Showing papers in "Brain Structure & Function in 2015"

Latent feature representation with stacked auto-encoder for AD/MCI diagnosis

Abstract: Recently, there have been great interests for computer-aided diagnosis of Alzheimer’s disease (AD) and its prodromal stage, mild cognitive impairment (MCI). Unlike the previous methods that considered simple low-level features such as gray matter tissue volumes from MRI, and mean signal intensities from PET, in this paper, we propose a deep learning-based latent feature representation with a stacked auto-encoder (SAE). We believe that there exist latent non-linear complicated patterns inherent in the low-level features such as relations among features. Combining the latent information with the original features helps build a robust model in AD/MCI classification, with high diagnostic accuracy. Furthermore, thanks to the unsupervised characteristic of the pre-training in deep learning, we can benefit from the target-unrelated samples to initialize parameters of SAE, thus finding optimal parameters in fine-tuning with the target-related samples, and further enhancing the classification performances across four binary classification problems: AD vs. healthy normal control (HC), MCI vs. HC, AD vs. MCI, and MCI converter (MCI-C) vs. MCI non-converter (MCI-NC). In our experiments on ADNI dataset, we validated the effectiveness of the proposed method, showing the accuracies of 98.8, 90.7, 83.7, and 83.3 % for AD/HC, MCI/HC, AD/MCI, and MCI-C/MCI-NC classification, respectively. We believe that deep learning can shed new light on the neuroimaging data analysis, and our work presented the applicability of this method to brain disease diagnosis.

Multivariate classification of social anxiety disorder using whole brain functional connectivity

Abstract: Recent research has shown that social anxiety disorder (SAD) is accompanied by abnormalities in brain functional connections. However, these findings are based on group comparisons, and, therefore, little is known about whether functional connections could be used in the diagnosis of an individual patient with SAD. Here, we explored the potential of the functional connectivity to be used for SAD diagnosis. Twenty patients with SAD and 20 healthy controls were scanned using resting-state functional magnetic resonance imaging. The whole brain was divided into 116 regions based on automated anatomical labeling atlas. The functional connectivity between each pair of regions was computed using Pearson’s correlation coefficient and used as classification feature. Multivariate pattern analysis was then used to classify patients from healthy controls. The pattern classifier was designed using linear support vector machine. Experimental results showed a correct classification rate of 82.5 % (p < 0.001) with sensitivity of 85.0 % and specificity of 80.0 %, using a leave-one-out cross-validation method. It was found that the consensus connections used to distinguish SAD were largely located within or across the default mode network, visual network, sensory-motor network, affective network, and cerebellar regions. Specifically, the right orbitofrontal region exhibited the highest weight in classification. The current study demonstrated that functional connectivity had good diagnostic potential for SAD, thus providing evidence for the possible use of whole brain functional connectivity as a complementary tool in clinical diagnosis. In addition, this study confirmed previous work and described novel pathophysiological mechanisms of SAD.

The role of the right temporoparietal junction in attention and social interaction as revealed by ALE meta-analysis

Abstract: The right temporoparietal junction (rTPJ) is frequently associated with different capacities that to shift attention to unexpected stimuli (reorienting of attention) and to understand others’ (false) mental state [theory of mind (ToM), typically represented by false belief tasks]. Competing hypotheses either suggest the rTPJ representing a unitary region involved in separate cognitive functions or consisting of subregions subserving distinct processes. We conducted activation likelihood estimation (ALE) meta-analyses to test these hypotheses. A conjunction analysis across ALE meta-analyses delineating regions consistently recruited by reorienting of attention and false belief studies revealed the anterior rTPJ, suggesting an overarching role of this specific region. Moreover, the anatomical difference analysis unravelled the posterior rTPJ as higher converging in false belief compared with reorienting of attention tasks. This supports the concept of an exclusive role of the posterior rTPJ in the social domain. These results were complemented by meta-analytic connectivity mapping (MACM) and resting-state functional connectivity (RSFC) analysis to investigate whole-brain connectivity patterns in task-constrained and task-free brain states. This allowed for detailing the functional separation of the anterior and posterior rTPJ. The combination of MACM and RSFC mapping showed that the posterior rTPJ has connectivity patterns with typical ToM regions, whereas the anterior part of rTPJ co-activates with the attentional network. Taken together, our data suggest that rTPJ contains two functionally fractionated subregions: while posterior rTPJ seems exclusively involved in the social domain, anterior rTPJ is involved in both, attention and ToM, conceivably indicating an attentional shifting role of this region.

A mu–delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks

Abstract: Opioid receptors are G protein-coupled receptors (GPCRs) that modulate brain function at all levels of neural integration, including autonomic, sensory, emotional and cognitive processing. Mu (MOR) and delta (DOR) opioid receptors functionally interact in vivo, but whether interactions occur at circuitry, cellular or molecular levels remains unsolved. To challenge the hypothesis of MOR/DOR heteromerization in the brain, we generated redMOR/greenDOR double knock-in mice and report dual receptor mapping throughout the nervous system. Data are organized as an interactive database offering an opioid receptor atlas with concomitant MOR/DOR visualization at subcellular resolution, accessible online. We also provide co-immunoprecipitation-based evidence for receptor heteromerization in these mice. In the forebrain, MOR and DOR are mainly detected in separate neurons, suggesting system-level interactions in high-order processing. In contrast, neuronal co-localization is detected in subcortical networks essential for survival involved in eating and sexual behaviors or perception and response to aversive stimuli. In addition, potential MOR/DOR intracellular interactions within the nociceptive pathway offer novel therapeutic perspectives.

Development of human brain cortical network architecture during infancy

Abstract: The brain’s mature functional network architecture has been extensively studied but the early emergence of the brain’s network organization remains largely unknown. In this study, leveraging a large sample (143 subjects) with longitudinal rsfMRI scans (333 datasets), we aimed to characterize the important developmental process of the brain’s functional network architecture during the first 2 years of life. Based on spatial independent component analysis and longitudinal linear mixed effect modeling, our results unveiled the detailed topology and growth trajectories of nine cortical functional networks. Within networks, our findings clearly separated the brains networks into two categories: primary networks were topologically adult-like in neonates while higher-order networks were topologically incomplete and isolated in neonates but demonstrated consistent synchronization during the first 2 years of life (connectivity increases 0.13–0.35). Between networks, our results demonstrated both network-level connectivity decreases (−0.02 to −0.64) and increases (0.05–0.18) but decreasing connections (n = 14) dominated increasing ones (n = 5). Finally, significant sex differences were observed with boys demonstrating faster network-level connectivity increases among the two frontoparietal networks (growth rate was 1.63e-4 per day for girls and 2.69e-4 per day for boys, p < 1e-4). Overall, our study delineated the development of the whole brain functional architecture during the first 2 years of life featuring significant changes of both within- and between-network interactions.

The left inferior fronto-occipital fasciculus subserves language semantics: a multilevel lesion study.

Abstract: Consequential works in cognitive neuroscience have led to the formulation of an interactive dual-stream model of language processing: the dorsal stream may process the phonological aspects of language, whereas the ventral stream may process the semantic aspects of language. While it is well-accepted that the dorsal route is subserved by the arcuate fasciculus, the structural connectivity of the semantic ventral stream is a matter of dispute. Here we designed a longitudinal study to gain new insights into this central but controversial question. Thirty-one patients harboring a left diffuse low-grade glioma—a rare neurological condition that infiltrates preferentially white matter associative pathways—were assessed with a prototypical task of language (i.e. verbal fluency) before and after surgery. All were operated under local anesthesia with a cortical and subcortical brain mapping—enabling to identify and preserve eloquent structures for language. We performed voxel-based lesion-symptom (VLSM) analyses on pre- and postoperative behavioral data. Preoperatively, we found a significant relationship between semantic fluency scores and the white matter fibers shaping the ventro-lateral connectivity (P < 0.05 corrected). The statistical map was found to substantially overlap with the spatial position of the inferior fronto-occipital fasciculus (IFOF) (37.7 %). Furthermore, a negative correlation was observed between semantic fluency scores and the infiltration volumes in this fasciculus (r = −0.4, P = 0.029). Postoperatively, VLSM analyses were inconclusive. Taken as a whole and when combined with the literature data, our findings strengthen the view that the IFOF plays an essential role in semantic processing and may subserve the direct ventral pathway of language.

Role of fronto-striatal tract and frontal aslant tract in movement and speech: an axonal mapping study.

Abstract: Despite a better understanding of their anatomy, the functional role of frontal pathways, i.e., the fronto-striatal tract (FST) and frontal aslant tract (FAT), remains obscure. We studied 19 patients who underwent awake surgery for a frontal glioma (14 left, 5 right) by performing intraoperative electrical mapping of both fascicles during motor and language tasks. Furthermore, we evaluated the relationship between these tracts and the eventual onset of transient postoperative disorders. We also performed post-surgical tract-specific measurements on probabilistic tractography. All patients but one experienced intraoperative inhibition of movement and/or speech during subcortical electrostimulation. On postoperative tractography, the subcortical distribution of stimulated sites corresponded to the spatial course of the FST and/or FAT. Furthermore, we found a significant correlation between postoperative worsening and distances between these tracts and resection cavity. A resection close to the (right or left) FST was correlated with transitory motor initiation disorders (p = 0.026), while a resection close to the left FAT was associated with transient speech initiation disorders (p = 0.003). Moreover, the measurements of average distances between resection cavity and left FAT showed a positive correlation with verbal fluency in both semantic (p = 0.019) and phonemic scores (p = 0.017), while average distances between surgical cavity and left FST showed a positive correlation with verbal fluency scores in both semantic (p = 0.0003) and phonemic modalities (p = 0.037). We suggest that FST and FAT would cooperatively play a role in self-initiated movement and speech, as a part of "negative motor network" involving the pre-supplementary motor area, left inferior frontal gyrus and caudate nucleus.

Definition and characterization of an extended social-affective default network

Abstract: Recent evidence suggests considerable overlap between the default mode network (DMN) and regions involved in social, affective and introspective processes We considered these overlapping regions as the social-affective part of the DMN In this study, we established a robust mapping of the underlying brain network formed by these regions and those strongly connected to them (the extended social-affective default network) We first seeded meta-analytic connectivity modeling and resting-state analyses in the meta-analytically defined DMN regions that showed statistical overlap with regions associated with social and affective processing Consensus connectivity of each seed was subsequently delineated by a conjunction across both connectivity analyses We then functionally characterized the ensuing regions and performed several cluster analyses Among the identified regions, the amygdala/hippocampus formed a cluster associated with emotional processes and memory functions The ventral striatum, anterior cingulum, subgenual cingulum and ventromedial prefrontal cortex formed a heterogeneous subgroup associated with motivation, reward and cognitive modulation of affect Posterior cingulum/precuneus and dorsomedial prefrontal cortex were associated with mentalizing, self-reference and autobiographic information The cluster formed by the temporo-parietal junction and anterior middle temporal sulcus/gyrus was associated with language and social cognition Taken together, the current work highlights a robustly interconnected network that may be central to introspective, socio-affective, that is, self- and other-related mental processes

Asymmetry, connectivity, and segmentation of the arcuate fascicle in the human brain

Abstract: The structure and function of the arcuate fascicle is still controversial. The goal of this study was to investigate the asymmetry, connectivity, and segmentation patterns of the arcuate fascicle. We employed diffusion spectrum imaging reconstructed by generalized q-sampling and we applied both a subject-specific approach (10 subjects) and a template approach (q-space diffeomorphic reconstruction of 30 subjects). We complemented our imaging investigation with fiber microdissection of five post-mortem human brains. Our results confirmed the highly leftward asymmetry of the arcuate fascicle. In the template, the left arcuate had a volume twice as large as the right one, and the left superior temporal gyrus provided five times more volume of fibers than its counterpart. We identified four cortical frontal areas of termination: pars opercularis, pars triangularis, ventral precentral gyrus, and caudal middle frontal gyrus. We found clear asymmetry of the frontal terminations at pars opercularis and ventral precentral gyrus. The analysis of patterns of connectivity revealed the existence of a strong structural segmentation in the left arcuate, but not in the right one. The left arcuate fascicle is formed by an inner or ventral pathway, which interconnects pars opercularis with superior and rostral middle temporal gyri; and an outer or dorsal pathway, which interconnects ventral precentral and caudal middle frontal gyri with caudal middle and inferior temporal gyri. The fiber microdissection results provided further support to our tractography studies. We propose the existence of primary and supplementary language pathways within the dominant arcuate fascicle with potentially distinct functional and lesional features.

Characterizing longitudinal white matter development during early childhood.

Abstract: Post-mortem studies have shown the maturation of the brain's myelinated white matter, crucial for efficient and coordinated brain communication, follows a nonlinear spatio-temporal pattern that corresponds with the onset and refinement of cognitive functions and behaviors. Unfortunately, investigation of myelination in vivo is challenging and, thus, little is known about the normative pattern of myelination, or its association with functional development. Using a novel quantitative magnetic resonance imaging technique sensitive to myelin we examined longitudinal white matter development in 108 typically developing children ranging in age from 2.5 months to 5.5 years. Using nonlinear mixed effects modeling, we provide the first in vivo longitudinal description of myelin water fraction development. Moreover, we show distinct male and female developmental patterns, and demonstrate significant relationships between myelin content and measures of cognitive function. These findings advance a new understanding of healthy brain development and provide a foundation from which to assess atypical development.

Contralateral cerebello-thalamo-cortical pathways with prominent involvement of associative areas in humans in vivo

Abstract: In addition to motor functions, it has become clear that in humans the cerebellum plays a significant role in cognition too, through connections with associative areas in the cerebral cortex. Classical anatomy indicates that neo-cerebellar regions are connected with the contralateral cerebral cortex through the dentate nucleus, superior cerebellar peduncle, red nucleus and ventrolateral anterior nucleus of the thalamus. The anatomical existence of these connections has been demonstrated using virus retrograde transport techniques in monkeys and rats ex vivo. In this study, using advanced diffusion MRI tractography we show that it is possible to calculate streamlines to reconstruct the pathway connecting the cerebellar cortex with contralateral cerebral cortex in humans in vivo. Corresponding areas of the cerebellar and cerebral cortex encompassed similar proportion (about 80 %) of the tract, suggesting that the majority of streamlines passing through the superior cerebellar peduncle connect the cerebellar hemispheres through the ventrolateral thalamus with contralateral associative areas. This result demonstrates that this kind of tractography is a useful tool to map connections between the cerebellum and the cerebral cortex and moreover could be used to support specific theories about the abnormal communication along these pathways in cognitive dysfunctions in pathologies ranging from dyslexia to autism.

In vivo correlation between axon diameter and conduction velocity in the human brain

Abstract: The understanding of the relationship between structure and function has always characterized biology in general and neurobiology in particular. One such fundamental relationship is that between axon diameter and the axon's conduction velocity (ACV). Measurement of these neuronal properties, however, requires invasive procedures that preclude direct elucidation of this relationship in vivo. Here we demonstrate that diffusion-based MRI is sensitive to the fine microstructural elements of brain wiring and can be used to quantify axon diameter in vivo. Moreover, we demonstrate the in vivo correlation between the diameter of an axon and its conduction velocity in the human brain. Using AxCaliber, a novel magnetic resonance imaging technique that enables us to estimate in vivo axon diameter distribution (ADD) and by measuring the interhemispheric transfer time (IHTT) by electroencephalography, we found significant linear correlation, across a cohort of subjects, between brain microstructure morphology (ADD) and its physiology (ACV) in the tactile and visual sensory domains. The ability to make a quantitative assessment of a fundamental physiological property in the human brain from in vivo measurements of ADD may shed new light on neurological processes occurring in neuroplasticity as well as in neurological disorders and neurodegenerative diseases.

In contrast to many other mammals, cetaceans have relatively small hippocampi that appear to lack adult neurogenesis

Abstract: The hippocampus is essential for the formation and retrieval of memories and is a crucial neural structure sub-serving complex cognition. Adult hippocampal neurogenesis, the birth, migration and integration of new neurons, is thought to contribute to hippocampal circuit plasticity to augment function. We evaluated hippocampal volume in relation to brain volume in 375 mammal species and examined 71 mammal species for the presence of adult hippocampal neurogenesis using immunohistochemistry for doublecortin, an endogenous marker of immature neurons that can be used as a proxy marker for the presence of adult neurogenesis. We identified that the hippocampus in cetaceans (whales, dolphins and porpoises) is both absolutely and relatively small for their overall brain size, and found that the mammalian hippocampus scaled as an exponential function in relation to brain volume. In contrast, the amygdala was found to scale as a linear function of brain volume, but again, the relative size of the amygdala in cetaceans was small. The cetacean hippocampus lacks staining for doublecortin in the dentate gyrus and thus shows no clear signs of adult hippocampal neurogenesis. This lack of evidence of adult hippocampal neurogenesis, along with the small hippocampus, questions current assumptions regarding cognitive abilities associated with hippocampal function in the cetaceans. These anatomical features of the cetacean hippocampus may be related to the lack of postnatal sleep, causing a postnatal cessation of hippocampal neurogenesis.

Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation.

Abstract: Cranial radiotherapy is used routinely to control the growth of primary and secondary brain tumors, but often results in serious and debilitating cognitive dysfunction. In part due to the beneficial dose depth distributions that may spare normal tissue damage, the use of protons to treat CNS and other tumor types is rapidly gaining popularity. Astronauts exposed to lower doses of protons in the space radiation environment are also at risk for developing adverse CNS complications. To explore the consequences of whole body proton irradiation, mice were subjected to 0.1 and 1 Gy and analyzed for morphometric changes in hippocampal neurons 10 and 30 days following exposure. Significant dose-dependent reductions (~33 %) in dendritic complexity were found, when dendritic length, branching and area were analyzed 30 days after exposure. At equivalent doses and times, significant reductions in the number (~30 %) and density (50-75 %) of dendritic spines along hippocampal neurons of the dentate gyrus were also observed. Immature spines (filopodia, long) exhibited the greatest sensitivity (1.5- to 3-fold) to irradiation, while more mature spines (mushroom) were more resistant to changes over a 1-month post-irradiation timeframe. Irradiated granule cell neurons spanning the subfields of the dentate gyrus showed significant and dose-responsive reductions in synaptophysin expression, while the expression of postsynaptic density protein (PSD-95) was increased significantly. These findings corroborate our past work using photon irradiation, and demonstrate for the first time, dose-responsive changes in dendritic complexity, spine density and morphology and synaptic protein levels following exposure to low-dose whole body proton irradiation.

Dynamic brain functional connectivity modulated by resting-state networks

Abstract: Studies of large-scale brain functional connectivity using the resting-state functional magnetic resonance imaging have advanced our understanding of human brain functions. Although the evidence of dynamic functional connectivity is accumulating, the variations of functional connectivity over time have not been well characterized. In the present study, we aimed to associate the variations of functional connectivity with the intrinsic activities of resting-state networks during a single resting-state scan by comparing functional connectivity differences between when a network had higher and lower intrinsic activities. The activities of the salience network, default mode network (DMN), and motor network were associated with changes of resting-state functional connectivity. Higher activity of the salience network was accompanied by greater functional connectivity between the fronto-parietal regions and the DMN regions, and between the regions within the DMN. Higher DMN activity was associated with less connectivity between the regions within the DMN, and greater connectivity between the regions within the fronto-parietal network. Higher motor network activity was correlated with greater connectivity between the regions within the motor network, and smaller connectivity between the DMN regions and fronto-parietal regions, and between the DMN regions and the motor regions. In addition, the whole brain network modularity was positively correlated with the motor network activity, suggesting that the brain is more segregated as sub-systems when the motor network is intrinsically activated. Together, these results demonstrate the association between the resting-state connectivity variations and the intrinsic activities of specific networks, which can provide insights on the dynamic changes in large-scale brain connectivity and network configurations.

Toward neurobiological characterization of functional homogeneity in the human cortex: regional variation, morphological association and functional covariance network organization

Abstract: Local functional homogeneity of the human cortex indicates the boundaries between functionally heterogeneous regions and varies remarkably across the cortical mantle. It is unclear whether these variations have the neurobiological and structural basis. We employed structural and resting-state functional magnetic resonance imaging scans from 482 healthy subjects and computed the vertex-wise regional homogeneity of low-frequency fluctuations (2dReHo) and five measures of cortical morphology. We then used these metrics to examine regional variation, morphological association and functional covariance network of 2dReHo. Within the ventral visual stream, increases of 2dReHo reflect reduced complexity of information processing or functional hierarchies. Along the divisions of the prefrontal cortex and posteromedial cortex, the gradients of 2dReHo revealed the hierarchical organization within the two association areas, respectively. Individual differences in 2dReHo are associated with those of cortical morphology, and their whole-brain inter-regional covariation is organized into a functional covariance network, comprising five hierarchically organized modules with hubs of both primary sensory and high-order association areas. These highly reproducible observations suggest that local functional homogeneity has neurobiological relevance that is likely determined by anatomical, developmental and neurocognitive factors and should serve as a neuroimaging marker to investigate the human brain function.

From genes to folds: a review of cortical gyrification theory

Abstract: Cortical gyrification is not a random process. Instead, the folds that develop are synonymous with the functional organization of the cortex, and form patterns that are remarkably consistent across individuals and even some species. How this happens is not well understood. Although many developmental features and evolutionary adaptations have been proposed as the primary cause of gyrencephaly, it is not evident that gyrification is reducible in this way. In recent years, we have greatly increased our understanding of the multiple factors that influence cortical folding, from the action of genes in health and disease to evolutionary adaptations that characterize distinctions between gyrencephalic and lissencephalic cortices. Nonetheless it is unclear how these factors which influence events at a small-scale synthesize to form the consistent and biologically meaningful large-scale features of sulci and gyri. In this article, we review the empirical evidence which suggests that gyrification is the product of a generalized mechanism, namely the differential expansion of the cortex. By considering the implications of this model, we demonstrate that it is possible to link the fundamental biological components of the cortex to its large-scale pattern-specific morphology and functional organization.

Acquisition of Paleolithic toolmaking abilities involves structural remodeling to inferior frontoparietal regions

Abstract: Human ancestors first modified stones into tools 2.6 million years ago, initiating a cascading increase in technological complexity that continues today. A parallel trend of brain expansion during the Paleolithic has motivated over 100 years of theorizing linking stone toolmaking and human brain evolution, but empirical support remains limited. Our study provides the first direct experimental evidence identifying likely neuroanatomical targets of natural selection acting on toolmaking ability. Subjects received MRI and DTI scans before, during, and after a 2-year Paleolithic toolmaking training program. White matter fractional anisotropy (FA) showed changes in branches of the superior longitudinal fasciculus leading into left supramarginal gyrus, bilateral ventral precentral gyri, and right inferior frontal gyrus pars triangularis. FA increased from Scan 1-2, a period of intense training, and decreased from Scan 2-3, a period of reduced training. Voxel-based morphometry found a similar trend toward gray matter expansion in the left supramarginal gyrus from Scan 1-2 and a reversal of this effect from Scan 2-3. FA changes correlated with training hours and with motor performance, and probabilistic tractography confirmed that white matter changes projected to gray matter changes and to regions that activate during Paleolithic toolmaking. These results show that acquisition of Paleolithic toolmaking skills elicits structural remodeling of recently evolved brain regions supporting human tool use, providing a mechanistic link between stone toolmaking and human brain evolution. These regions participate not only in toolmaking, but also in other complex functions including action planning and language, in keeping with the hypothesized co-evolution of these functions.

Cerebellar control of gait and interlimb coordination.

Abstract: Synaptic and intrinsic processing in Purkinje cells, interneurons and granule cells of the cerebellar cortex have been shown to underlie various relatively simple, single-joint, reflex types of motor learning, including eyeblink conditioning and adaptation of the vestibulo-ocular reflex. However, to what extent these processes contribute to more complex, multi-joint motor behaviors, such as locomotion performance and adaptation during obstacle crossing, is not well understood. Here, we investigated these functions using the Erasmus Ladder in cell-specific mouse mutant lines that suffer from impaired Purkinje cell output (Pcd), Purkinje cell potentiation (L7-Pp2b), molecular layer interneuron output (L7-Δγ2), and granule cell output (α6-Cacna1a). We found that locomotion performance was severely impaired with small steps and long step times in Pcd and L7-Pp2b mice, whereas it was mildly altered in L7-Δγ2 and not significantly affected in α6-Cacna1a mice. Locomotion adaptation triggered by pairing obstacle appearances with preceding tones at fixed time intervals was impaired in all four mouse lines, in that they all showed inaccurate and inconsistent adaptive walking patterns. Furthermore, all mutants exhibited altered front–hind and left–right interlimb coordination during both performance and adaptation, and inconsistent walking stepping patterns while crossing obstacles. Instead, motivation and avoidance behavior were not compromised in any of the mutants during the Erasmus Ladder task. Our findings indicate that cell type-specific abnormalities in cerebellar microcircuitry can translate into pronounced impairments in locomotion performance and adaptation as well as interlimb coordination, highlighting the general role of the cerebellar cortex in spatiotemporal control of complex multi-joint movements.

Loss of hippocampal interneurons and epileptogenesis: a comparison of two animal models of acquired epilepsy.

Abstract: Reduced hippocampal GABAergic inhibition is acknowledged to be associated with epilepsy. However, there are no studies that had quantitatively compared the loss of various interneuron populations in different models of epilepsy. We tested a hypothesis that the more severe the loss of hippocampal interneurons, the more severe was the epilepsy. Epileptogenesis was triggered in adult rats by status epilepticus (SE) (56 SE, 24 controls) or by traumatic brain injury (TBI) (45 TBI, 23 controls). The total number of hippocampal parvalbumin (PARV), cholecystokinin (CCK), calretinin (CR), somatostatin (SOM), or neuropeptide Y (NPY) positive neurons was estimated using unbiased stereology at 1 or 6 months post-insult. The rats with TBI had no spontaneous seizures but showed increased seizure susceptibility. Eleven of the 28 rats (39 %) in the SE group had spontaneous seizures. The most affected hippocampal area after TBI was the ipsilateral dentate gyrus, where 62 % of PARV-immunoreactive (ir) (p < 0.001 compared to controls), 77 % of CR-ir (p < 0.05), 46 % of SOM-ir (p < 0.001), and 59 % of NPY-ir (p < 0.001) cells remained at 1 month after TBI. At 6 months post-TBI, only 35 % of PARV-ir (p < 0.001 compared to controls), 63 % of CCK-ir (p < 0.01), 74 % of CR-ir (p < 0.001), 55 % of SOM-ir (p < 0.001), and 51 % of NPY-ir (p < 0.001) cells were remaining. Moreover, the reduction in PARV-ir, CCK-ir, and CR-ir neurons was bilateral (all p < 0.05). Substantial reductions in different neuronal populations were also found in subfields of the CA3 and CA1. In rats with epilepsy after SE, the number of PARV-ir neurons was reduced in the ipsilateral CA1 (80 % remaining, p < 0.05) and the number of NPY-ir neurons bilaterally in the dentate gyrus (33-37 %, p < 0.01) and the CA3 (54-57 %, p < 0.05). Taken together, interneuron loss was substantially more severe, widespread, progressive, and included more interneuron subclasses after TBI than after SE. Interneurons responsible for perisomatic inhibition were more vulnerable to TBI than those providing dendritic inhibition. Unlike expected, we could not demonstrate any etiology-independent link between the severity of hippocampal interneuron loss and the overall risk of spontaneous seizures.

Not all sharks are "swimming noses": variation in olfactory bulb size in cartilaginous fishes.

Abstract: Olfaction is a universal modality by which all animals sample chemical stimuli from their environment. In cartilaginous fishes, olfaction is critical for various survival tasks including localizing prey, avoiding predators, and chemosensory communication with conspecifics. Little is known, however, about interspecific variation in olfactory capability in these fishes, or whether the relative importance of olfaction in relation to other sensory systems varies with regard to ecological factors, such as habitat and lifestyle. In this study, we have addressed these questions by directly examining interspecific variation in the size of the olfactory bulbs (OB), the region of the brain that receives the primary sensory projections from the olfactory nerve, in 58 species of cartilaginous fishes. Relative OB size was compared among species occupying different ecological niches. Our results show that the OBs maintain a substantial level of allometric independence from the rest of the brain across cartilaginous fishes and that OB size is highly variable among species. These findings are supported by phylogenetic generalized least-squares models, which show that this variability is correlated with ecological niche, particularly habitat. The relatively largest OBs were found in pelagic-coastal/oceanic sharks, especially migratory species such as Carcharodon carcharias and Galeocerdo cuvier. Deep-sea species also possess large OBs, suggesting a greater reliance on olfaction in habitats where vision may be compromised. In contrast, the smallest OBs were found in the majority of reef-associated species, including sharks from the families Carcharhinidae and Hemiscyllidae and dasyatid batoids. These results suggest that there is great variability in the degree to which these fishes rely on olfactory cues. The OBs have been widely used as a neuroanatomical proxy for olfactory capability in vertebrates, and we speculate that differences in olfactory capabilities may be the result of functional rather than phylogenetic adaptations.

Higher volume of ventral striatum and right prefrontal cortex in pathological gambling

Abstract: Functional neuroimaging studies have implicated an involvement of the prefrontal cortex and mesolimbic reward system (i.e., ventral striatum) in pathological gambling (PG). However, there is a lack of studies focusing on structural changes in frontostriatal brain regions in adult subjects with PG. In order to study differences in local grey matter volume, 20 male subjects with PG and 21 matched controls underwent structural magnetic resonance imaging. Structural brain data were analysed via voxel-based morphometry with a focus on prefrontal areas and ventral striatum. By comparing grey matter volumes in brain regions highly relevant for brain functional changes in PG, the present study found a higher volume in right ventral striatum and right prefrontal cortex by means of voxel-wise morphometry in PG subjects as compared to controls. Our findings demonstrate local grey matter changes in brain areas that have previously been associated with functional changes in PG. Hypertrophy in the prefrontal cortex might be an adaptation at least partly induced by the higher grey matter volume in the ventral striatum and may help to increase cognitive control over gambling impulses. Future research should explore the relationship between functional and structural alterations as well as the course of changes in PG.

A predictive model of the cat cortical connectome based on cytoarchitecture and distance.

Abstract: Information processing in the brain is strongly constrained by anatomical connectivity. However, the principles governing the organization of corticocortical connections remain elusive. Here, we tested three models of relationships between the organization of cortical structure and features of connections linking 49 areas of the cat cerebral cortex. Factors taken into account were relative cytoarchitectonic differentiation ('structural model'), relative spatial position ('distance model'), or relative hierarchical position ('hierarchical model') of the areas. Cytoarchitectonic differentiation and spatial distance (themselves uncorrelated) correlated strongly with the existence of inter-areal connections, whereas no correlation was found with relative hierarchical position. Moreover, a strong correlation was observed between patterns of laminar projection origin or termination and cytoarchitectonic differentiation. Additionally, cytoarchitectonic differentiation correlated with the absolute number of corticocortical connections formed by areas, and varied characteristically between different cortical subnetworks, including a 'rich-club' module of hub areas. Thus, connections between areas of the cat cerebral cortex can, to a large part, be explained by the two independent factors of relative cytoarchitectonic differentiation and spatial distance of brain regions. As both the structural and distance model were originally formulated in the macaque monkey, their applicability in another mammalian species suggests a general principle of global cortical organization.

Motor cortex excitability and connectivity in chronic stroke: a multimodal model of functional reorganization.

Abstract: Cerebral ischemia triggers a cascade of cellular processes, which induce neuroprotection, inflammation, apoptosis and regeneration. At the neural network level, lesions concomitantly induce cerebral plasticity. Yet, many stroke survivors are left with a permanent motor deficit, and only little is known about the neurobiological factors that determine functional outcome after stroke. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) are non-invasive approaches that allow insights into the functional (re-) organization of the cortical motor system. We here combined neuronavigated TMS, MRI and analyses of connectivity to investigate to which degree recovery of hand function depends on corticospinal tract (CST) damage and biomarkers of cerebral plasticity like cortical excitability and motor network effective connectivity. As expected, individual motor performance of 12 stroke patients with persistent motor deficits was found to depend upon the degree of CST damage but also motor cortex excitability and interhemispheric connectivity. In addition, the data revealed a strong correlation between reduced ipsilesional motor cortex excitability and reduced interhemispheric inhibition in severely impaired patients. Interindividual differences in ipsilesional motor cortex excitability were stronger related to the motor deficit than abnormal interhemispheric connectivity or CST damage. Multivariate linear regression analysis combining the three factors accounted for more than 80 % of the variance in functional impairment. The inter-relation of cortical excitability and reduced interhemispheric inhibition provides direct multi-modal evidence for the disinhibition theory of the contralesional hemisphere following stroke. Finally, our data reveal a key mechanism (i.e., the excitability-related reduction in interhemispheric inhibition) accounting for the rehabilitative potential of novel therapeutic approaches which aim at modulating cortical excitability in stroke patients.

Estradiol mediates dendritic spine plasticity in the nucleus accumbens core through activation of mGluR5.

Abstract: Accumulating evidence from human and rodent studies suggests that females are more sensitive to the motivating and rewarding properties of drugs of abuse. Numerous reports implicate estradiol in enhancing drug-related responses in females, yet the neurobiological mechanisms underlying this effect of estradiol are unknown. Because dendritic spine plasticity in the nucleus accumbens (NAc) is linked to the addictive effects of drugs, we examined the influence of estradiol on dendritic spines in this region. Previously our laboratory demonstrated that in female medium spiny neurons, estradiol activates metabotropic glutamate receptor subtype five (mGluR5), a G protein-coupled receptor already implicated in the etiology of drug addiction. Thus, we sought to determine whether mGluR5 is a part of the mechanism by which estradiol affects dendritic spine density in the NAc. To test this hypothesis, ovariectomized female rats were treated with the mGluR5 antagonist, MPEP, or vehicle prior to estradiol (or oil) treatment and 24 h later dendritic spine density was evaluated by DiI labeling and confocal microscopy. We found that estradiol decreased dendritic spine density in the NAc core and that pretreatment with MPEP blocked this effect. In contrast, MPEP had no effect on dendritic spine density in the NAc shell or CA1 region of the hippocampus, two regions in which estradiol increased the density of dendritic spines. As dendritic spine plasticity in the NAc core has behavioral consequences for drug addiction, these data provide a clue as to how estradiol acts in females to enhance behavioral responses to drugs of abuse.

Repetitive magnetic stimulation induces plasticity of excitatory postsynapses on proximal dendrites of cultured mouse CA1 pyramidal neurons

Abstract: Repetitive transcranial magnetic stimulation (rTMS) of the human brain can lead to long-lasting changes in cortical excitability. However, the cellular and molecular mechanisms which underlie rTMS-induced plasticity remain incompletely understood. Here, we used repetitive magnetic stimulation (rMS) of mouse entorhino-hippocampal slice cultures to study rMS-induced plasticity of excitatory postsynapses. By employing whole-cell patch-clamp recordings of CA1 pyramidal neurons, local electrical stimulations, immunostainings for the glutamate receptor subunit GluA1 and compartmental modeling, we found evidence for a preferential potentiation of excitatory synapses on proximal dendrites of CA1 neurons (2–4 h after stimulation). This rMS-induced synaptic potentiation required the activation of voltage-gated sodium channels, L-type voltage-gated calcium channels and N-methyl-d-aspartate-receptors. In view of these findings we propose a cellular model for the preferential strengthening of excitatory synapses on proximal dendrites following rMS in vitro, which is based on a cooperative effect of synaptic glutamatergic transmission and postsynaptic depolarization.

Possible anatomical pathways for short-latency multisensory integration processes in primary sensory cortices

Abstract: Multisensory integration does not only recruit higher-level association cortex, but also low-level and even primary sensory cortices. Here, we will describe and quantify two types of anatomical pathways, a thalamocortical and a corticocortical that possibly underlie short-latency multisensory integration processes in the primary auditory (A1), somatosensory (S1), and visual cortex (V1). Results were obtained from Mongolian gerbils, a common model-species in neuroscience, using simultaneous injections of different retrograde tracers into A1, S1, and V1. Several auditory, visual, and somatosensory thalamic nuclei project not only to the primary sensory area of their own (matched) but also to areas of other (non-matched) modalities. The crossmodal output ratios of these nuclei, belonging to both core and non-core sensory pathways, vary between 0.4 and 63.5 % of the labeled neurons. Approximately 0.3 % of the sensory thalamic input to A1, 5.0 % to S1, and 2.1 % to V1 arise from non-matched nuclei. V1 has most crossmodal corticocortical connections, projecting strongest to S1 and receiving a similar amount of moderate inputs from A1 and S1. S1 is mainly interconnected with V1. A1 has slightly more projections to V1 than S1, but gets just faint inputs from there. Concerning the layer-specific distribution of the retrogradely labeled somata in cortex, V1 provides the most pronounced feedforward-type outputs and receives (together with S1) most pronounced feedback-type inputs. In contrast, A1 has most pronounced feedback-type outputs and feedforward-type inputs in this network. Functionally, the different sets of thalamocortical and corticocortical connections could underlie distinctive types of integration mechanisms for different modality pairings.

Not on speaking terms: hallucinations and structural network disconnectivity in schizophrenia

Abstract: Auditory verbal hallucinations (AVH) in schizophrenia have previously been associated with functional deficiencies in language networks, specifically with functional disconnectivity in fronto-temporal connections in the left hemisphere and in interhemispheric connections between frontal regions. Here, we investigate whether AVH are accompanied by white matter abnormalities in tracts connecting the frontal, parietal and temporal lobes, also engaged during language tasks. We combined diffusion tensor imaging with tract-based spatial statistics and found white matter abnormalities in patients with schizophrenia as compared with healthy controls. The patients showed reduced fractional anisotropy bilaterally: in the anterior thalamic radiation (ATR), body of the corpus callosum (forceps minor), cingulum, temporal part of the superior longitudinal fasciculus (SLF) and a small area in the inferior fronto-occipital fasciculus (IFOF); and in the right hemisphere: in the visual cortex, forceps major, body of the corpus callosum (posterior parts) and inferior parietal cortex. Compared to patients without current hallucinations, patients with hallucinations revealed decreased fractional anisotropy in the left IFOF, uncinate fasciculus, arcuate fasciculus with SLF, corpus callosum (posterior parts-forceps major), cingulate, corticospinal tract and ATR. The severity of hallucinations correlated negatively with white matter integrity in tracts connecting the left frontal lobe with temporal regions (uncinate fasciculus, IFOF, cingulum, arcuate fasciculus anterior and long part and superior long fasciculus frontal part) and in interhemispheric connections (anterior corona radiata). These findings support the hypothesis that hallucinations in schizophrenia are accompanied by a complex pattern of white matter alterations that negatively affect the language, emotion and attention/perception networks.

Descriptive anatomy of Heschl’s gyri in 430 healthy volunteers, including 198 left-handers

Abstract: This study describes the gyrification patterns and surface areas of Heschl’s gyrus (HG) in 430 healthy volunteers mapped with magnetic resonance imaging. Among the 232 right-handers, we found a large occurrence of duplication (64 %), especially on the right (49 vs. 37 % on the left). Partial duplication was twice more frequent on the left than complete duplication. On the opposite, in the right hemisphere, complete duplication was 10 % more frequent than partial duplication. The most frequent inter-hemispheric gyrification patterns were bilateral single HG (36 %) and left single-right duplication (27 %). The least common patterns were left duplication-right single (22 %) and bilateral duplication (15 %). Duplication was associated with decreased anterior HG surface area on the corresponding side, independently of the type of duplication, and increased total HG surface area (including the second gyrus). Inter-hemispheric gyrification patterns strongly influenced both anterior and total HG surface area asymmetries, leftward asymmetry of the anterior HG surface was observed in all patterns except double left HG, and total HG surface asymmetry favored the side of duplication. Compared to right-handers, the 198 left-handers exhibited lower occurrence of duplication, and larger right anterior HG surface and total HG surface areas. Left-handers’ HG surface asymmetries were thus significantly different from those of right-handers, with a loss of leftward asymmetry of their anterior HG surface, and with significant rightward asymmetry of their total HG surface. In summary, gyrification patterns have a strong impact on HG surface and asymmetry. The observed reduced lateralization of HG duplications and anterior HG asymmetry in left-handers highlights HG inter-hemispheric gyrification patterns as a potential candidate marker of speech lateralization.

Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus

Abstract: Emerging data support roles for microRNA (miRNA) in the pathogenesis of various neurologic disorders including epilepsy. MicroRNA-134 (miR-134) is enriched in dendrites of hippocampal neurons, where it negatively regulates spine volume. Recent work identified upregulation of miR-134 in experimental and human epilepsy. Targeting miR-134 in vivo using antagomirs had potent anticonvulsant effects against kainic acid-induced seizures and was associated with a reduction in dendritic spine number. In the present study, we measured dendritic spine volume in mice injected with miR-134-targeting antagomirs and tested effects of the antagomirs on status epilepticus triggered by the cholinergic agonist pilocarpine. Morphometric analysis of over 6,400 dendritic spines in Lucifer yellow-injected CA3 pyramidal neurons revealed increased spine volume in mice given antagomirs compared to controls that received a scrambled sequence. Treatment of mice with miR-134 antagomirs did not alter performance in a behavioral test (novel object location). Status epilepticus induced by pilocarpine was associated with upregulation of miR-134 within the hippocampus of mice. Pretreatment of mice with miR-134 antagomirs reduced the proportion of animals that developed status epilepticus following pilocarpine and increased animal survival. In antagomir-treated mice that did develop status epilepticus, seizure onset was delayed and total seizure power was reduced. These studies provide in vivo evidence that miR-134 regulates spine volume in the hippocampus and validation of the seizure-suppressive effects of miR-134 antagomirs in a model with a different triggering mechanism, indicating broad conservation of anticonvulsant effects.