Showing papers in "Brain Structure & Function in 2019"

The cingulate cortex and limbic systems for emotion, action, and memory

Abstract: Evidence is provided for a new conceptualization of the connectivity and functions of the cingulate cortex in emotion, action, and memory. The anterior cingulate cortex receives information from the orbitofrontal cortex about reward and non-reward outcomes. The posterior cingulate cortex receives spatial and action-related information from parietal cortical areas. It is argued that these inputs allow the cingulate cortex to perform action–outcome learning, with outputs from the midcingulate motor area to premotor areas. In addition, because the anterior cingulate cortex connects rewards to actions, it is involved in emotion; and because the posterior cingulate cortex has outputs to the hippocampal system, it is involved in memory. These apparently multiple different functions of the cingulate cortex are related to the place of this proisocortical limbic region in brain connectivity.

The Structural Model: a theory linking connections, plasticity, pathology, development and evolution of the cerebral cortex

Abstract: The classical theory of cortical systematic variation has been independently described in reptiles, monotremes, marsupials and placental mammals, including primates, suggesting a common bauplan in the evolution of the cortex. The Structural Model is based on the systematic variation of the cortex and is a platform for advancing testable hypotheses about cortical organization and function across species, including humans. The Structural Model captures the overall laminar structure of areas by dividing the cortical architectonic continuum into discrete categories (cortical types), which can be used to test hypotheses about cortical organization. By type, the phylogenetically ancient limbic cortices-which form a ring at the base of the cerebral hemisphere-are agranular if they lack layer IV, or dysgranular if they have an incipient granular layer IV. Beyond the dysgranular areas, eulaminate type cortices have six layers. The number and laminar elaboration of eulaminate areas differ depending on species or cortical system within a species. The construct of cortical type retains the topology of the systematic variation of the cortex and forms the basis for a predictive Structural Model, which has successfully linked cortical variation to the laminar pattern and strength of cortical connections, the continuum of plasticity and stability of areas, the regularities in the distribution of classical and novel markers, and the preferential vulnerability of limbic areas to neurodegenerative and psychiatric diseases. The origin of cortical types has been recently traced to cortical development, and helps explain the variability of diseases with an onset in ontogeny.

Along-axon diameter variation and axonal orientation dispersion revealed with 3D electron microscopy: implications for quantifying brain white matter microstructure with histology and diffusion MRI

Abstract: Tissue microstructure modeling of diffusion MRI signal is an active research area striving to bridge the gap between macroscopic MRI resolution and cellular-level tissue architecture. Such modeling in neuronal tissue relies on a number of assumptions about the microstructural features of axonal fiber bundles, such as the axonal shape (e.g., perfect cylinders) and the fiber orientation dispersion. However, these assumptions have not yet been validated by sufficiently high-resolution 3-dimensional histology. Here, we reconstructed sequential scanning electron microscopy images in mouse brain corpus callosum, and introduced a random-walker (RaW)-based algorithm to rapidly segment individual intra-axonal spaces and myelin sheaths of myelinated axons. Confirmed by a segmentation based on human annotations initiated with conventional machine-learning-based carving, our semi-automatic algorithm is reliable and less time-consuming. Based on the segmentation, we calculated MRI-relevant estimates of size-related parameters (inner axonal diameter, its distribution, along-axon variation, and myelin g-ratio), and orientation-related parameters (fiber orientation distribution and its rotational invariants; dispersion angle). The reported dispersion angle is consistent with previous 2-dimensional histology studies and diffusion MRI measurements, while the reported diameter exceeds those in other mouse brain studies. Furthermore, we calculated how these quantities would evolve in actual diffusion MRI experiments as a function of diffusion time, thereby providing a coarse-graining window on the microstructure, and showed that the orientation-related metrics have negligible diffusion time-dependence over clinical and pre-clinical diffusion time ranges. However, the MRI-measured inner axonal diameters, dominated by the widest cross sections, effectively decrease with diffusion time by ~ 17% due to the coarse-graining over axonal caliber variations. Furthermore, our 3d measurement showed that there is significant variation of the diameter along the axon. Hence, fiber orientation dispersion estimated from MRI should be relatively stable, while the “apparent” inner axonal diameters are sensitive to experimental settings, and cannot be modeled by perfectly cylindrical axons.

Microglia contribute to the glia limitans around arteries, capillaries and veins under physiological conditions, in a model of neuroinflammation and in human brain tissue.

Abstract: Microglia represent resident immune cells of the central nervous system (CNS), which have been shown to be involved in the pathophysiology of practically every neuropathology. As microglia were described to participate in the formation of the astroglial glia limitans around CNS vessels, they are part of the neurovascular unit (NVU). Since the NVU is a highly specialized structure, being functionally and morphologically adapted to differing demands in the arterial, capillary, and venous segments, the present study was aimed to systematically investigate the microglial contribution to the glia limitans along the vascular tree. Thereby, the microglial participation in the glia limitans was demonstrated for arteries, capillaries, and veins by immunoelectron microscopy in wild-type mice. Furthermore, analysis by confocal laser scanning microscopy revealed the highest density of microglial endfeet contacting the glial basement membrane around capillaries, with significantly lower densities around arteries and veins. Importantly, this pattern appeared to be unaltered in the setting of experimental autoimmune encephalomyelitis (EAE) in CX3CR1CreERT2:R26-Tomato reporter mice, although perivascular infiltrates of blood-borne leukocytes predominantly occur at the level of post-capillary venules. However, EAE animals exhibited significantly increased contact sizes of individual microglial endfeet around arteries and veins. Noteworthy, under EAE conditions, the upregulation of MHC-II was not limited to microglia of the glia limitans of veins showing infiltrates of leukocytes, but also appeared at the capillary level. As a microglial contribution to the glia limitans was also observed in human brain tissue, these findings may help characterizing microglial alterations within the NVU in various neuropathologies.

Common and distinct neural correlates of dual-tasking and task-switching: a meta-analytic review and a neuro-cognitive processing model of human multitasking.

Abstract: Although there are well-known limitations of the human cognitive system in performing two tasks simultaneously (dual-tasking) or alternatingly (task-switching), the question for a common vs. distinct neural basis of these multitasking limitations is still open. We performed two Activation Likelihood Estimation meta-analyses of neuroimaging studies on dual-tasking or task-switching and tested for commonalities and differences in the brain regions associated with either domain. We found a common core network related to multitasking comprising bilateral intraparietal sulcus (IPS), left dorsal premotor cortex (dPMC), and right anterior insula. Meta-analytic contrasts revealed eight fronto-parietal clusters more consistently activated in dual-tasking (bilateral frontal operculum, dPMC, and anterior IPS, left inferior frontal sulcus and left inferior frontal gyrus) and, conversely, four clusters (left inferior frontal junction, posterior IPS, and precuneus as well as frontomedial cortex) more consistently activated in task-switching. Together with sub-analyses of preparation effects in task-switching, our results argue against purely passive structural processing limitations in multitasking. Based on these findings and drawing on current theorizing, we present a neuro-cognitive processing model of multitasking.

Infralimbic prefrontal cortex structural and functional connectivity with the limbic forebrain: a combined viral genetic and optogenetic analysis.

Abstract: The medial prefrontal cortex is critical for contextual appraisal, executive function, and goal-directed behavior. Additionally, the infralimbic (IL) subregion of the prefrontal cortex has been implicated in stress responding, mood, and fear memory. However, the specific circuit mechanisms that mediate these effects are largely unknown. To date, IL output to the limbic forebrain has been examined largely qualitatively or within a restricted number of sites. To quantify IL presynaptic input to structures throughout the forebrain, we utilized a lentiviral construct expressing synaptophysin-mCherry. Thus, allowing quantification of IL efferents that are specifically synaptic, as opposed to fibers of passage. Additionally, this approach permitted the determination of IL innervation on a sub-structural level within the multiple heterogeneous limbic nuclei. To examine the functional output of the IL, optogenetic activation of IL projections was followed by quantification of neuronal activation throughout the limbic forebrain via fos-related antigen (Fra). Quantification of synaptophysin-mCherry indicated that the IL provides robust synaptic input to a number of regions within the thalamus, hypothalamus, amygdala, and bed nucleus of the stria terminalis, with limited input to the hippocampus and nucleus accumbens. Furthermore, there was high concordance between structural connectivity and functional activation. Interestingly, some regions receiving substantial synaptic input did not exhibit significant increases in Fra-immunoreactivity. Collectively, these studies represent a step toward a comprehensive and quantitative analysis of output circuits. This large-scale efferent quantification or ‘projectome’ also opens the door for data-driven analyses of the downstream synaptic mechanisms that mediate the integrative aspects of cortico–limbic interactions.

Basal forebrain subcortical projections.

Abstract: The basal forebrain (BF) contains at least three distinct populations of neurons (cholinergic, glutamatergic, and GABA-ergic) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata). Much attention has focused on the BF’s ascending projections to cortex, but less is known about descending projections to subcortical regions. Given the neurochemical and anatomical heterogeneity of the BF, we used conditional anterograde tracing to map the patterns of subcortical projections from multiple BF regions and neurochemical cell types using mice that express Cre recombinase only in cholinergic, glutamatergic, or GABAergic neurons. We confirmed that different BF regions innervate distinct subcortical targets, with more subcortical projections arising from neurons in the caudal and lateral BF (substantia innominata and magnocellular preoptic area). Additionally, glutamatergic and GABAergic BF neurons have distinct patterns of descending projections, while cholinergic descending projections are sparse. Considering the intensity of glutamatergic and GABAergic descending projections, the BF likely acts through subcortical targets to promote arousal, motivation, and other behaviors.

Thyroid hormone availability in the human fetal brain: novel entry pathways and role of radial glia.

Abstract: Thyroid hormones (TH) are crucial for brain development; their deficiency during neurodevelopment impairs neural cell differentiation and causes irreversible neurological alterations. Understanding TH action, and in particular the mechanisms regulating TH availability in the prenatal human brain is essential to design therapeutic strategies for neurological diseases due to impaired TH signaling during neurodevelopment. We aimed at the identification of cells involved in the regulation of TH availability in the human brain at fetal stages. To this end, we studied the distribution of the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1), as well as the TH-metabolizing enzymes types 2 and 3 deiodinases (DIO2 and DIO3). Paraffin-embedded human brain sections obtained from necropsies of thirteen fetuses from 14 to 38 gestational weeks were analyzed by immunohistochemistry and in situ hybridization. We found these proteins localized along radial glial cells, in brain barriers, in Cajal-Retzius cells, in migrating fibers of the brainstem and in some neurons and glial cells with particular and complex spatiotemporal patterns. Our findings point to an important role of radial glia in controlling TH delivery and metabolism and suggest two additional novel pathways for TH availability in the prenatal human brain: the outer, and the inner cerebrospinal fluid–brain barriers. Based on our data we propose a model of TH availability for neural cells in the human prenatal brain in which several cell types have the ability to autonomously control the required TH content.

A SENtence Supramodal Areas AtlaS (SENSAAS) based on multiple task-induced activation mapping and graph analysis of intrinsic connectivity in 144 healthy right-handers.

Abstract: We herein propose an atlas of 32 sentence-related areas based on a 3-step method combining the analysis of activation and asymmetry during multiple language tasks with hierarchical clustering of resting-state connectivity and graph analyses. 144 healthy right-handers performed fMRI runs based on language production, reading and listening, both with sentences and lists of over-learned words. Sentence minus word-list BOLD contrast and left-minus-right BOLD asymmetry for each task were computed in pairs of homotopic regions of interest (hROIs) from the AICHA atlas. Thirty-two hROIs were identified that were conjointly activated and leftward asymmetrical in each of the three language contrasts. Analysis of resting-state temporal correlations of BOLD variations between these 32 hROIs allowed the segregation of a core network, SENT_CORE including 18 hROIs. Resting-state graph analysis applied to SENT_CORE hROIs revealed that the pars triangularis of the inferior frontal gyrus and the superior temporal sulcus were hubs based on their degree centrality (DC), betweenness, and participation values corresponding to epicentres of sentence processing. Positive correlations between DC and BOLD activation values for SENT_CORE hROIs were observed across individuals and across regions regardless of the task: the more a SENT_CORE area is connected at rest the stronger it is activated during sentence processing. DC measurements in SENT_CORE may thus be a valuable index for the evaluation of inter-individual variations in language areas functional activity in relation to anatomical or clinical patterns in large populations. SENSAAS (SENtence Supramodal Areas AtlaS), comprising the 32 supramodal sentence areas, including SENT_CORE network, can be downloaded at http://www.gin.cnrs.fr/en/tools/.

A population-based atlas of the human pyramidal tract in 410 healthy participants

Abstract: With the advances in diffusion MRI and tractography, numerous atlases of the human pyramidal tract (PyT) have been proposed, but the inherent limitation of tractography to resolve crossing bundles within the centrum semiovale has so far prevented the complete description of the most lateral PyT projections. Here, we combined a precise manual positioning of individual subcortical regions of interest along the descending pathway of the PyT with a new bundle-specific tractography algorithm. This later is based on anatomical priors to improve streamlines tracking in crossing areas. We then extracted both left and right PyT in a large cohort of 410 healthy participants and built a population-based atlas of the whole-fanning PyT with a complete description of its most corticolateral projections. Clinical applications are envisaged, the whole-fanning PyT atlas being likely a better marker of corticospinal integrity metrics than those currently used within the frame of prediction of poststroke motor recovery. The present population-based PyT, freely available, provides an interesting tool for clinical applications to locate specific PyT damage and its impact to the short- and long-term motor recovery after stroke.

Magnetic resonance imaging of noradrenergic neurons

Abstract: Noradrenaline is a neurotransmitter involved in general arousal, selective attention, memory, inflammation, and neurodegeneration. The purpose of this work was to delineate noradrenergic neurons in vivo by T1-weighted MRI with magnetization transfer (MT). In the brainstem of human and mice, MRI identified the locus coeruleus, dorsal motor vagus nucleus, and nucleus tractus solitarius. Given (1) the long T1 and low magnetization transfer ratio for the noradrenergic cell groups compared to other gray matter, (2) significant correlation between MT MRI signal intensity and proton density, and (3) no correlation between magnetization transfer ratio (or R1) and iron, copper, or manganese in human brain, the high MRI signal of the noradrenergic neurons must be attributed to abundant water protons interacting with any T1-shortening paramagnetic ions in active cells rather than to specific T1-shortening molecules. The absence of a high MRI signal from the locus coeruleus of Ear2(-/-) mice lacking noradrenergic neurons confirms that cell bodies of noradrenergic neurons are the source of the bright MRI appearance. The observation of this high signal in DBH(-/-) mice, in 3-week-old mice, and in mice under hyperoxia/hypercapnia/hypoxia together with the general absence of neuromelanin (NM) in noradrenergic neurons of young rodents further excludes that it is due to NM, dopamine β-hydroxylase, their binding to paramagnetic ions, blood inflow, or hemoglobin. Instead, these findings indicate a high density of water protons whose T1 is shortened by paramagnetic ions as the relevant source of the high MRI signal. In the brain of APP/PS1/Ear2(-/-) mice, a transgenic model of Alzheimer's disease, MRI detected noradrenergic neuron loss in the locus coeruleus. Proton magnetic resonance spectroscopy revealed that a 60-75% reduction of noradrenaline is responsible for a reduction of N-acetylaspartate and glutamate in the hippocampus as well as for a shortening of the water proton T2 in the frontal cortex. These results suggest that a concurrent shortage of noradrenaline in Alzheimer's disease accelerates pathologic processes such as inflammation and neuron loss.

Neurite orientation dispersion and density imaging of mouse brain microstructure.

Abstract: Advanced biophysical models like neurite orientation dispersion and density imaging (NODDI) have been developed to estimate the microstructural complexity of voxels enriched in dendrites and axons for both in vivo and ex vivo studies. NODDI metrics derived from high spatial and angular resolution diffusion MRI using the fixed mouse brain as a reference template have not yet been reported due in part to the extremely long scan time required. In this study, we modified the three-dimensional diffusion-weighted spin-echo pulse sequence for multi-shell and undersampling acquisition to reduce the scan time. This allowed us to acquire several exhaustive datasets that would otherwise not be attainable. NODDI metrics were derived from a complex 8-shell diffusion (1000–8000 s/mm2) dataset with 384 diffusion gradient-encoding directions at 50 µm isotropic resolution. These provided a foundation for exploration of tradeoffs among acquisition parameters. A three-shell acquisition strategy covering low, medium, and high b values with at least angular resolution of 64 is essential for ex vivo NODDI experiments. The good agreement between neurite density index (NDI) and the orientation dispersion index (ODI) with the subsequent histochemical analysis of myelin and neuronal density highlights that NODDI could provide new insight into the microstructure of the brain. Furthermore, we found that NDI is sensitive to microstructural variations in the corpus callosum using a well-established demyelination cuprizone model. The study lays the ground work for developing protocols for routine use of high-resolution NODDI method in characterizing brain microstructure in mouse models.

Associative white matter connecting the dorsal and ventral posterior human cortex

Abstract: Historically, the primary focus of studies of human white matter tracts has been on large tracts that connect anterior-to-posterior cortical regions. These include the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus (ILF), and the inferior fronto-occipital fasciculus (IFOF). Recently, more refined and well-understood tractography methods have facilitated the characterization of several tracts in the posterior of the human brain that connect dorsal-to-ventral cortical regions. These include the vertical occipital fasciculus (VOF), the posterior arcuate fasciculus (pArc), the temporo-parietal connection (TP-SPL), and the middle longitudinal fasciculus (MdLF). The addition of these dorso-ventral connective tracts to our standard picture of white matter architecture results in a more complicated pattern of white matter connectivity than previously considered. Dorso-ventral connective tracts may play a role in transferring information from superior horizontal tracts, such as the SLF, to inferior horizontal tracts, such as the IFOF and ILF. We present a full anatomical delineation of these major dorso-ventral connective white matter tracts (the VOF, pArc, TP-SPL, and MdLF). We show their spatial layout and cortical termination mappings in relation to the more established horizontal tracts (SLF, IFOF, ILF, and Arc) and consider standard values for quantitative features associated with the aforementioned tracts. We hope to facilitate further study on these tracts and their relations. To this end, we also share links to automated code that segments these tracts, thereby providing a standard approach to obtaining these tracts for subsequent analysis. We developed open source software to allow reproducible segmentation of the tracts: https://github.com/brainlife/Vertical_Tracts . Finally, we make the segmentation method available as an open cloud service on the data and analyses sharing platform brainlife.io. Investigators will be able to access these services and upload their data to segment these tracts.

Source-based morphometry: a decade of covarying structural brain patterns.

Abstract: In this paper, we review and discuss brain imaging studies which have used the source-based morphometry (SBM) approach over the past decade. SBM is a data-driven linear multivariate approach for decomposing structural brain imaging data into commonly covarying imaging components and subject-specific loading parameters. It is a well-established technique which has predominantly been used to study neuroanatomic differences between healthy controls and patients with neuropsychiatric diseases. We start by discussing the advantages of this technique over univariate analysis for imaging studies, followed by a discussion of results from recent studies which have successfully applied this methodology. We also present recent extensions of this framework including nonlinear SBM, biclustered independent component analysis (B-ICA) and conclude with the possible directions of work for future.

Gradients of connectivity distance in the cerebral cortex of the macaque monkey.

Abstract: Cortical connectivity conforms to a series of organizing principles that are common across species. Spatial proximity, similar cortical type, and similar connectional profile all constitute factors for determining the connectivity between cortical regions. We previously demonstrated another principle of connectivity that is closely related to the spatial layout of the cerebral cortex. Using functional connectivity from resting-state fMRI in the human cortex, we found that the further a region is located from primary cortex, the more distant are its functional connections with the other areas of the cortex. However, it remains unknown whether this relationship between cortical layout and connectivity extends to other primate species. Here, we investigated this relationship using both resting-state functional connectivity as well as gold-standard tract-tracing connectivity in the macaque monkey cortex. For both measures of connectivity, we found a gradient of connectivity distance extending between primary and frontoparietal regions. In the human cortex, the further a region is located from primary areas, the stronger its connections to distant portions of the cortex, with connectivity distance highest in frontal and parietal regions. The similarity between the human and macaque findings provides evidence for a phylogenetically conserved relationship between the spatial layout of cortical areas and connectivity.

Cell-type specific parallel circuits in the bed nucleus of the stria terminalis and the central nucleus of the amygdala of the mouse.

Abstract: The central extended amygdala (EAc) is a forebrain macrosystem which has been widely implicated in reward, fear, anxiety, and pain. Its two key structures, the lateral bed nucleus of the stria terminalis (BSTL) and the central nucleus of the amygdala (CeA), share similar mesoscale connectivity. However, it is not known whether they also share similar cell-specific neuronal circuits. We addressed this question using tract-tracing and immunofluorescence to reveal the EAc microcircuits involving two neuronal populations expressing either protein kinase C delta (PKCδ) or somatostatin (SOM). PKCδ and SOM are expressed predominantly in the dorsal BSTL (BSTLD) and in the lateral/capsular parts of CeA (CeL/C). We found that, in both BSTLD and CeL/C, PKCδ+ cells are the main recipient of extra-EAc inputs from the lateral parabrachial nucleus (LPB), while SOM+ cells constitute the main source of long-range projections to extra-EAc targets, including LPB and periaqueductal gray. PKCδ+ cells can also integrate inputs from the basolateral nucleus of the amygdala or insular cortex. Within EAc, PKCδ+, but not SOM+ neurons, serve as the major source of inputs to the ventral BSTL and to the medial part of CeA. However, both cell types can be involved in mutual connections between BSTLD and CeL/C. These results unveil the pivotal positions of PKCδ+ and SOM+ neurons in organizing parallel cell-specific neuronal circuits within CeA and BSTL, but also between them, which further reinforce the notion of EAc as a structural and functional macrosystem.

Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal

Abstract: Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the nucleus accumbens shell (NAcSh) and core (NAcC) sub-regions in hopes of identifying excitatory plasticity that may contribute to unique facets of opioid addiction-related behavior. Following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the NAcShl and NAcC, whereas only the frequency of events was elevated at D2-MSNs in the NAcSh. In contrast, spontaneous somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100 mg/kg) enhanced mEPSC frequency specifically at D2-MSNs in the NAcSh. Similar to previous findings, excitatory drive was elevated at NAcSh D1-MSNs after 10–14 days home cage abstinence. Following abstinence, an acute drug re-exposure produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference—a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. Moreover, while differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following drug re-exposure, our findings indicate this plasticity has distinct behavioral consequences.

Dissociating motor–speech from lexico-semantic systems in the left frontal lobe: insight from a series of 17 awake intraoperative mappings in glioma patients

Abstract: Functional brain mapping during awake surgery procedures is the gold standard technique in the management of left frontal lobe tumors. Nevertheless, a unified picture of the language subsystems encountered during left frontal lobe mapping is still lacking. We retrospectively analyzed the 49 cortical and the 33 axonal sites of functional language mapping performed in 17 patients operated for a left frontal lobe glioma under awake conditions. Sites were tagged on the postoperative MRI, based on anatomical landmarks and intraoperative photography. All MRIs and tags were then registered in the MNI template. Speech disturbances related to motor functions (speech arrest—with or without superior limb arrest—, stuttering, and vocalization) were grouped together as “motor–speech” responses. Anomias, semantic paraphasia, perseverations, and PPTT errors were classified as “lexico-semantic” responses. MNI-registered axonal sites were used as seed for computing disconnectome maps from a tractogram atlas of ten healthy individuals, as implemented in the BCB toolkit. The cortical distribution of lexico-semantic responses appeared to be located anteriorly (pars triangularis of the inferior frontal gyrus and posterior end of the middle and superior frontal gyrus) compared to motor–speech responses (lower end of the precentral gyrus and pars opercularis). Within the white matter, motor–speech responses and lexico-semantic responses overlapped on the trajectory of the aslant and fronto-striatal tracts, but the lexico-semantic sites were located more anteriorly (mean Y coordinate on the MNI system was 21.2 mm for lexico-semantic sites and 14.3 mm for the motor–speech sites; Wilcoxon test: W = 60.5, p = 0.03). Moreover, disconnectome maps evidenced a clear distinction between the two subsystems: posterior fronto-striatal and frontal aslant tracts, corpus callosum and cortico-spinal tract were related to the motor–speech sites, whereas anterior frontal aslant tract, inferior-fronto-occipital fasciculus (IFOF) and anterior thalamic radiations were related to the lexico-semantic sites. Hence, we evidenced distinct anatomical substrates for the motor–speech and lexico-semantic systems. Regarding the aslant/fronto-striatal system, an anterior to posterior gradient was found, with a lexico-semantic role for the anterior part and a motor–speech involvement for the posterior part. For tumors abutting the precentral sulcus, posterior boundaries of the resection are made of motor–speech sites, meaning that the anteriorly located lexico-semantic system is no more functional, as a result of network reorganization by plasticity.

Associations of age and sex with brain volumes and asymmetry in 2–5-week-old infants

Abstract: Information on normal brain structure and development facilitates the recognition of abnormal developmental trajectories and thus needs to be studied in more detail. We imaged 68 healthy infants aged 2–5 weeks with high-resolution structural MRI (magnetic resonance imaging) and investigated hemispheric asymmetry as well as the associations of various total and lobar brain volumes with infant age and sex. We found similar hemispheric asymmetry in both sexes, seen as larger volumes of the right temporal lobe, and of the left parietal and occipital lobes. The degree of asymmetry did not vary with age. Regardless of controlling for gestational age, gray and white matter had different age-related growth patterns. This is a reflection of gray matter growth being greater in the first years, while white matter growth extends into early adulthood. Sex-dependent differences were seen in gray matter as larger regional absolute volumes in males and as larger regional relative volumes in females. Our results are in line with previous studies and expand our understanding of infant brain development.

Linking structural and effective brain connectivity: structurally informed Parametric Empirical Bayes (si-PEB)

Abstract: Despite the potential for better understanding functional neuroanatomy, the complex relationship between neuroimaging measures of brain structure and function has confounded integrative, multimodal analyses of brain connectivity. This is particularly true for task-related effective connectivity, which describes the causal influences between neuronal populations. Here, we assess whether measures of structural connectivity may usefully inform estimates of effective connectivity in larger scale brain networks. To this end, we introduce an integrative approach, capitalising on two recent statistical advances: Parametric Empirical Bayes, which provides group-level estimates of effective connectivity, and Bayesian model reduction, which enables rapid comparison of competing models. Crucially, we show that structural priors derived from high angular resolution diffusion imaging on a dynamic causal model of a 12-region network—based on functional MRI data from the same subjects—substantially improve model evidence (posterior probability 1.00). This provides definitive evidence that structural and effective connectivity depend upon each other in mediating distributed, large-scale interactions in the brain. Furthermore, this work offers novel perspectives for understanding normal brain architecture and its disintegration in clinical conditions.

Structure, asymmetry, and connectivity of the human temporo-parietal aslant and vertical occipital fasciculi.

Abstract: We previously proposed a bipartite ‘dorsal–ventral’ model of human arcuate fasciculus (AF) morphology. This model does not, however, account for the ‘vertical,’ temporo-parietal subdivision of the AF described in earlier dissection and tractographic studies. In an effort to address the absence of the vertical AF (VAF) within ‘dorsal–ventral’ nomenclature, we conducted a dedicated tractographic and white-matter dissection study of this tract and another short, vertical, posterior-hemispheric fascicle: the vertical occipital fasciculus (VOF). We conducted atlas-based, non-tensor, deterministic tractography in 30 single subjects from the Human Connectome Project database and verified our results using an average diffusion atlas compiled from 842 separate normal subjects. We also performed white-matter dissection in four post-mortem specimens. Our tractography results demonstrate that the VAF is, in fact, a bipartite system connecting the ventral parietal and temporal regions, with variable connective, and no volumetric lateralization. The VOF is a non-lateralized, non-segmented system connecting lateral occipital areas with basal–temporal regions. Importantly, the VOF was spatially dissociated from the VAF. As the VAF demonstrates no overall connective or volumetric lateralization, we postulate its distinction from the AF system and propose its re-naming to the ‘temporo-parietal aslant tract,’ (TPAT), with unique dorsal and ventral subdivisions. Our tractography results were supported by diffusion atlas and white-matter dissection findings.

Aldosterone-sensitive HSD2 neurons in mice

Abstract: Sodium deficiency elevates aldosterone, which in addition to epithelial tissues acts on the brain to promote dysphoric symptoms and salt intake. Aldosterone boosts the activity of neurons that express 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2), a hallmark of aldosterone-sensitive cells. To better characterize these neurons, we combine immunolabeling and in situ hybridization with fate mapping and Cre-conditional axon tracing in mice. Many cells throughout the brain have a developmental history of Hsd11b2 expression, but in the adult brain one small brainstem region with a leaky blood–brain barrier contains HSD2 neurons. These neurons express Hsd11b2, Nr3c2 (mineralocorticoid receptor), Agtr1a (angiotensin receptor), Slc17a6 (vesicular glutamate transporter 2), Phox2b, and Nxph4; many also express Cartpt or Lmx1b. No HSD2 neurons express cholinergic, monoaminergic, or several other neuropeptidergic markers. Their axons project to the parabrachial complex (PB), where they intermingle with AgRP-immunoreactive axons to form dense terminal fields overlapping FoxP2 neurons in the central lateral subnucleus (PBcL) and pre-locus coeruleus (pLC). Their axons also extend to the forebrain, intermingling with AgRP- and CGRP-immunoreactive axons to form dense terminals surrounding GABAergic neurons in the ventrolateral bed nucleus of the stria terminalis (BSTvL). Sparse axons target the periaqueductal gray, ventral tegmental area, lateral hypothalamic area, paraventricular hypothalamic nucleus, and central nucleus of the amygdala. Dual retrograde tracing revealed that largely separate HSD2 neurons project to pLC/PB or BSTvL. This projection pattern raises the possibility that a subset of HSD2 neurons promotes the dysphoric, anorexic, and anhedonic symptoms of hyperaldosteronism via AgRP-inhibited relay neurons in PB.

Controllable stress elicits circuit-specific patterns of prefrontal plasticity in males, but not females

Abstract: Actual or perceived behavioral control during a traumatic event can promote resilience against future adversity, but the long-term cellular and circuit mechanisms by which this protection is conferred have not been identified. Clinical outcomes following trauma exposure differ in men and women, and, therefore, it is especially important in preclinical research to dissect these processes in both males and females. In male adult rats, an experience with behavioral control over tail shock ("escapable stress", ES) has been shown to block the neurochemical and behavioral outcomes produced by later uncontrollable tail shock ("inescapable stress", IS), a phenomenon termed "behavioral immunization". Here, we determined whether behavioral immunization is present in females. Unlike males, the stress-buffering effects of behavioral control were absent in female rats. We next examined the effects of ES and IS on spine morphology of dorsal raphe nucleus (DRN)-projecting prelimbic (PL) neurons, a circuit critical to the immunizing effects of ES in males. In males, IS elicited broad, non-specific alterations in PL spine size, while ES elicited PL-DRN circuit-specific spine changes. In contrast, females exhibited broad, non-specific spine enlargement after ES but only minor alterations after IS. These data provide evidence for a circuit-specific mechanism of structural plasticity that could underlie sexual divergence in the protective effects of behavioral control.

Chronic fornix deep brain stimulation in a transgenic Alzheimer???s rat model reduces amyloid burden, inflammation, and neuronal loss

Abstract: Recent studies have suggested deep brain stimulation (DBS) as a promising therapy in patients with Alzheimer's disease (AD). Particularly, the stimulation of the forniceal area was found to slow down the cognitive decline of some AD patients, but the biochemical and anatomical modifications underlying these effects remain poorly understood. We evaluated the effects of chronic forniceal stimulation on amyloid burden, inflammation, and neuronal loss in a transgenic Alzheimer rat model TgF344-AD, as well as in age-matched control rats. 18-month-old rats were surgically implanted with electrodes in stereotactic conditions and connected to a portable microstimulator for chronic DBS in freely moving rats. The stimulation was continuous during 5 weeks and animals were immediately sacrificed for immunohistochemical analysis of pathological markers. Implanted, but non-stimulated rats were used as controls. We found that chronic forniceal DBS in the Tg-AD rat significantly reduces amyloid deposition in the hippocampus and cortex, decreases astrogliosis and microglial activation and lowers neuronal loss, as determined by NeuN staining. In control animals, the stimulation neither affects neuroinflammation nor neuronal count. In the Tg-F344-AD rat model, 5 weeks of forniceal DBS decreased amyloidosis, inflammatory responses, and neuronal loss in both cortex and hippocampus. These findings strongly suggest a neuroprotective effect of DBS and support the beneficial effects of targeting the fornix in Alzheimer's disease patients.

Anodal tDCS affects neuromodulatory effects of the norepinephrine system on superior frontal theta activity during response inhibition.

Abstract: Medial and superior frontal theta oscillations are important for response inhibition. The norepinephrine (NE) system has been shown to modulate these oscillations possibly via gain control mechanisms, which depend on the modulation of neuron membrane potentials. Because the latter are also modulated by tDCS, the interrelation of tDCS and NE effects on superior frontal theta band activity needs investigation. We test the hypothesis that anodal tDCS affects modulatory effects of the NE system on theta band activity during inhibitory control in superior frontal regions. Using EEG beamforming, theta band activity in the superior frontal gyrus (SFG) was integrated (correlated) with the pupil diameter data as an indirect index of NE activity. In a within-subject design, healthy participants completed a response inhibition task in two sessions in which they received 2 mA anodal tDCS over the vertex, or sham stimulation. There were no behavioral effects of anodal tDCS. Yet, tDCS affected correlations between SFG theta band activity time course and the pupil diameter time course. Correlations were evident after sham stimulation (r = .701; p < .004), but absent after anodal tDCS. The observed power of this dissociation was above 95%. The data suggest that anodal tDCS may eliminate neuromodulatory effects, likely of the NE system, on theta band activity during response inhibition in a structure of the response inhibition network. The NE system and tDCS seem to target similar mechanisms important for cognitive control in the prefrontal cortex. The results provide a hint why tDCS often fails to induce overt behavioral effects and shows that neurobiological systems, which may exert similar effects as tDCS on neural processes should closely be monitored in tDCS experiments.

Ventral tegmental area connections to motor and sensory cortical fields in humans.

Abstract: In humans, sensorimotor cortical areas receive relevant dopaminergic innervation—although an anatomic description of the underlying fiber projections is lacking so far. In general, dopaminergic projections towards the cortex originate within the ventral tegmental area (VTA) and are organized in a meso-cortico-limbic system. Using a DTI-based global tractography approach, we recently characterized the superolateral branch of the medial forebrain bundle (slMFB), a prominent pathway providing dopaminergic (and other transmitters) innervation for the pre-frontal cortex (Coenen et al., NeuroImage Clin 18:770–783, 2018). To define the connections between VTA and sensory–motor cortical fields that should contain dopaminergic fibers, we use the slMFB as a key structure to lead our fiber selection procedure: using a similar tracking-seed and tractography algorithm, we describe a dorsal extension of this slMFB that covers sensorimotor fields that are dorsally appended to pre-frontal cortical areas. This “motorMFB”, that connects the VTA to sensorimotor cortical fields, can be further segregated into three sub-bundles with a seed-based fiber-selection strategy: A PFC bundle that is attendant to the pre-frontal cortex, passes the lateral VTA, runs through the border zone between the posterior and lateral ventral thalamic nucleus, and involves the pre- and postcentral gyrus. An MB bundle that is attendant to the mammillary bodies runs directly through the medial VTA, passes the lateral ventral thalamic nucleus, and involves the pre- and postcentral gyrus as well as the supplementary motor area (SMA) and the dorsal premotor cortex (dPMC). Finally, a BC bundle that is attendant to the brainstem and cerebellum runs through the lateral VTA, passes the anterior ventral thalamic nucleus, and covers the SMA, pre-SMA, and the dPMC. We, furthermore, included a fiber tracking of the well-defined dentato-rubro-thalamic tract (DRT) that is known to lie in close proximity with respect to fiber orientation and projection areas. As expected, the tract is characterized by a decussation at the ponto-mesencephal level and a projection covering the superior-frontal and precentral cortex. In addition to the physiological role of these particular bundles, the physiological and pathophysiological impact of dopaminergic signaling within sensorimotor cortical fields becomes discussed. However, some limitations have to be taken into account in consequence of the method: the transmitter content, the directionality, and the occurrence of interposed synaptic contacts cannot be specified.

Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging

Abstract: Classic anatomical atlases depict a contralateral hemispheral representation of each side of the face. Recently, however, a bilateral projection of each hemiface was hypothesized, based on animal studies that showed the coexistence of an additional trigeminothalamic tract sprouting from the trigeminal principal sensory nucleus that ascends ipsilaterally. This study aims to provide an anatomical substrate for the hypothesized bilateral projection. Three post-mortem human brainstems were scanned for anatomical and diffusion magnetic resonance imaging at 11.7T. The trigeminal tracts were delineated in each brainstem using track density imaging (TDI) and tractography. To evaluate the reconstructed tracts, the same brainstems were sectioned for polarized light imaging (PLI). Anatomical 11.7T MRI shows a dispersion of the trigeminal tract (tt) into a ventral and dorsal portion. This bifurcation was also seen on the TDI maps, tractography results and PLI images of all three specimens. Referring to a similar anatomic feature in primate brains, the dorsal and ventral tracts were named the dorsal and ventral trigeminothalamic tract (dtt and vtt), respectively. This study shows that both the dtt and vtt are present in humans, indicating that each hemiface has a bilateral projection, although the functional relevance of these tracts cannot be determined by the present anatomical study. If both tracts convey noxious stimuli, this could open up new insights into and treatments for orofacial pain in patients.

Gene expression and neurochemical characterization of the rostromedial tegmental nucleus (RMTg) in rats and mice

Abstract: The rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area (tVTA), is a GABAergic structure identified in 2009 that receives strong inputs from the lateral habenula and other sources, sends dense inhibitory projections to midbrain dopamine (DA) neurons, and plays increasingly recognized roles in aversive learning, addiction, and other motivated behaviors. In general, little is known about the genetic identity of these neurons. However, recent work has identified the transcription factor FoxP1 as enhanced in the mouse RMTg (Lahti et al. in Development 143(3):516–529, 2016). Hence, in the current study, we used RNA sequencing to identify genes significantly enhanced in the rat RMTg as compared to adjacent VTA, and then examined the detailed distribution of two genes in particular, prepronociceptin (Pnoc) and FoxP1. In rats and mice, both Pnoc and FoxP1 were expressed at high levels in the RMTg and colocalized strongly with previously established RMTg markers. FoxP1 was particularly selective for RMTg neurons, as it was absent in most adjacent brain regions. We used these gene expression patterns to refine the anatomic characterization of RMTg in rats, extend this characterization to mice, and show that optogenetic manipulation of RMTg in mice bidirectionally modulates real-time place preference. Hence, RMTg neurons in both rats and mice exhibit distinct genetic profiles that correlate with their distinct connectivity and function.

A balanced evaluation of the evidence for adult neurogenesis in humans: implication for neuropsychiatric disorders.

Abstract: There is a widespread belief that neurogenesis exists in adult human brain, especially in the dentate gyrus, and it is to be maintained and, if possible, augmented with different stimuli including exercise and certain drugs. Here, we examine the evidence for adult human neurogenesis and note important limitations of the methodologies used to study it. A balanced review of the literature and evaluation of the data indicate that adult neurogenesis in human brain is improbable. In fact, in several high-quality recent studies in adult human brain, unlike in adult brains of other species, neurogenesis was not detectable. These findings suggest that the human brain requires a permanent set of neurons to maintain acquired knowledge for decades, which is essential for complex high cognitive functions unique to humans. Thus, stimulation and/or injection of neural stem cells into human brains may not only disrupt brain homeostatic systems, but also disturb normal neuronal circuits. We propose that the focus of research should be the preservation of brain neurons by prevention of damage, not replacement.

The neural correlates of auditory-verbal short-term memory: a voxel-based lesion-symptom mapping study on 103 patients after glioma removal

Abstract: The relationship between verbal-auditory short-term memory (STM) and language is an open area of debate and contrasting hypotheses have been proposed, suggesting either that STM would strongly rely on language-related processes, or that it depends on a dedicated system related to language, but independent from it. In this study we examined 103 patients undergoing surgery for glioma resection in the left or right hemisphere, and we conducted a VLSM analysis on their behavioral performance on auditory-verbal STM, as well as on more general verbal and nonverbal tasks. The aim was to investigate whether the anatomical correlates of auditory-verbal STM were part of the language system or they were spatially segregated from it. VLSM results showed that digit span scores were linked to lesions in both the left supramarginal gyrus and superior-posterior temporal areas, as reported in the literature on patients with a selective deficit of auditory-verbal STM. Conversely, other verbal tasks involved areas only partly overlapping with those found for digit span, with repetition being affected by lesions in more anterior regions in the parietal, temporal, and frontal lobes, and word comprehension by lesions in a network including cortical and subcortical pathways in the temporal lobe. The present results, thus, show that auditory-verbal STM neural correlates are only partially overlapping with those supporting comprehension and production: while the left posterior–superior temporal cortex, involved in speech perception, takes part in both functions, the left supramarginal gyrus has a consistent and specific role only in STM, supporting the hypothesis of interacting but segregated networks.