Orbital and Medial Prefrontal Cortex Functional Connectivity of Major Depression Vulnerability and Disease.

BACKGROUND: Pathophysiology models of major depression (MD) center on the dysfunction of various cortical areas within the orbital and medial prefrontal cortex. While independent structural and functional abnormalities in these areas are consistent findings in MD, the complex interactions among them and the rest of the cortex remain largely unexplored. METHODS: We used resting-state functional magnetic resonance imaging connectivity to systematically map alterations in the communication between orbital and medial prefrontal cortex fields and the rest of the brain in MD. Functional connectivity (FC) maps from participants with current MD (n = 35), unaffected first-degree relatives (n = 36), and healthy control subjects (n = 38) were subjected to conjunction analyses to distinguish FC markers of MD vulnerability and FC markers of MD disease. RESULTS: FC abnormalities in MD vulnerability were found for dorsal medial wall regions and the anterior insula and concerned altered communication of these areas with the inferior parietal cortex and dorsal posterior cingulate, occipital areas and the brainstem. FC aberrations in current MD included the anterior insula, rostral and dorsal anterior cingulate cortex, and lateral orbitofrontal areas and concerned altered communication with the dorsal striatum, the cerebellum, the precuneus, the anterior prefrontal cortex, somatomotor cortex, dorsolateral prefrontal cortex, and visual areas in the occipital and inferior temporal lobes. CONCLUSIONS: Functionally delineated parcellation maps can be used to identify putative connectivity markers in extended cortical regions such as the orbital and medial prefrontal cortex. The anterior insula and the rostral anterior cingulate cortex play a central role in the pathophysiology of MD, being consistently implicated both in the MD vulnerability and MD disease states.

Human orbital and anterior medial prefrontal cortex: Intrinsic connectivity parcellation and functional organization.

The orbital and medial prefrontal cortex (OMPFC) has been implicated in decision-making, reward and emotion processing, and psychopathology, such as depression and obsessive-compulsive disorder. Human and monkey anatomical studies indicate the presence of various cortical subdivisions and suggest that these are organized in two extended networks, a medial and an orbital one. Attempts have been made to replicate these neuroanatomical findings in vivo using MRI techniques for imaging connectivity. These revealed several consistencies, but also many inconsistencies between reported results. Here, we use fMRI resting-state functional connectivity (FC) and data-driven modularity optimization to parcellate the OMPFC to investigate replicability of in vivo parcellation more systematically. By collecting two resting-state data sets per participant, we were able to quantify the reliability of the observed modules and their boundaries. Results show that there was significantly more than chance overlap in modules and their boundaries at the level of individual data sets. Moreover, some of these consistent boundaries significantly co-localized across participants. Hierarchical clustering showed that the whole-brain FC profiles of the OMPFC subregions separate them in two networks, a medial and orbital one, which overlap with the organization proposed by Barbas and Pandya (J Comp Neurol 286:353-375, 1989) and Ongür and Price (Cereb Cortex 10:206-219, 2000). We conclude that in vivo resting-state FC can delineate reliable and neuroanatomically plausible subdivisions that agree with established cytoarchitectonic trends and connectivity patterns, while other subdivisions do not show the same consistency across data sets and studies.

Principles of ipsilateral and contralateral cortico-cortical connectivity in the mouse.

Structural connectivity among cortical areas provides the substrate for information exchange in the cerebral cortex and is characterized by systematic patterns of presence or absence of connections. What principles govern this cortical wiring diagram? Here, we investigate the relation of physical distance and cytoarchitecture with the connectional architecture of the mouse cortex. Moreover, we examine the relation between patterns of ipsilateral and contralateral connections. Our analysis reveals a mirrored and attenuated organization of contralateral connections when compared with ipsilateral connections. Both physical distance and cytoarchitectonic similarity of cortical areas are related to the presence or absence of connections. Notably, our analysis demonstrates that the combination of these factors relates better to cortico-cortical connectivity than each factor in isolation and that the two factors relate differently to ipsilateral and contralateral connectivity. Physical distance is more tightly related to the presence or absence of ipsilateral connections, but its relevance greatly diminishes for contralateral connections, while the contribution of cytoarchitectonic similarity remains relatively stable. Our results, together with similar findings in the cat and macaque cortex, suggest that a common set of principles underlies the macroscale wiring of the mammalian cerebral cortex.

Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study.

OBJECTIVES: Neuroimaging studies have revealed lithium-related increases in the volume of gray matter in the prefrontal cortex (PFC) and hippocampus. Postmortem human studies have reported alterations in neuronal and glial cell density and size in the PFC of lithium-treated subjects. Rodents treated with lithium exhibit cell proliferation in the dentate gyrus (DG) of the hippocampus. However, it is not known whether hippocampal and PFC volume are also increased in these animals or whether cell number in the PFC is altered. METHODS: Using stereological methods, this study estimated the total numbers of neurons and glia, and the packing density of astrocytes in the DG and PFC of normal adult mice treated with lithium, and evaluated the total volume of these regions and the entire neocortex. RESULTS: Lithium treatment increased the total numbers of neurons and glia in the DG (by 25% and 21%, respectively) and the density of astrocytes but did not alter total numbers in the PFC. However, the volumes of the hippocampus and its subfields, the PFC and its subareas, and the entire neocortex were not altered by lithium. CONCLUSIONS: Both neuronal and glial cells accounted for lithium-induced cell proliferation in the DG. That the numbers of neurons and glia were unchanged in the PFC is consistent with the view that this region is not a neurogenic zone. Further studies are required to clarify the impact of lithium treatment on the PFC under pathological conditions and to investigate the dissociation between increased cell proliferation and unchanged volume in the hippocampus.

Axonal and dendritic density field estimation from incomplete single-slice neuronal reconstructions.

Neuronal information processing in cortical networks critically depends on the organization of synaptic connectivity. Synaptic connections can form when axons and dendrites come in close proximity of each other. The spatial innervation of neuronal arborizations can be described by their axonal and dendritic density fields. Recently we showed that potential locations of synapses between neurons can be estimated from their overlapping axonal and dendritic density fields. However, deriving density fields from single-slice neuronal reconstructions is hampered by incompleteness because of cut branches. Here, we describe a method for recovering the lost axonal and dendritic mass. This so-called completion method is based on an estimation of the mass inside the slice and an extrapolation to the space outside the slice, assuming axial symmetry in the mass distribution. We validated the method using a set of neurons generated with our NETMORPH simulator. The model-generated neurons were artificially sliced and subsequently recovered by the completion method. Depending on slice thickness and arbor extent, branches that have lost their outside parents (orphan branches) may occur inside the slice. Not connected anymore to the contiguous structure of the sliced neuron, orphan branches result in an underestimation of neurite mass. For 300 µm thick slices, however, the validation showed a full recovery of dendritic and an almost full recovery of axonal mass. The completion method was applied to three experimental data sets of reconstructed rat cortical L2/3 pyramidal neurons. The results showed that in 300 µm thick slices intracortical axons lost about 50% and dendrites about 16% of their mass. The completion method can be applied to single-slice reconstructions as long as axial symmetry can be assumed in the mass distribution. This opens up the possibility of using incomplete neuronal reconstructions from open-access data bases to determine population mean mass density fields.

Comparative analysis of the macroscale structural connectivity in the macaque and human brain.

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.

Comparison of (stereotactic) parcellations in mouse prefrontal cortex.

This study compares the cytoarchitectonic parcellation of the prefrontal cortex (PFC) in the mouse as presented in publications that are commonly used for identifying brain areas. Agreement was found to be greater for boundaries in the medial PFC than in the lateral PFC and lowest for those in the orbital areas of the PFC. In this review, we explain and illustrate in a selected series of photographs and stereotactic pictures the differences in location and terminology of the different prefrontal cortical areas. The significance of cytoarchitectonic parcellation is discussed.

Mapping the hierarchical layout of the structural network of the macaque prefrontal cortex.

A consensus on the prefrontal cortex (PFC) holds that it is pivotal for flexible behavior and the integration of the cognitive, affective, and motivational domains. Certain models have been put forth and a dominant model postulates a hierarchical anterior-posterior gradient. The structural connectivity principles of this model dictate that increasingly anterior PFC regions exhibit more efferent connections toward posterior ones than vice versa. Such hierarchical asymmetry principles are thought to pertain to the macaque PFC. Additionally, the laminar patterns of the connectivity of PFC regions can be used for defining hierarchies. In the current study, we formally tested the asymmetry-based hierarchical principles of the anterior-posterior model by employing an exhaustive dataset on macaque PFC connectivity and tools from network science. On the one hand, the asymmetry-based principles and predictions of the hierarchical anterior-posterior model were not confirmed. The wiring of the macaque PFC does not fully correspond to the principles of the model, and its asymmetry-based hierarchical layout does not follow a strict anterior-posterior gradient. On the other hand, our results suggest that the laminar-based hierarchy seems a more tenable working hypothesis for models advocating an anterior-posterior gradient. Our results can inform models of the human PFC.

Cognitive inflexibility in obsessive-compulsive disorder and major depression is associated with distinct neural correlates.

Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are frequently co-morbid, and dysfunctional frontal-striatal circuits have been implicated in both disorders. Neurobiological distinctions between OCD and MDD are insufficiently clear, and comparative neuroimaging studies are extremely scarce. OCD and MDD may be characterized by cognitive rigidity at the phenotype level, and frontal-striatal brain circuits constitute the neural substrate of intact cognitive flexibility. In the present study, 18 non-medicated MDD-free patients with OCD, 19 non-medicated OCD-free patients with MDD, and 29 matched healthy controls underwent functional magnetic resonance imaging during performance of a self-paced letter/digit task switching paradigm. Results showed that both patient groups responded slower relative to controls during repeat events, but only in OCD patients slowing was associated with decreased error rates. During switching, patients with OCD showed increased activation of the putamen, anterior cingulate and insula, whereas MDD patients recruited inferior parietal cortex and precuneus to a lesser extent. Patients with OCD and MDD commonly failed to reveal anterior prefrontal cortex activation during switching. This study shows subtle behavioral abnormalities on a measure of cognitive flexibility in MDD and OCD, associated with differential frontal-striatal brain dysfunction in both disorders. These findings may add to the development of biological markers that more precisely characterize frequently co-morbid neuropsychiatric disorders such as OCD and MDD.

Decreased gray matter diffusivity: a potential early Alzheimer's disease biomarker?

BACKGROUND: Gray matter atrophy, an important biomarker for early Alzheimer's disease, might be due to white matter changes within gray matter. METHODS: Twenty older participants with significant memory decline over a 12-year period (T12) were matched to 20 nondeclining participants. All participants were magnetic resonance imaging scanned at T12. Cortical thickness and diffusion tensor imaging analyses were performed. RESULTS: Lower cortical thickness values were associated with lower diffusion values in frontal and parietal gray matter areas. This association was only present in the memory decline group. The cortical thickness-diffusion tensor imaging correlations showed significant group differences in the posterior cingulate gyrus, precuneus, and superior frontal gyrus. CONCLUSIONS: Decreased gray matter diffusivity in the posterior cingulate/precuneus area might be a disease-specific process and a potential new biomarker for early Alzheimer's disease. Future studies should validate its potential as a biomarker and focus on cellular changes underlying diffusivity changes in gray matter.

Patterns of gray and white matter changes in individuals at risk for Alzheimer's disease.

Structural brain changes precede cognitive and clinical symptoms in Alzheimer's disease (AD). We aimed to examine the gray and white matter tissue changes in individuals with memory decline over a 12-year period, who might be at risk for AD. The participants were selected from the longitudinal Maastricht Aging Study based on their scores on the verbal word learning task. A group with profound memory decline over a 12-year period (n = 20) was identified and matched with a group that did not meet this criterion (n = 20). All of the participants underwent MRI scanning. Diffusion tensor imaging and cortical thickness analyses were performed to investigate the white and gray matter differences respectively. We found decreased white matter integrity in the memory decline group compared to the control group in frontal and parietal brain regions and in several cortico-cortical and cortico-subcortical tracts. Cortical thinning in the memory decline group was found in frontal, parietal, medial temporal and occipital areas. These results showed similarities with the structural brain changes observed in early AD. Thus, not only may cognitive changes be detected years before the clinical diagnosis, but typical gray and white matter changes appear to be present in older people with memory decline as well. This suggests that a combination of cognitive decline and structural brain changes might be an ideal biomarker for AD pathogenesis.

Unravelling the intrinsic functional organization of the human lateral frontal cortex: a parcellation scheme based on resting state fMRI.

Human and nonhuman primates exhibit flexible behavior. Functional, anatomical, and lesion studies indicate that the lateral frontal cortex (LFC) plays a pivotal role in such behavior. LFC consists of distinct subregions exhibiting distinct connectivity patterns that possibly relate to functional specializations. Inference about the border of each subregion in the human brain is performed with the aid of macroscopic landmarks and/or cytoarchitectonic parcellations extrapolated in a stereotaxic system. However, the high interindividual variability, the limited availability of cytoarchitectonic probabilistic maps, and the absence of robust functional localizers render the in vivo delineation and examination of the LFC subregions challenging. In this study, we use resting state fMRI for the in vivo parcellation of the human LFC on a subjectwise and data-driven manner. This approach succeeds in uncovering neuroanatomically realistic subregions, with potential anatomical substrates including BA 46, 44, 45, 9 and related (sub)divisions. Ventral LFC subregions exhibit different functional connectivity (FC), which can account for different contributions in the language domain, while more dorsal adjacent subregions mark a transition to visuospatial/sensorimotor networks. Dorsal LFC subregions participate in known large-scale networks obeying an external/internal information processing dichotomy. Furthermore, we traced "families" of LFC subregions organized along the dorsal-ventral and anterior-posterior axis with distinct functional networks also encompassing specialized cingulate divisions. Similarities with the connectivity of macaque candidate homologs were observed, such as the premotor affiliation of presumed BA 46. The current findings partially support dominant LFC models.

Are there three subdivisions in the primate subthalamic nucleus?

The prevailing academic opinion holds that the subthalamic nucleus (STN) consists of three parts, each anatomically distinct and selectively associated with cognitive, emotional, or motor functioning. We independently tested this assumption by summarizing the results from 33 studies on STN subdivisions in human and nonhuman primates. The studies were conducted from 1925 to 2010 and feature three different techniques: electrical lesions, anterograde and retrograde tracers, and classical cytoarchitectonics. Our results reveal scant evidence in support of a tripartite STN. Instead, our results show that the variability across studies is surprisingly large, both in the number of subdivisions and in their anatomical localization. We conclude that the number of subdivisions in the STN remains uncertain, and that academic consensus in support of a tripartite STN is presently unwarranted.

Co-occurrence of different pathologies in dementia: implications for dementia diagnosis.

The standard for differentiating between dementia subtypes is currently based on neuropathological changes and follows traditional nosological classifications. However, the high incidence of comorbid neuropathologies complicates the differentiation between dementia diagnoses in the clinic. The aim of this study was to investigate the grades of agreement between clinical and neuropathological diagnoses in neurodegenerative disorders, to compare them with rates found in previous studies, and to propose implications for dementia diagnostics. Patients, who donated their brains to the Brain Bank of Navarre (Pamplona, Spain), had been diagnosed with a neurodegenerative disorder during life (clinical diagnosis) and postmortem (neuropathological diagnosis). We studied a sample of patients with a short average time interval between the last clinical assessment and death (4.6 months). Overall, there was a mean grade of agreement of 44.0% between the clinical diagnosis and the pure neuropathological diagnosis (i.e., without co-morbid neuropathological disorders). This grade of agreement differed between dementia subtypes: e.g., 85% for prion disease, 49% for Alzheimer's disease, and 0% for Lewy body dementia. Our data confirm that co-occurrence of multiple neuropathological disorders is very common in individuals with dementia, and that the underlying neuropathology often differs from the neuropathology implied by the clinical diagnosis. These findings support a multidimensional approach to diagnosing dementia, in which dementia syndromes are not categorized into diagnostic subtypes, but are seen as syndromes characterized by a combination of various neuropathological dimensions.

Parietal cortex matters in Alzheimer's disease: an overview of structural, functional and metabolic findings.

Atrophy of the medial temporal lobe, especially the hippocampus and the parahippocampal gyrus, is considered to be the most predictive structural brain biomarker for Alzheimer's Dementia (AD). However, recent neuroimaging studies reported a possible mismatch between structural and metabolic findings, showing medial temporal lobe atrophy and medial parietal hypoperfusion as biomarkers for AD. The role of the parietal lobe in the development of AD is only recently beginning to attract attention. The current review discusses parietal lobe involvement in the early stages of AD, viz. mild cognitive impairment, as reported from structural, functional, perfusion and metabolic neuroimaging studies. The medial and posterior parts of the parietal lobe seem to be preferentially affected, compared to the other parietal lobe parts. On the basis of the reviewed literature we propose a model showing the relationship between the various pathological events, as measured by different neuroimaging techniques, in the development of AD. In this model myelin breakdown is a beginning of the chain of pathological events leading to AD pathology and an AD diagnosis.

Extraordinary neoteny of synaptic spines in the human prefrontal cortex.

The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by two- to threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders.

Increasing the diagnostic accuracy of medial temporal lobe atrophy in Alzheimer's disease.

Medial temporal lobe (MTL) atrophy is considered to be one of the most important predictors of Alzheimer's disease (AD). This study investigates whether atrophy in parietal and prefrontal areas increases the predictive value of MTL atrophy in three groups of different cognitive status. Seventy-five older adults were classified as cognitively stable (n = 38) or cognitively declining (n = 37) after three years follow-up. At follow-up, the grey matter of the MTL, inferior prefrontal cortex (IPC), and inferior parietal lobule (IPL) was delineated on MRI scans. Six years later, a dementia assessment resulted in distinguishing and separating a third group (n = 9) who can be considered as preclinical AD cases at scan time. Ordinal logistic regressions analysis showed that the left and right MTL, as well as the right IPC and IPL accurately predicted group membership. Receiver Operating Curves showed that the MTL was best in distinguishing cognitively stable from cognitively declining individuals. The accuracy of the differentiation between preclinical AD and cognitively stable participants improved when MTL and IPL volumes were combined, while differentiating preclinical AD and cognitively declined participants was accomplished most accurately by the combined volume of all three areas. We conclude that depending on the current cognitive status of an individual, adding IPL or IPC atrophy improved the accuracy of predicting conversion to AD by up to 22%. Diagnosis of preclinical AD may lead to more false positive outcomes if only the MTL atrophy is considered.

Atrophy of the parietal lobe in preclinical dementia.

Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults (38 cognitively stable and 37 individuals with cognitive decline after 3 years). Dementia screening 6 years after scanning resulted in nine AD cases from the cognitively stable (n=3) and cognitive decline group (n=6), who were assigned to a third group, the preclinical AD group. When regional differences in cortical volume in the parietal lobe areas were compared between groups, significant differences were found between either the cognitive decline or stable group on the one hand and preclinical AD individuals on the other hand in the inferior parietal lobule. Group membership was best predicted by the grey matter volume of the inferior parietal lobule, compared to the other parietal lobe areas. The parietal lobe was characterised by a differential atrophy pattern based on cognitive status, which is in agreement with the 'last-developed-first-atrophied' principle. Future studies should investigate the surplus value of the inferior parietal lobe as a potential marker for the diagnosis of AD compared to other brain regions, such as the medial temporal lobe and the prefrontal lobe.

The Flatness of Bifurcations in 3D Dendritic Trees: An Optimal Design.

The geometry of natural branching systems generally reflects functional optimization. A common property is that their bifurcations are planar and that daughter segments do not turn back in the direction of the parent segment. The present study investigates whether this also applies to bifurcations in 3D dendritic arborizations. This question was earlier addressed in a first study of flatness of 3D dendritic bifurcations by Uylings and Smit (1975), who used the apex angle of the right circular cone as flatness measure. The present study was inspired by recent renewed interest in this measure. Because we encountered ourselves shortcomings of this cone angle measure, the search for an optimal measure for flatness of 3D bifurcation was the second aim of our study. Therefore, a number of measures has been developed in order to quantify flatness and orientation properties of spatial bifurcations. All these measures have been expressed mathematically in terms of the three bifurcation angles between the three pairs of segments in the bifurcation. The flatness measures have been applied and evaluated to bifurcations in rat cortical pyramidal cell basal and apical dendritic trees, and to random spatial bifurcations. Dendritic and random bifurcations show significant different flatness measure distributions, supporting the conclusion that dendritic bifurcations are significantly more flat than random bifurcations. Basal dendritic bifurcations also show the property that their parent segments are generally aligned oppositely to the bisector of the angle between their daughter segments, resulting in "symmetrical" configurations. Such geometries may arise when during neuronal development the segments at a newly formed bifurcation are subjected to elastic tensions, which force the bifurcation into an equilibrium planar shape. Apical bifurcations, however, have parent segments oppositely aligned with one of the daughter segments. These geometries arise in the case of side branching from an existing apical main stem. The aligned "apical" parent and "apical" daughter segment form together with the side branch daughter segment already geometrically a flat configuration. These properties are clearly reflected in the flatness measure distributions. Comparison of the different flatness measures made clear that they all capture flatness properties in a different way. Selection of the most appropriate measure thus depends on the question of research. For our purpose of quantifying flatness and orientation of the segments, the dihedral angle ß was found to be the most discriminative and applicable single measure. Alternatively, the parent elevation and azimuth angle formed an orthogonal pair of measures most clearly demonstrating the dendritic bifurcation "symmetry" properties.