show tau binding, three with presymptomatic MAPT mutations and four with non-tau mutations who acted as disease controls) underwent clinical characterization, tau-PET scanning with 18F-MK-6240, amyloid-PET imaging with 18F-NAV-4694 to rule out confounding Alzheimer's pathology, and high-resolution structural MRI. Tau-PET scans of all three symptomatic MAPT carriers demonstrated at least mild 18F-MK-6240 binding in expected regions, with particularly strong binding in a subject with an R406W MAPT mutation (known to be associated with Alzheimer's like neurofibrillary tangles). Two asymptomatic MAPT carriers estimated to be 5 years from disease onset both showed modest 18F-MK-6240 binding, while one â¼30 years from disease onset did not exhibit any binding. Additionally, four individuals with symptomatic frontotemporal dementia caused by a non-tau mutation were scanned (two C9orf72; one GRN; one VCP): 18F-MK-6240 scans were negative for three subjects, while one advanced C9orf72 case showed minimal regionally non-specific binding. All 10 amyloid-PET scans were negative. Furthermore, a general linear model contrasting genetic frontotemporal dementia subjects to a set of 83 age-matched controls showed significant binding only in the MAPT carriers in selected frontal, temporal and subcortical regions. In summary, our findings demonstrate mild but significant binding of MK-6240 in amyloid-negative P301L and R406W MAPT mutation subjects, with higher standardized uptake value ratio in the R406W mutation associated with the presence of NFTs, and little non-specific binding. These results highlight that a positive 18F-MK-6240 tau-PET does not necessarily imply a diagnosis of Alzheimer's disease and point towards a potential use for 18F-MK-6240 as a biomarker in certain tauopathies beyond Alzheimer's, although further patient recruitment and autopsy studies will be necessary to determine clinical applicability.
Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença de Alzheimer/patologia , Proteína C9orf72/genética , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Isoquinolinas , Mutação , Emaranhados Neurofibrilares/patologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
INTRODUCTION: Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed. METHODS: We measured cerebrospinal fluid (CSF) and plasma concentrations of N-terminal tau fragments (NTA-tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aß) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments. RESULTS: CSF and plasma NTA-tau concentrations were specifically increased in cognitively impaired Aß-positive groups. CSF and plasma NTA-tau concentrations displayed stronger correlations with tau PET than with Aß PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA-tau are preferentially associated with tau pathology. Moreover, plasma NTA-tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum. DISCUSSION: NTA-tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials. HIGHLIGHTS: An assay for detecting N-terminal tau fragments (NTA-tau) in plasma and CSF was evaluated. NTA-tau is more closely associated with tau PET than amyloid PET or neurodegeneration. NTA-tau can successfully track in vivo tau deposition across the AD continuum. Plasma NTA-tau increased over time only in cognitively impaired amyloid-ß positive individuals.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Emaranhados Neurofibrilares/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/diagnósticoRESUMO
INTRODUCTION: Phosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-ß (Aß) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aß and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI). METHODS: We assessed 138 CU and 87 CI with available plasma p-tau231, 217+ , and 181, Aß42/40, GFAP and Aß- and tau-PET. RESULTS: In CU, only plasma p-tau231 and p-tau217+ significantly improved the performance of the demographics in detecting Aß-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217+ and GFAP significantly contributed to demographics to identify both Aß-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity. DISCUSSION: Our results support plasma p-tau231 and p-tau217+ as state markers of early Aß deposition, but in later disease stages they inform on tau tangle accumulation. HIGHLIGHTS: It is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex). Plasma p-tau231 and p-tau217+ contribute to demographic information to identify brain Aß pathology in preclinical AD. In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217+ and GFAP inform on both Aß deposition and tau pathology.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Plasma , Biomarcadores , Proteínas tau , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: Previous studies have shown that microglial activation (MA) plays a key role in the physiopathology and progression of Alzheimer's disease (AD). Unpublished data suggest that MA is highly associated with the development of neuropsychiatric symptoms (NPS) in patients with AD. Thus, we aim to investigate here the contribution of each NPS domain to this association across individuals in the AD continuum. METHOD: We assessed 132 individuals (86 cognitively unimpaired (CU), 28 MCI, and 18 AD dementia) from the TRIAD cohort who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI-Q), and had positron emission tomography (PET) for amyloid-ß (Aß) ([18F]AZD4694), tau tangles ([18F]MK6240) and MA ([11C]PBR28) at the same visit. Regions were tailored using Desikan-Killiany (DK) atlas. SUVRs were calculated using the cerebellum gray matter as a reference. Linear regression tested the association between biomarkers accounting for age, sex, and cognitive status. RESULT: NPI-Q total score was significantly associated with [11C]PBR28 in the cingulate, inferior temporal, and precuneus accounting for age, sex, and after false discovery rate (FDR) correction for multiple comparisons (Figure 1A). This association was independent of Aß and tau levels (Table 1). When we stratify NPI-Q domains (agitation, irritability, motor disturbance, disinhibition, elation, delusion, hallucinations, nighttime disturbance, depression, anxiety, apathy, and appetite disturbance) severity score, we found that the hyperactivity subdomain (agitation, irritability, motor disturbance, disinhibition, and elation) showed the larger contribution to the results (Figure 1B). Bootstrapping each NPI-Q domain from the NPI-Q total score, linear regression analysis reveals that irritability, nighttime disturbance, and agitation are the main contributors to the association between NPS and MA (Figure 1C). Removing these domains, but no other combination of two or three NPI-Q domains, from the NPI-Q total score, abolishes this association (Figure 1D). CONCLUSION: Our results suggest that MA is associated with neuropsychiatric dysfunction in AD. Notably, we found that irritability, nighttime disturbance, and agitation drive the association between NPS and MA.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Tomografia por Emissão de Pósitrons , Humanos , Feminino , Masculino , Idoso , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Disfunção Cognitiva , Testes Neuropsicológicos/estatística & dados numéricos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/metabolismo , Estudos de Coortes , Idoso de 80 Anos ou mais , BiomarcadoresRESUMO
Both cortical and subcortical structures are organized into a large number of distinct areas reflecting functional and cytoarchitectonic differences. Mapping these areas is of fundamental importance to neuroscience. A central obstacle to this task is the inaccuracy associated with bringing results from individuals into a common space. The vast individual differences in morphology pose a serious problem for volumetric registration. Surface-based approaches fare substantially better, but have thus far been used only for cortical parcellation, leaving subcortical parcellation in volumetric space. We extend the surface-based approach to include also the subcortical deep gray-matter structures, thus achieving a uniform representation across both cortex and subcortex, suitable for use with surface-based metrics that span these structures, for example, white/gray contrast. Using data from the Enhanced Nathan Klein Institute-Rockland Sample, limited to individuals between 19 and 69 years of age, we generate a functional parcellation of both the cortical and subcortical surfaces. To assess this extended parcellation, we show that (a) our parcellation provides greater homogeneity of functional connectivity patterns than do arbitrary parcellations matching in the number and size of parcels; (b) our parcels align with known cortical and subcortical architecture; and (c) our extended functional parcellation provides an improved fit to the complexity of life-span (6-85 years) changes in white/gray contrast data compared to arbitrary parcellations matching in the number and size of parcels, supporting its use with surface-based measures. We provide our extended functional parcellation for the use of the neuroimaging community.
Assuntos
Córtex Cerebral/diagnóstico por imagem , Conectoma , Substância Cinzenta/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET). METHODS: Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [18 F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [11 C]Pittsburgh Compound-B (PiB) and [18 F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models. RESULTS: [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. CONCLUSIONS: In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.
Assuntos
Doença de Alzheimer , Amiloidose , Disfunção Cognitiva , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Amiloidose/metabolismo , Compostos de Anilina , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Fluordesoxiglucose F18/metabolismo , Glucose/metabolismo , Humanos , Tomografia por Emissão de Pósitrons/métodosRESUMO
Cortical activity has distinct features across scales, from the spiking statistics of individual cells to global resting-state networks. We here describe the first full-density multi-area spiking network model of cortex, using macaque visual cortex as a test system. The model represents each area by a microcircuit with area-specific architecture and features layer- and population-resolved connectivity between areas. Simulations reveal a structured asynchronous irregular ground state. In a metastable regime, the network reproduces spiking statistics from electrophysiological recordings and cortico-cortical interaction patterns in fMRI functional connectivity under resting-state conditions. Stable inter-area propagation is supported by cortico-cortical synapses that are moderately strong onto excitatory neurons and stronger onto inhibitory neurons. Causal interactions depend on both cortical structure and the dynamical state of populations. Activity propagates mainly in the feedback direction, similar to experimental results associated with visual imagery and sleep. The model unifies local and large-scale accounts of cortex, and clarifies how the detailed connectivity of cortex shapes its dynamics on multiple scales. Based on our simulations, we hypothesize that in the spontaneous condition the brain operates in a metastable regime where cortico-cortical projections target excitatory and inhibitory populations in a balanced manner that produces substantial inter-area interactions while maintaining global stability.
Assuntos
Potenciais de Ação/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Córtex Visual/fisiologia , Algoritmos , Animais , Biologia Computacional , Eletroencefalografia , Neuroestimuladores Implantáveis , Macaca , Masculino , Estimulação Luminosa , SonoRESUMO
Understanding how the structure of cognition arises from the topographical organization of the cortex is a primary goal in neuroscience. Previous work has described local functional gradients extending from perceptual and motor regions to cortical areas representing more abstract functions, but an overarching framework for the association between structure and function is still lacking. Here, we show that the principal gradient revealed by the decomposition of connectivity data in humans and the macaque monkey is anchored by, at one end, regions serving primary sensory/motor functions and at the other end, transmodal regions that, in humans, are known as the default-mode network (DMN). These DMN regions exhibit the greatest geodesic distance along the cortical surface-and are precisely equidistant-from primary sensory/motor morphological landmarks. The principal gradient also provides an organizing spatial framework for multiple large-scale networks and characterizes a spectrum from unimodal to heteromodal activity in a functional metaanalysis. Together, these observations provide a characterization of the topographical organization of cortex and indicate that the role of the DMN in cognition might arise from its position at one extreme of a hierarchy, allowing it to process transmodal information that is unrelated to immediate sensory input.
Assuntos
Encéfalo/fisiologia , Rede Nervosa/fisiologia , Sensação/fisiologia , Córtex Sensório-Motor/fisiologia , Animais , Mapeamento Encefálico , Humanos , Macaca , Imageamento por Ressonância Magnética/métodos , Modelos NeurológicosRESUMO
The functional interaction between the brain's two hemispheres includes a unique set of connections between corresponding regions in opposite hemispheres (i.e., homotopic regions) that are consistently reported to be exceptionally strong compared with other interhemispheric (i.e., heterotopic) connections. The strength of homotopic functional connectivity (FC) is thought to be mediated by the regions' shared functional roles and their structural connectivity. Recently, homotopic FC was reported to be stable over time despite the presence of dynamic FC across both intrahemispheric and heterotopic connections. Here we build on this work by considering whether homotopic FC is also stable across conditions. We additionally test the hypothesis that strong and stable homotopic FC is supported by the underlying structural connectivity. Consistent with previous findings, interhemispheric FC between homotopic regions were significantly stronger in both humans and macaques. Across conditions, homotopic FC was most resistant to change and therefore was more stable than heterotopic or intrahemispheric connections. Across time, homotopic FC had significantly greater temporal stability than other types of connections. Temporal stability of homotopic FC was facilitated by direct anatomical projections. Importantly, temporal stability varied with the change in conductive properties of callosal axons along the anterior-posterior axis. Taken together, these findings suggest a notable role for the corpus callosum in maintaining stable functional communication between hemispheres.
Assuntos
Corpo Caloso/anatomia & histologia , Corpo Caloso/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Transmissão Sináptica/fisiologia , Animais , Mapeamento Encefálico , Feminino , Lateralidade Funcional/fisiologia , Humanos , Macaca , Imageamento por Ressonância Magnética , Masculino , Especificidade da EspécieRESUMO
Modern systems neuroscience increasingly leans on large-scale multi-lab neuroinformatics initiatives to provide necessary capacity for biologically realistic modeling of primate whole-brain activity. Here, we present a framework to assemble primate brain's biologically plausible anatomical backbone for such modeling initiatives. In this framework, structural connectivity is determined by adding complementary information from invasive macaque axonal tract tracing and non-invasive human diffusion tensor imaging. Both modalities are combined by means of available interspecies registration tools and a newly developed Bayesian probabilistic modeling approach to extract common connectivity evidence. We demonstrate how this novel framework is embedded in the whole-brain simulation platform called The Virtual Brain (TVB). Hum Brain Mapp 38:2080-2093, 2017. © 2017 Wiley Periodicals, Inc.
Assuntos
Mapeamento Encefálico , Encéfalo/anatomia & histologia , Bibliotecas Digitais , Modelos Neurológicos , Vias Neurais/anatomia & histologia , Adolescente , Adulto , Algoritmos , Animais , Encéfalo/diagnóstico por imagem , Conectoma , Bases de Dados Factuais , Imagem de Tensor de Difusão , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Macaca , Masculino , Modelos Estatísticos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Especificidade da Espécie , Adulto JovemRESUMO
The structural organization of the brain constrains the range of interactions between different regions and shapes ongoing information processing. Therefore, it is expected that large-scale dynamic functional connectivity (FC) patterns, a surrogate measure of coordination between brain regions, will be closely tied to the fiber pathways that form the underlying structural network. Here, we empirically examined the influence of network structure on FC dynamics by comparing resting-state FC (rsFC) obtained using BOLD-fMRI in macaques (Macaca fascicularis) to structural connectivity derived from macaque axonal tract tracing studies. Consistent with predictions from simulation studies, the correspondence between rsFC and structural connectivity increased as the sample duration increased. Regions with reciprocal structural connections showed the most stable rsFC across time. The data suggest that the transient nature of FC is in part dependent on direct underlying structural connections, but also that dynamic coordination can occur via polysynaptic pathways. Temporal stability was found to be dependent on structural topology, with functional connections within the rich-club core exhibiting the greatest stability over time. We discuss these findings in light of highly variable functional hubs. The results further elucidate how large-scale dynamic functional coordination exists within a fixed structural architecture.
Assuntos
Mapeamento Encefálico , Encéfalo/fisiologia , Modelos Neurológicos , Vias Neurais/fisiologia , Dinâmica não Linear , Animais , Encéfalo/irrigação sanguínea , Feminino , Processamento de Imagem Assistida por Computador , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/irrigação sanguínea , Oxigênio/sangueRESUMO
Visual behavior is guided by memories from prior experience and knowledge of the visual scene. The hippocampal system (HC), in particular, has been implicated in the guidance of saccades: Amnesic patients, following damage to the HC, exhibit selective deficits in their gaze patterns. However, the neural circuitry by which mnemonic representations influence the oculomotor system remains unknown. We used a data-driven, network-based approach on directed anatomical connectivity from the macaque brain to reveal an extensive set of polysnaptic pathways spanning the extrastriate, posterior parietal and prefrontal cortices that potentially mediate the exchange of information between the memory and visuo-oculomotor systems. We additionally show how the potential for directed information flow from the hippocampus to oculomotor control areas is exceptionally high. In particular, the dorsolateral pFC and FEF-regions known to be responsible for the cognitive control of saccades-are topologically well positioned to receive information from the hippocampus. Together with neuropsychological evidence of altered gaze patterns following damage to the hippocampus, our findings suggest that a reconsideration of hippocampal involvement in oculomotor guidance is needed.
RESUMO
In systems neuroscience, the term "connectivity" has been defined in numerous ways, according to the particular empirical modality from which it is derived. Due to large differences in the phenomena measured by these modalities, the assumptions necessary to make inferences about axonal connections, and the limitations accompanying each, brain connectivity remains an elusive concept. Despite this, only a handful of studies have directly compared connectivity as inferred from multiple modalities, and there remains much ambiguity over what the term is actually referring to as a biological construct. Here, we perform a direct comparison based on the high-resolution and high-contrast Enhanced Nathan Klein Institute (NKI) Rockland Sample neuroimaging data set, and the CoCoMac database of tract tracing studies. We compare four types of commonly-used primate connectivity analyses: tract tracing experiments, compiled in CoCoMac; group-wise correlation of cortical thickness; tractographic networks computed from diffusion-weighted MRI (DWI); and correlational networks obtained from resting-state BOLD (fMRI). We find generally poor correspondence between all four modalities, in terms of correlated edge weights, binarized comparisons of thresholded networks, and clustering patterns. fMRI and DWI had the best agreement, followed by DWI and CoCoMac, while other comparisons showed striking divergence. Networks had the best correspondence for local ipsilateral and homotopic contralateral connections, and the worst correspondence for long-range and heterotopic contralateral connections. k-Means clustering highlighted the lowest cross-modal and cross-species consensus in lateral and medial temporal lobes, anterior cingulate, and the temporoparietal junction. Comparing the NKI results to those of the lower resolution/contrast International Consortium for Brain Imaging (ICBM) dataset, we find that the relative pattern of intermodal relationships is preserved, but the correspondence between human imaging connectomes is substantially better for NKI. These findings caution against using "connectivity" as an umbrella term for results derived from single empirical modalities, and suggest that any interpretation of these results should account for (and ideally help explain) the lack of multimodal correspondence.
Assuntos
Encéfalo/anatomia & histologia , Conectoma/métodos , Vias Neurais/anatomia & histologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Encéfalo/fisiologia , Criança , Análise por Conglomerados , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiologia , Primatas , Especificidade da Espécie , Adulto JovemRESUMO
The macaque brain serves as a model for the human brain, but its suitability is challenged by unique human features, including connectivity reconfigurations, which emerged during primate evolution. We perform a quantitative comparative analysis of the whole brain macroscale structural connectivity of the two species. Our findings suggest that the human and macaque brain as a whole are similarly wired. A region-wise analysis reveals many interspecies similarities of connectivity patterns, but also lack thereof, primarily involving cingulate regions. We unravel a common structural backbone in both species involving a highly overlapping set of regions. This structural backbone, important for mediating information across the brain, seems to constitute a feature of the primate brain persevering evolution. Our findings illustrate novel evolutionary aspects at the macroscale connectivity level and offer a quantitative translational bridge between macaque and human research.
Assuntos
Encéfalo/fisiologia , Conectoma , Adulto , Animais , Anisotropia , Mapeamento Encefálico , Análise por Conglomerados , Difusão , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Macaca , Masculino , Rede Nervosa , Vias Neurais , Especificidade da EspécieRESUMO
fMRI neurofeedback using autobiographical memory recall to upregulate the amygdala is associated with resting-state functional connectivity (rsFC) changes between the amygdala and the salience and default mode networks (SN and DMN, respectively). We hypothesize the existence of anatomical circuits underlying these rsFC changes. Using a cross-species brain parcellation, we identified in non-human primates locations homologous to the regions of interest (ROIs) from studies showing pre-to-post-neurofeedback changes in rsFC with the left amygdala. We injected bidirectional tracers in the basolateral, lateral, and central amygdala nuclei of adult macaques and used bright- and dark-field microscopy to identify cells and axon terminals in each ROI (SN: anterior cingulate, ventrolateral, and insular cortices; DMN: temporal pole, middle frontal gyrus, angular gyrus, precuneus, posterior cingulate cortex, parahippocampal gyrus, hippocampus, and thalamus). We also performed additional injections in specific ROIs to validate the results following amygdala injections and delineate potential disynaptic pathways. Finally, we used high-resolution diffusion MRI data from four post-mortem macaque brains and one in vivo human brain to translate our findings to the neuroimaging domain. Different amygdala nuclei had significant monosynaptic connections with all the SN and DMN ipsilateral ROIs. Amygdala connections with the DMN contralateral ROIs are disynaptic through the hippocampus and parahippocampal gyrus. Diffusion MRI in both species benefitted from using the ground-truth tracer data to validate its findings, as we identified false-negative ipsilateral and false-positive contralateral connectivity results. This study provides the foundation for future causal investigations of amygdala neurofeedback modulation of the SN and DMN through these anatomic connections.
RESUMO
The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aß) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aß- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aß and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aß-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aß and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aß and tau's synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aß-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.
RESUMO
Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-ß (Aß) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aß and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aß-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.