Showing papers in "Brain Structure & Function in 2016"
TL;DR: A statistical normative atlas of the frontal lobe connections in stereotaxic space is built, using state-of-the-art spherical deconvolution tractography, to build the capacity of clinicians to further understand the mechanisms involved in brain recovery and plasticity and assist clinicians in the diagnosis of disconnection or abnormality within specific tracts of individual patients with various brain diseases.
Abstract: In neuroscience, there is a growing consensus that higher cognitive functions may be supported by distributed networks involving different cerebral regions, rather than by single brain areas. Communication within these networks is mediated by white matter tracts and is particularly prominent in the frontal lobes for the control and integration of information. However, the detailed mapping of frontal connections remains incomplete, albeit crucial to an increased understanding of these cognitive functions. Based on 47 high-resolution diffusion-weighted imaging datasets (age range 22–71 years), we built a statistical normative atlas of the frontal lobe connections in stereotaxic space, using state-of-the-art spherical deconvo-lution tractography. We dissected 55 tracts including U-shaped fibers. We further characterized these tracts by measuring their correlation with age and education level. We reported age-related differences in the microstructural organization of several, specific frontal fiber tracts, but found no correlation with education level. Future voxel-based analyses, such as voxel-based morphometry or tract-based spatial statistics studies, may benefit from our atlas by identifying the tracts and networks involved in frontal functions. Our atlas will also build the capacity of clinicians to further understand the mechanisms involved in brain recovery and plasticity, as well as assist clinicians in the diagnosis of disconnection or abnormality within specific tracts of individual patients with various brain diseases.
306 citations
TL;DR: The present mapping study could serve as the basis for genetically driven specific targeting of the different subcomponents of the mouse raphe system.
Abstract: Serotoninergic innervation of the central nervous system is provided by hindbrain raphe nuclei (B1–B9). The extent to which each raphe subdivision has distinct topographic organization of their projections is still unclear. We provide a comprehensive description of the main targets of the rostral serotonin (5-HT) raphe subgroups (B5–B9) in the mouse brain. Adeno-associated viruses that conditionally express GFP under the control of the 5-HT transporter promoter were used to label small groups of 5-HT neurons in the dorsal (B7d), ventral (B7v), lateral (B7l), and caudal (B6) subcomponents of the dorsal raphe (DR) nucleus as well as in the rostral and caudal parts of the median raphe (MR) nucleus (B8 and B5, respectively), and in the supralemniscal (B9) cell group. We illustrate the distinctive and largely non-overlapping projection areas of these cell groups: for instance, DR (B7) projects to basal parts of the forebrain, such as the amygdala, whereas MR (B8) is the main 5-HT source to the hippocampus, septum, and mesopontine tegmental nuclei. Distinct subsets of B7 have preferential brain targets: B7v is the main source of 5-HT for the cortex and amygdala while B7d innervates the hypothalamus. We reveal for the first time the target areas of the B9 cell group, demonstrating projections to the caudate, prefrontal cortex, substantia nigra, locus coeruleus and to the raphe cell groups. The broad topographic organization of the different raphe subnuclei is likely to underlie the different functional roles in which 5-HT has been implicated in the brain. The present mapping study could serve as the basis for genetically driven specific targeting of the different subcomponents of the mouse raphe system.
218 citations
TL;DR: A novel method to describe human white matter anatomy using an approach that is both intuitive and simple to use, and which automatically extracts white matter tracts from diffusion MRI volumes, which simplifies the quantification and statistical analysis ofwhite matter tracts on large diffusion MRI databases.
Abstract: We have developed a novel method to describe human white matter anatomy using an approach that is both intuitive and simple to use, and which automatically extracts white matter tracts from diffusion MRI volumes. Further, our method simplifies the quantification and statistical analysis of white matter tracts on large diffusion MRI databases. This work reflects the careful syntactical definition of major white matter fiber tracts in the human brain based on a neuroanatomist's expert knowledge. The framework is based on a novel query language with a near-to-English textual syntax. This query language makes it possible to construct a dictionary of anatomical definitions that describe white matter tracts. The definitions include adjacent gray and white matter regions, and rules for spatial relations. This novel method makes it possible to automatically label white matter anatomy across subjects. After describing this method, we provide an example of its implementation where we encode anatomical knowledge in human white matter for ten association and 15 projection tracts per hemisphere, along with seven commissural tracts. Importantly, this novel method is comparable in accuracy to manual labeling. Finally, we present results applying this method to create a white matter atlas from 77 healthy subjects, and we use this atlas in a small proof-of-concept study to detect changes in association tracts that characterize schizophrenia.
186 citations
TL;DR: A strong asymmetry of the dorsal SLF (SLF-II), where the connectivity between the supramarginal gyrus with the dorsal precentral gyrus and the caudal middle frontal gyrus was only present in the left hemisphere, is identified.
Abstract: The subcomponents of the human superior longitudinal fasciculus (SLF) are disputed. The objective of this study was to investigate the segments, connectivity and asymmetry of the SLF. We performed high angular diffusion spectrum imaging (DSI) analysis on ten healthy adults. We also conducted fiber tracking on a 30-subject DSI template (CMU-30) and 488-subject template from the Human Connectome Project (HCP-488). In addition, five normal brains obtained at autopsy were microdissected. Based on tractography and microdissection results, we show that the human SLF differs significantly from that of monkey. The fibers corresponding to SLF-I found in 6 out of 20 hemispheres proved to be part of the cingulum fiber system in all cases and confirmed on both DSI and HCP-488 template. The most common patterns of connectivity bilaterally were as follows: from angular gyrus to caudal middle frontal gyrus and dorsal precentral gyrus representing SLF-II (or dorsal SLF), and from supramarginal gyrus to ventral precentral gyrus and pars opercularis to form SLF-III (or ventral SLF). Some connectivity features were, however, clearly asymmetric. Thus, we identified a strong asymmetry of the dorsal SLF (SLF-II), where the connectivity between the supramarginal gyrus with the dorsal precentral gyrus and the caudal middle frontal gyrus was only present in the left hemisphere. Contrarily, the ventral SLF (SLF-III) showed fairly constant connectivity with pars triangularis only in the right hemisphere. The results provide a novel neuroanatomy of the SLF that may help to better understand its functional role in the human brain.
186 citations
TL;DR: Patients with chronic pain exhibited less anticorrelated FC between the SN and DMN, and the degree of cross- network abnormality tracked pain and disease-related symptoms, suggesting that cross-network FC is a metric of functional brain abnormality in chronic pain.
Abstract: Cortical functioning within the default mode network (DMN) and salience network (SN) is altered in chronic pain patients. The mechanisms underlying these alterations are unknown, but a novel unexamined source is cross-network communication. Aberrant functional connectivity (FC) between the DMN and SN, whose activity is normally anticorrelated, reflects disease severity in many brain disorders. Further, stronger FC between the posterior cingulate cortex (PCC) and anterior insula has been reported in chronic pain, pointing to abnormal DMN–SN interactions. Here, we tested the hypothesis that cross-network FC between the DMN and SN is abnormal in chronic pain, and is related to pain and associated symptoms. We used resting state fMRI to examine FC within and between the DMN and SN in 20 patients with chronic pain due to ankylosing spondylitis and 20 healthy controls. A whole-network analysis revealed that compared to healthy controls, patients exhibited less anticorrelated FC between the SN and DMN, and the degree of cross-network abnormality tracked pain and disease-related symptoms. This suggests that cross-network FC is a metric of functional brain abnormality in chronic pain. In a complementary seed-based analysis, the PCC was strongly connected with the SN and weakly connected with the DMN in chronic pain compared to healthy controls, suggesting that the PCC acts as a hub for altered network interaction. Sensorimotor cortex cross-network FC correlated with measures of physical function, suggesting that physical functioning also impacts brain network interaction in chronic pain. Our study implicates altered communication between brain networks as a key factor underlying chronic pain.
156 citations
TL;DR: A congruent functional and structural link is observed between the vestibular nuclei and the ipsilateral and contralateral PIVC, which takes the form of a structure of a rope ladder extending from the brainstem to the cortex.
Abstract: Structural and functional interconnections of the bilateral central vestibular network have not yet been completely delineated. This includes both ipsilateral and contralateral pathways and crossing sites on the way from the vestibular nuclei via the thalamic relay stations to multiple "vestibular cortex" areas. This study investigated "vestibular" connectivity in the living human brain in between the vestibular nuclei and the parieto-insular vestibular cortex (PIVC) by combined structural and functional connectivity mapping using diffusion tensor imaging and functional connectivity magnetic resonance imaging in 24 healthy right-handed volunteers. We observed a congruent functional and structural link between the vestibular nuclei and the ipsilateral and contralateral PIVC. Five separate and distinct vestibular pathways were identified: three run ipsilaterally, while the two others cross either in the pons or the midbrain. Two of the ipsilateral projections run through the posterolateral or paramedian thalamic subnuclei, while the third bypasses the thalamus to reach the inferior part of the insular cortex directly. Both contralateral pathways travel through the posterolateral thalamus. At the cortical level, the PIVC regions of both hemispheres with a right hemispherical dominance are interconnected transcallosally through the antero-caudal splenium. The above-described bilateral vestibular circuitry in its entirety takes the form of a structure of a rope ladder extending from the brainstem to the cortex with three crossings in the brainstem (vestibular nuclei, pons, midbrain), none at thalamic level and a fourth cortical crossing through the splenium of the corpus callosum.
133 citations
TL;DR: A novel deep architecture to recursively discard uninformative features by performing sparse multi-task learning in a hierarchical fashion is proposed and the superiority of the proposed method is shown by comparing with the state-of-the-art methods.
Abstract: Recently, neuroimaging-based Alzheimer's disease (AD) or mild cognitive impairment (MCI) diagnosis has attracted researchers in the field, due to the increasing prevalence of the diseases Unfortunately, the unfavorable high-dimensional nature of neuroimaging data, but a limited small number of samples available, makes it challenging to build a robust computer-aided diagnosis system Machine learning techniques have been considered as a useful tool in this respect and, among various methods, sparse regression has shown its validity in the literature However, to our best knowledge, the existing sparse regression methods mostly try to select features based on the optimal regression coefficients in one step We argue that since the training feature vectors are composed of both informative and uninformative or less informative features, the resulting optimal regression coefficients are inevidently affected by the uninformative or less informative features To this end, we first propose a novel deep architecture to recursively discard uninformative features by performing sparse multi-task learning in a hierarchical fashion We further hypothesize that the optimal regression coefficients reflect the relative importance of features in representing the target response variables In this regard, we use the optimal regression coefficients learned in one hierarchy as feature weighting factors in the following hierarchy, and formulate a weighted sparse multi-task learning method Lastly, we also take into account the distributional characteristics of samples per class and use clustering-induced subclass label vectors as target response values in our sparse regression model In our experiments on the ADNI cohort, we performed both binary and multi-class classification tasks in AD/MCI diagnosis and showed the superiority of the proposed method by comparing with the state-of-the-art methods
131 citations
TL;DR: The findings are the first to relate the FAT with fluent speech production in stuttering, adding to the current knowledge of the functional role that this tract plays in speech production and to the literature of the etiology of persistent developmental stuttering.
Abstract: The frontal aslant tract (FAT) is a pathway that connects the inferior frontal gyrus with the supplementary motor area (SMA) and pre-SMA. The FAT was recently identified and introduced as part of a "motor stream" that plays an important role in speech production. In this study, we use diffusion imaging to examine the hypothesis that the FAT underlies speech fluency, by studying its properties in individuals with persistent developmental stuttering, a speech disorder that disrupts the production of fluent speech. We use tractography to quantify the volume and diffusion properties of the FAT in a group of adults who stutter (AWS) and fluent controls. Additionally, we use tractography to extract these measures from the corticospinal tract (CST), a well-known component of the motor system. We compute diffusion measures in multiple points along the tracts, and examine the correlation between these diffusion measures and behavioral measures of speech fluency. Our data show increased mean diffusivity in bilateral FAT of AWS compared with controls. In addition, the results show regions within the left FAT and the left CST where diffusivity values are increased in AWS compared with controls. Last, we report that in AWS, diffusivity values measured within sub-regions of the left FAT negatively correlate with speech fluency. Our findings are the first to relate the FAT with fluent speech production in stuttering, thus adding to the current knowledge of the functional role that this tract plays in speech production and to the literature of the etiology of persistent developmental stuttering.
125 citations
TL;DR: The results suggested that impaired cognitive control in IGD adolescents is likely to be mediated through the abnormal interactions and structural connection between intrinsic large-scale brain networks.
Abstract: Regardless of whether it is conceptualized as a behavioral addiction or an impulse-control disorder, internet gaming disorder (IGD) has been speculated to be associated with impaired cognitive control. Efficient cognitive behavior involves the coordinated activity of large-scale brain networks, however, whether the interactions among these networks during resting state modulated cognitive control behavior in IGD adolescents remain unclear. Twenty-eight IGD adolescents and twenty-five age-, gender-, and education-matched healthy controls participated in our study. Stroop color-word task was conducted to evaluate the cognitive control deficits in IGD adolescents. Functional connectivity and Granger Causal Analysis were employed to investigate the functional and effective connections within and between the salience, central executive, and default mode networks. Meanwhile, diffusion tensor imaging was used to assess the structural integrity of abnormal network connections. The abnormal functional connectivity within central executive networks and effective connectivity within salience network in IGD adolescents were detected. Moreover, the inefficient interactions between these two brain networks were observed. In addition, we identified reduced fractional anisotropy in salience network, right central executive network tracts, and between-network (the anterior cingulate cortex-right dorsolateral prefrontal cortex tracts) pathways in IGD individuals. Notably, we observed a significant correlation between the effective and structural connection from salience network to central executive network and the number of errors during incongruent condition in Stroop task in both IGD and control subjects. Our results suggested that impaired cognitive control in IGD adolescents is likely to be mediated through the abnormal interactions and structural connection between intrinsic large-scale brain networks.
123 citations
TL;DR: An impairment of global integration occurs in MS and is associated with cognitive deficits, and a regional redistribution of network properties contributes to cognitive status and phenotypic variability of these patients.
Abstract: Aim of this study was to explore the topological organization of functional brain network connectivity in a large cohort of multiple sclerosis (MS) patients and to assess whether its disruption contributes to disease clinical manifestations. Graph theoretical analysis was applied to resting state fMRI data from 246 MS patients and 55 matched healthy controls (HC). Functional connectivity between 116 cortical and subcortical brain regions was estimated using a bivariate correlation analysis. Global network properties (network degree, global efficiency, hierarchy, path length and assortativity) were abnormal in MS patients vs HC, and contributed to distinguish cognitively impaired MS patients (34%) from HC, but not the main MS clinical phenotypes. Compared to HC, MS patients also showed: (1) a loss of hubs in the superior frontal gyrus, precuneus and anterior cingulum in the left hemisphere; (2) a different lateralization of basal ganglia hubs (mostly located in the left hemisphere in HC, and in the right hemisphere in MS patients); and (3) a formation of hubs, not seen in HC, in the left temporal pole and cerebellum. MS patients also experienced a decreased nodal degree in the bilateral caudate nucleus and right cerebellum. Such a modification of regional network properties contributed to cognitive impairment and phenotypic variability of MS. An impairment of global integration (likely to reflect a reduced competence in information exchange between distant brain areas) occurs in MS and is associated with cognitive deficits. A regional redistribution of network properties contributes to cognitive status and phenotypic variability of these patients.
113 citations
TL;DR: A large number of empirical network data conform to the small-world features of short paths combined with high clustering, including many neural networks—but do these features captured in the Watts and Strogatz model?
Abstract: It is commonly assumed that the brain is a small-world network (e.g., Sporns and Honey 2006). Indeed, one of the present authors claimed as much 15 years ago (Hilgetag et al. 2000). The small-worldness is believed to be a crucial aspect of efficient brain organization that confers significant advantages in signal processing (e.g., LagoFernandez et al. 2000). Correspondingly, the small-world organization is deemed essential for healthy brain function, as alterations of small-world features are observed in patient groups with Alzheimer’s disease (Stam et al. 2007), autism (Barttfeld et al. 2011) or schizophrenia spectrum diseases (Liu et al. 2008; Wang et al. 2012; Zalesky et al. 2011). While the colloquial idea of a small, interconnected world has a long tradition (e.g., Klemperer 1938), the present concept of small-world features of networks is frequently associated with the Milgram experiment (Milgram 1967) that demonstrated surprisingly short paths across social networks (‘six degrees of separation’). The concept was formalized by Watts and Strogatz (1998), who derived small-world networks from regular networks by including a small proportion of random network shortcuts. Such an organization results in short paths across the whole network—almost as small as in random networks—combined with local ‘cliquishness’ (or clustering) of neighboring nodes, due to dense local interconnections. These features can be mathematically summarized by the smallworld coefficient (Humphries et al. 2006), which is defined as the clustering coefficient of a given network (normalized by the clustering coefficient of a same-size random network) divided by the network’s normalized average shortest pathlength. While any network that has a smallworld coefficient larger than one is formally a small-world network, for many researchers, the term has become associated with the specific Watts and Strogatz model that is based on the partial random rewiring of a regular network (Fig. 1a). Indeed, the estimation of the rewiring probability has been used to directly associate real-world networks with the Watts and Strogatz model (Humphries and Gurney 2008). Incidentally, the small-world coefficient might not faithfully capture the small-world property as originally described by Watts and Strogatz (1998). Therefore, an alternative coefficient has been proposed that compares the clustering of the network to a lattice instead of a random network (Telesford et al. 2011). A large number of empirical network data conform to the small-world features of short paths combined with high clustering, including many neural networks—but do these Electronic supplementary material The online version of this article (doi:10.1007/s00429-015-1035-6) contains supplementary material, which is available to authorized users.
TL;DR: It is demonstrated that children with above-average ability show differential trajectories of myelin development compared to average and below average ability children, even when controlling for socioeconomic status, gestation, and birth weight, and the results reinforce the necessity of a longitudinal perspective in investigating typical or suspected atypical cognitive maturation.
Abstract: Infancy and early childhood are periods of rapid brain development, during which brain structure and function mature alongside evolving cognitive ability. An important neurodevelopmental process during this postnatal period is the maturation of the myelinated white matter, which facilitates rapid communication across neural systems and networks. Though prior brain imaging studies in children (4 years of age and above), adolescents, and adults have consistently linked white matter development with cognitive maturation and intelligence, few studies have examined how these processes are related throughout early development (birth to 4 years of age). Here, we show that the profile of white matter myelination across the first 5 years of life is strongly and specifically related to cognitive ability. Using a longitudinal design, coupled with advanced magnetic resonance imaging, we demonstrate that children with above-average ability show differential trajectories of myelin development compared to average and below average ability children, even when controlling for socioeconomic status, gestation, and birth weight. Specifically, higher ability children exhibit slower but more prolonged early development, resulting in overall increased myelin measures by ~3 years of age. These results provide new insight into the early neuroanatomical correlates of cognitive ability, and suggest an early period of prolonged maturation with associated protracted white matter plasticity may result in strengthened neural networks that can better support later development. Further, these results reinforce the necessity of a longitudinal perspective in investigating typical or suspected atypical cognitive maturation.
TL;DR: This study elucidates alterations in human brain function after long-duration spaceflight and finds significant differences in resting-state functional connectivity between motor cortex and cerebellum, as well as changes within the default mode network.
Abstract: To date, hampered physiological function after exposure to microgravity has been primarily attributed to deprived peripheral neuro-sensory systems. For the first time, this study elucidates alterations in human brain function after long-duration spaceflight. More specifically, we found significant differences in resting-state functional connectivity between motor cortex and cerebellum, as well as changes within the default mode network. In addition, the cosmonaut showed changes in the supplementary motor areas during a motor imagery task. These results highlight the underlying neural basis for the observed physiological deconditioning due to spaceflight and are relevant for future interplanetary missions and vestibular patients.
TL;DR: Findings validate the critical role for PL afferents to the NAcore in simultaneously regulating both reinstated behavior and the associated transient synaptic potentiation in cue-induced cocaine seeking.
Abstract: Animal models of relapse reveal that the motivation to seek drug is regulated by enduring morphological and physiological changes in the nucleus accumbens, as well as transient synaptic potentiation in the accumbens core (NAcore) that parallels drug-seeking behavior. The current study sought to examine the link between the behavioral and synaptic consequences of cue-induced cocaine seeking by optically silencing glutamatergic afferents to the NAcore from the prelimbic cortex (PL). Adeno-associated virus coding for the inhibitory opsin archaerhodopsin was microinjected into PL, and optical fibers were targeted to NAcore. Animals were trained to self-administer cocaine followed by extinction training, and then underwent cue-induced reinstatement in the presence or absence of 15 min of optically induced inhibition of PL fibers in NAcore. Inhibiting the PL-to-NAcore projection blocked reinstated behavior and was paralleled by decreased dendritic spine head diameter and AMPA/NMDA ratio relative to sham-laser control rats. Interestingly, while spine density was elevated after extinction training, no further effects were observed by cued reinstatement or optical inhibition. These findings validate the critical role for PL afferents to the NAcore in simultaneously regulating both reinstated behavior and the associated transient synaptic potentiation.
TL;DR: To establish shared and distinct anatomical correlates of semantic and phonemic fluency, assumption-free voxel-based and region-of-interest-based lesion-symptom mapping in 93 patients with ischemic stroke is applied, indicating that anatomical correlations overlap in the left inferior frontal gyrus and insula, reflecting shared underlying cognitive processes.
Abstract: Semantic and phonemic fluency tasks are frequently used to test executive functioning, speed and attention, and access to the mental lexicon. In semantic fluency tasks, subjects are required to generate words belonging to a category (e.g., animals) within a limited time window, whereas in phonemic fluency tasks subjects have to generate words starting with a given letter. Anatomical correlates of semantic and phonemic fluency are currently assumed to overlap in left frontal structures, reflecting shared executive processes, and to be distinct in left temporal and right frontal structures, reflecting involvement of distinct memory processes and search strategies. Definite evidence for this assumption is lacking. To further establish the anatomical correlates of semantic and phonemic fluency, we applied assumption-free voxel-based and region-of-interest-based lesion-symptom mapping in 93 patients with ischemic stroke. Fluency was assessed by asking patients to name animals (semantic), and words starting with the letter N and A (phonemic). Our findings indicate that anatomical correlates of semantic and phonemic fluency overlap in the left inferior frontal gyrus and insula, reflecting shared underlying cognitive processes. Phonemic fluency additionally draws on the left rolandic operculum, which might reflect a search through phonological memory, and the middle frontal gyrus. Semantic fluency additionally draws on left medial temporal regions, probably reflecting a search through semantic memory, and the right inferior frontal gyrus, which might reflect the application of a visuospatial mental imagery strategy in semantic fluency. These findings establish shared and distinct anatomical correlates of semantic and phonemic fluency.
TL;DR: MRI data implicate the UF system in the pathological outcomes of repeated concussion as they relate to impulsive behaviour and a support vector machine has potential utility in the general assessment and diagnosis of brain abnormalities following concussion.
Abstract: The frontotemporal cortical network is associated with behaviours such as impulsivity and aggression. The health of the uncinate fasciculus (UF) that connects the orbitofrontal cortex (OFC) with the anterior temporal lobe (ATL) may be a crucial determinant of behavioural regulation. Behavioural changes can emerge after repeated concussion and thus we used MRI to examine the UF and connected gray matter as it relates to impulsivity and aggression in retired professional football players who had sustained multiple concussions. Behaviourally, athletes had faster reaction times and an increased error rate on a go/no-go task, and increased aggression and mania compared to controls. MRI revealed that the athletes had (1) cortical thinning of the ATL, (2) negative correlations of OFC thickness with aggression and task errors, indicative of impulsivity, (3) negative correlations of UF axial diffusivity with error rates and aggression, and (4) elevated resting-state functional connectivity between the ATL and OFC. Using machine learning, we found that UF diffusion imaging differentiates athletes from healthy controls with significant classifiers based on UF mean and radial diffusivity showing 79–84 % sensitivity and specificity, and 0.8 areas under the ROC curves. The spatial pattern of classifier weights revealed hot spots at the orbitofrontal and temporal ends of the UF. These data implicate the UF system in the pathological outcomes of repeated concussion as they relate to impulsive behaviour. Furthermore, a support vector machine has potential utility in the general assessment and diagnosis of brain abnormalities following concussion.
TL;DR: Results indicate that AIE exposure increases HDACs and decreases CBP levels that may be associated with a decrease in histone H3 acetylation in the hippocampus, which may be involved in AIE-induced behavioral abnormalities, including anxiety, in adulthood.
Abstract: Binge drinking during adolescence is a risk factor for neuropsychiatric disorders that can develop later in life. Histone acetylation is an important epigenetic mechanism that contributes to neurodevelopment. We investigated the effects of adolescent intermittent ethanol (AIE) exposure, as opposed to normal saline (AIS) exposure, on histone acetylation-mediated regulation of brain-derived neurotrophic factor (BDNF) expression and developmental stages of neurogenesis (proliferating and immature neurons) in the hippocampus in adulthood. AIE exposure increased whole hippocampal histone deacetylase (HDAC) activity and decreased binding protein of cyclic adenosine monophosphate response element binding protein (CBP) and histone H3-K9 acetylation levels in the CA1, CA2, and CA3 regions of the hippocampus. BDNF protein and exon IV mRNA levels in the CA1 and CA3 regions of the hippocampus of AIE-exposed adult rats were decreased as compared to AIS-exposed adult rats. AIE-induced anxiety-like behaviors and deficits in histone H3 acetylation at BDNF exon IV promoter in the hippocampus during adulthood, which were reversed by treatment with the HDAC inhibitor, trichostatin A (TSA). Similarly, neurogenesis was inhibited by AIE in adulthood as demonstrated by the decrease in Ki-67 and doublecortin (DCX)-positive cells in the dentate gyrus, which was normalized by TSA treatment. These results indicate that AIE exposure increases HDACs and decreases CBP levels that may be associated with a decrease in histone H3 acetylation in the hippocampus. These epigenetic changes potentially decrease BDNF expression and inhibit neurogenesis in the hippocampus that may be involved in AIE-induced behavioral abnormalities, including anxiety, in adulthood.
TL;DR: Nearly all amygdalar projections to the mPFC and to the LHA originated from different neurons suggesting amygdala and amygdala–mPFC processing influence the L HA independently, and the balance of these parallel pathways ultimately controls motivated behaviors.
Abstract: The amygdala and medial prefrontal cortex (mPFC) are highly interconnected telencephalic areas critical for cognitive processes, including associative learning and decision making. Both structures strongly innervate the lateral hypothalamus (LHA), an important component of the networks underlying the control of feeding and other motivated behaviors. The amygdala–prefrontal–lateral hypothalamic system is therefore well positioned to exert cognitive control over behavior. However, the organization of this system is not well defined, particularly the topography of specific circuitries between distinct cell groups within these complex, heterogeneous regions. This study used two retrograde tracers to map the connections from the amygdala (central and basolateral area nuclei) and mPFC to the LHA in detail, and to determine whether amygdalar pathways to the mPFC and to LHA originate from the same or different neurons. One tracer was placed into a distinct mPFC area (dorsal anterior cingulate, prelimbic, infralimbic, or rostromedial orbital), and the other into dorsal or ventral LHA. We report that the central nucleus and basolateral area of the amygdala send projections to distinct LHA regions, dorsal and ventral, respectively. The basolateral area, but not central nucleus, also sends substantial projections to the mPFC, topographically organized rostrocaudal to dorsoventral. The entire mPFC, in turn, projects to the LHA, providing a separate route for potential amygdalar influence following mPFC processing. Nearly all amygdalar projections to the mPFC and to the LHA originated from different neurons suggesting amygdala and amygdala–mPFC processing influence the LHA independently, and the balance of these parallel pathways ultimately controls motivated behaviors.
TL;DR: It is shown for the first time that interoceptive awareness changes intra-insula signal flows in the low-frequency range, and it is speculated that the selective inhibition of slow signal progression along the posterior-to-anterior insula pathway during interoception awareness allows the salient and noiseless detection of one’s own heartbeat.
Abstract: Interoceptive awareness describes the ability to consciously perceive inner bodily signals, such as one's own heartbeat. The right anterior insula is assumed to mediate this ability. The role of the posterior insula, particularly posterior-to-anterior insula signal flows is less clear in this respect. We scanned 27 healthy people with either high or low interoceptive awareness using 3T fMRI, while they either monitored their own heartbeats, or external tones, respectively. We used a combination of network centrality and bivariate connectivity analyses to characterize changes in cortical signal flows between the posterior insula and the anterior insula during interoceptive awareness or exteroceptive awareness, respectively. We show that heartbeat monitoring was accompanied by reduced network centrality of the right posterior insula, and decreased functional connectivity strengths between the right posterior insula and the right mid and anterior insula. In addition, decreased signal flows between the right posterior insula and the bilateral anterior cingulate cortices, and the bilateral orbitofrontal cortices were observed during interoceptive awareness. Functional connectivity changes were only shown by people with high interoceptive awareness, and occurred specifically within the low-frequency range (i.e., <0.1 Hz). Both groups did not differ in their functional connectivity profiles during rest. Our results show for the first time that interoceptive awareness changes intra-insula signal flows in the low-frequency range. We speculate that the selective inhibition of slow signal progression along the posterior-to-anterior insula pathway during interoceptive awareness allows the salient and noiseless detection of one's own heartbeat.
TL;DR: Results revealed that a single nucleus may have functional connections with multiple cortical regions or even multiple functional networks, and may be potentially related to the function of mediation or modulation of multiple cortical networks.
Abstract: Various studies have indicated that the thalamus is involved in controlling both cortico-cortical information flow and cortical communication with the rest of the brain. Detailed anatomy and functional connectivity patterns of the thalamocortical system are essential to understanding the cortical organization and pathophysiology of a wide range of thalamus-related neurological and neuropsychiatric diseases. The current study used resting-state fMRI to investigate the topography of the human thalamocortical system from a functional perspective. The thalamus-related cortical networks were identified by performing independent component analysis on voxel-based thalamic functional connectivity maps across a large group of subjects. The resulting functional brain networks were very similar to well-established resting-state network maps. Using these brain network components in a spatial regression model with each thalamic voxel’s functional connectivity map, we localized the thalamic subdivisions related to each brain network. For instance, the medial dorsal nucleus was shown to be associated with the default mode, the bilateral executive, the medial visual networks; and the pulvinar nucleus was involved in both the dorsal attention and the visual networks. These results revealed that a single nucleus may have functional connections with multiple cortical regions or even multiple functional networks, and may be potentially related to the function of mediation or modulation of multiple cortical networks. This observed organization of thalamocortical system provided a reference for studying the functions of thalamic sub-regions. The importance of intrinsic connectivity-based mapping of the thalamocortical relationship is discussed, as well as the applicability of the approach for future studies.
TL;DR: Data suggest that BA 44 acts as an interface between language and (meaningful) action thereby supporting parcellation schemes (based on connectivity and receptor mapping) which revealed a BA 44 sub-area involved in semantic processing.
Abstract: It is debated how language and praxis are co-represented in the left hemisphere (LH). As voxel-based lesion-symptom mapping in LH stroke patients with aphasia and/or apraxia may contribute to this debate, we here investigated the relationship between language and praxis deficits at the behavioral and lesion levels in 50 sub-acute stroke patients. We hypothesized that language and (meaningful) action are linked via semantic processing in Broca's region. Behaviorally, half of the patients suffered from co-morbid aphasia and apraxia. While 24% (n = 12) of all patients exhibited aphasia without apraxia, apraxia without aphasia was rare (n = 2, 4%). Left inferior frontal, insular, inferior parietal, and superior temporal lesions were specifically associated with deficits in naming, reading, writing, or auditory comprehension. In contrast, lesions affecting the left inferior frontal gyrus, premotor cortex, and the central region as well as the inferior parietal lobe were associated with apraxic deficits (i.e., pantomime, imitation of meaningful and meaningless gestures). Thus, contrary to the predictions of the embodied cognition theory, lesions to sensorimotor and premotor areas were associated with the severity of praxis but not language deficits. Lesions of Brodmann area (BA) 44 led to combined apraxic and aphasic deficits. Data suggest that BA 44 acts as an interface between language and (meaningful) action thereby supporting parcellation schemes (based on connectivity and receptor mapping) which revealed a BA 44 sub-area involved in semantic processing.
TL;DR: The use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent the obstacle of limited ability to effectively localize these receptors at a cellular level in the brain is combined to demonstrate that central AT1R are positioned to regulate blood pressure, metabolism, and stress responses.
Abstract: Angiotensin-II acts at its type-1 receptor (AT1R) in the brain to regulate body fluid homeostasis, sympathetic outflow and blood pressure. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of limited ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual immunohistochemistry (IHC)/ISH studies conducted in AT2R-eGFP reporter mice found that eGFP and AT2R mRNA were highly co-localized within the brain. Qualitative analysis of eGFP immunoreactivity in the brain then revealed localization to neurons within nuclei that regulate blood pressure, metabolism, and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]), as well as limbic and cortical areas known to impact stress responding and mood. Subsequently, dual IHC/ISH studies uncovered the phenotype of specific populations of AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-1 (80.3 ± 2.8 %), while a smaller subset express vesicular glutamate transporter-2 (18.2 ± 2.9 %) or AT1R (8.7 ± 1.0 %). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular nucleus (PVN) of the hypothalamus, eGFP immunoreactivity is localized to efferents terminating in the PVN and within GABAergic neurons surrounding this nucleus. These studies demonstrate that central AT2R are positioned to regulate blood pressure, metabolism, and stress responses.
TL;DR: In humans, it is shown that the ventrolateral prefrontal cortex innervations are broadly similar to those in the macaque, suggesting that evolutionary changes in the human extreme capsule fiber complex are likely more gradual than punctuated.
Abstract: We compared the course and cortical projections of white matter fibers passing through the extreme capsule in humans and macaques. Previous comparisons of this tract have suggested a uniquely human posterior projection, but these studies have always employed different techniques in the different species. Here we used the same technique, diffusion MRI, in both species to avoid attributing differences in techniques to differences in species. Diffusion MRI-based probabilistic tractography was performed from a seed area in the extreme capsule in both human and macaques. We compared in vivo data of humans and macaques as well as one high-resolution ex vivo macaque dataset. Tractography in the macaque was able to replicate most results known from macaque tracer studies, including selective innervation of frontal cortical areas and targets in the superior temporal cortex. In addition, however, we also observed some tracts that are not commonly reported in macaque tracer studies and that are more reminiscent of results previously only reported in the human. In humans, we show that the ventrolateral prefrontal cortex innervations are broadly similar to those in the macaque. These results suggest that evolutionary changes in the human extreme capsule fiber complex are likely more gradual than punctuated. Further, they demonstrate both the potential and limitations of diffusion MRI tractography.
TL;DR: It is shown that acallosal BTBR T+tpr3tf/J (BTBR) mice, an idiopathic model of autism, exhibit impaired intra-hemispheric connectivity in fronto-cortical, but not in posterior sensory cortical areas, and the observed long-range connectivity impairments recapitulate hallmark neuroimaging findings in autism.
Abstract: Agenesis of the corpus callosum (AgCC) is a congenital condition associated with wide-ranging emotional and social impairments often overlapping with the diagnostic criteria for autism. Mapping functional connectivity in the acallosal brain can help identify neural correlates of the deficits associated with this condition, and elucidate how congenital white matter alterations shape the topology of large-scale functional networks. By using resting-state BOLD functional magnetic resonance imaging (rsfMRI), here we show that acallosal BTBR T+tpr3tf/J (BTBR) mice, an idiopathic model of autism, exhibit impaired intra-hemispheric connectivity in fronto-cortical, but not in posterior sensory cortical areas. We also document profoundly altered subcortical and intra-hemispheric connectivity networks, with evidence of marked fronto-thalamic and striatal disconnectivity, along with aberrant spatial extension and strength of ipsilateral and local connectivity. Importantly, inter-hemispheric tracing of monosynaptic connections in the primary visual cortex using recombinant rabies virus confirmed the absence of direct homotopic pathways between posterior cortical areas of BTBR mice, suggesting a polysynaptic origin for the synchronous rsfMRI signal observed in these regions. Collectively, the observed long-range connectivity impairments recapitulate hallmark neuroimaging findings in autism, and are consistent with the behavioral phenotype of BTBR mice. In contrast to recent rsfMRI studies in high functioning AgCC individuals, the profound fronto-cortical and subcortical disconnectivity mapped suggest that compensatory mechanism may not necessarily restore the full connectional topology of the brain, resulting in residual connectivity alterations that serve as plausible substrates for the cognitive and emotional deficits often associated with AgCC.
TL;DR: A new stereotaxic brain atlas of the Mongolian gerbil (Meriones unguiculatus), an important animal model in neurosciences, is presented and an easily reproducible protocol allows sectioning of experimental brains in the standard frontal plane of the atlas.
Abstract: A new stereotaxic brain atlas of the Mongolian gerbil (Meriones unguiculatus), an important animal model in neurosciences, is presented. It combines high-quality histological material for identification of brain structures with reliable stereotaxic coordinates. The atlas consists of high-resolution images of frontal sections alternately stained for cell bodies (Nissl) and myelinated fibers (Gallyas) of 62 rostro-caudal levels at intervals of 350 μm. Brain structures were named according to the Paxinos nomenclature for rodents. The accuracy of the stereotaxic coordinate system was improved substantially by comparing and matching the series of histological sections to in vivo brain images of the gerbil obtained by magnetic resonance imaging (MRI). The skull outlines corresponding to the MR images were acquired using X-ray computerized tomography (CT) and were used to establish the relationship between coordinates of brain structures and skull. Landmarks such as lambda, bregma, ear canals and occipital crest can be used to line up skull and brain in standard atlas coordinates. An easily reproducible protocol allows sectioning of experimental brains in the standard frontal plane of the atlas.
TL;DR: The results provide novel evidence for GM abnormalities in sensory, motor, emotional, cognitive, and pain modulatory regions in children with CRPS and is the first study to demonstrate rapid treatment-induced GM and FC changes in areas implicated in sensation, emotion, cognition, andPain modulation.
Abstract: To date, brain structure and function changes in children with complex regional pain syndrome (CRPS) as a result of disease and treatment remain unknown. Here, we investigated (a) gray matter (GM) differences between patients with CRPS and healthy controls and (b) GM and functional connectivity (FC) changes in patients following intensive interdisciplinary psychophysical pain treatment. Twenty-three patients (13 females, 9 males; average age ± SD = 13.3 ± 2.5 years) and 21 healthy sex- and age-matched controls underwent magnetic resonance imaging. Compared to controls, patients had reduced GM in the primary motor cortex, premotor cortex, supplementary motor area, midcingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex, precuneus, basal ganglia, thalamus, and hippocampus. Following treatment, patients had increased GM in the dlPFC, thalamus, basal ganglia, amygdala, and hippocampus, and enhanced FC between the dlPFC and the periaqueductal gray, two regions involved in descending pain modulation. Accordingly, our results provide novel evidence for GM abnormalities in sensory, motor, emotional, cognitive, and pain modulatory regions in children with CRPS. Furthermore, this is the first study to demonstrate rapid treatment-induced GM and FC changes in areas implicated in sensation, emotion, cognition, and pain modulation.
TL;DR: A generalizable account of the anatomo-functional associations as well as the connectivity of representational codes underlying numerical processing as suggested by the triple code model (TCM) of numerical cognition is provided.
Abstract: The current study provides a generalizable account of the anatomo-functional associations as well as the connectivity of representational codes underlying numerical processing as suggested by the triple code model (TCM) of numerical cognition. By evaluating the neural networks subserving numerical cognition in two specific and substantially different numerical tasks with regard to both grey matter localizations as well as white matter tracts we (1) considered the possibility of additional memory-related cortex areas crucial for arithmetic fact retrieval (e.g., the hippocampus); (2) specified the functional involvement of prefrontal areas in number magnitude processing, and, finally; (3) identified the connections between these anatomo-functional instantiations of the representations involved in number magnitude processing and arithmetic fact retrieval employing probabilistic fiber tracking. The resulting amendments to the TCM are summarized in a schematic update, and ideas concerning the possible functional interplay between number magnitude processing and arithmetic fact retrieval are discussed.
TL;DR: These findings allow to define correlated anatomical and physiological identities of serotonin raphe neurons that help understanding how discrete raphe cells subpopulations account for the heterogeneous activities of the midbrain serotonergic system.
Abstract: Serotonergic neurons of the raphe nuclei exhibit anatomical, neurochemical and elecrophysiological heterogeneity that likely underpins their specific role in multiple behaviors. However, the precise organization of serotonin (5-HT) neurons to orchestrate 5-HT release patterns throughout the brain is not well understood. We compared the electrophysiological and neurochemical properties of dorsal and median raphe 5-HT neurons projecting to the medial prefrontal cortex (mPFC), amygdala (BLA) and dorsal hippocampus (dHP), combining retrograde tract tracing with brain slice electrophysiology and single-cell RT-PCR in Pet1-EGFP mice. Our results show that 5-HT neurons projecting to the dHP and the mPFC and the BLA form largely non-overlapping populations and that BLA-projecting neurons have characteristic excitability and membrane properties. In addition, using an unbiased clustering method that correlates anatomical, molecular and electrophysiological phenotypes, we find that 5-HT neurons with projections to the mPFC and the dHP segregate from those projecting to the BLA. Single-cell gene profiling showed a restricted expression of the peptide galanin in the population of 5-HT neurons projecting to the mPFC. Finally, cluster analysis allowed identifying an atypical subtype of 5-HT neuron with low excitability, long firing delays and preferential expression of the vesicular glutamate transporter type 3. Overall, these findings allow to define correlated anatomical and physiological identities of serotonin raphe neurons that help understanding how discrete raphe cells subpopulations account for the heterogeneous activities of the midbrain serotonergic system.
TL;DR: It is suggested that the association of larger total WMH volume with lower perceptual speed is independent of total gray matter volume, which helps elucidate the pathological processes leading to lower cognitive function in aging.
Abstract: Both presence of white matter hyperintensities (WMH) and smaller total gray matter volume on brain magnetic resonance imaging (MRI) are common findings in old age, and contribute to impaired cognition. We tested whether total WMH volume and gray matter volume had independent associations with cognition in community-dwelling individuals without dementia or mild cognitive impairment (MCI). We used data from participants of the Rush Memory and Aging Project. Brain MRI was available in 209 subjects without dementia or MCI (mean age 80; education = 15 years; 74 % women). WMH and gray matter were automatically segmented, and the total WMH and gray matter volumes were measured. Both MRI-derived measures were normalized by the intracranial volume. Cognitive data included composite measures of five different cognitive domains, based on 19 individual tests. Linear regression analyses, adjusted for age, sex, and education, were used to examine the relationship of logarithmically-transformed total WMH volume and of total gray matter volume to cognition. Larger total WMH volumes were associated with lower levels of perceptual speed (p 0.10). Smaller total gray matter volumes were associated with lower levels of perceptual speed (p = 0.013) and episodic memory (p = 0.001), but not with the other three cognitive domains (all p > 0.14). Larger total WMH volume was correlated with smaller total gray matter volume (p < 0.001). In a model with both MRI-derived measures included, the relation of WMH to perceptual speed remained significant (p < 0.001), while gray matter volumes were no longer related (p = 0.14). This study of older community-dwelling individuals without overt cognitive impairment suggests that the association of larger total WMH volume with lower perceptual speed is independent of total gray matter volume. These results help elucidate the pathological processes leading to lower cognitive function in aging.
TL;DR: The posterior hippocampal connectivity to memory processing regions, including the dorsolateral prefrontal cortex, parahippocampal, inferior temporal and fusiform gyri and the precuneus, predicted interindividual relational memory performance and provided important support for the integration of structural and functional connectivity in understanding the brain networks underlying episodic memory.
Abstract: Recent research suggests the anterior and posterior hippocampus form part of two distinct functional neural networks. Here we investigate the structural underpinnings of this functional connectivity difference using diffusion-weighted imaging-based parcellation. Using this technique, we substantiated that the hippocampus can be parcellated into distinct anterior and posterior segments. These structurally defined segments did indeed show different patterns of resting state functional connectivity, in that the anterior segment showed greater connectivity with temporal and orbitofrontal cortex, whereas the posterior segment was more highly connected to medial and lateral parietal cortex. Furthermore, we showed that the posterior hippocampal connectivity to memory processing regions, including the dorsolateral prefrontal cortex, parahippocampal, inferior temporal and fusiform gyri and the precuneus, predicted interindividual relational memory performance. These findings provide important support for the integration of structural and functional connectivity in understanding the brain networks underlying episodic memory.