Showing papers in "Brain Structure & Function in 2013"
TL;DR: It is shown that the anatomical substrate of this recurrent message passing is a hierarchical system consisting of functionally asymmetric driving (ascending) and modulatory (descending) connections: an arrangement that is almost exactly recapitulated in the motor system, in terms of its laminar, topographic and physiological characteristics.
Abstract: The descending projections from motor cortex share many features with top-down or backward connections in visual cortex; for example, corticospinal projections originate in infragranular layers, are highly divergent and (along with descending cortico-cortical projections) target cells expressing NMDA receptors. This is somewhat paradoxical because backward modulatory characteristics would not be expected of driving motor command signals. We resolve this apparent paradox using a functional characterisation of the motor system based on Helmholtz’s ideas about perception; namely, that perception is inference on the causes of visual sensations. We explain behaviour in terms of inference on the causes of proprioceptive sensations. This explanation appeals to active inference, in which higher cortical levels send descending proprioceptive predictions, rather than motor commands. This process mirrors perceptual inference in sensory cortex, where descending connections convey predictions, while ascending connections convey prediction errors. The anatomical substrate of this recurrent message passing is a hierarchical system consisting of functionally asymmetric driving (ascending) and modulatory (descending) connections: an arrangement that we show is almost exactly recapitulated in the motor system, in terms of its laminar, topographic and physiological characteristics. This perspective casts classical motor reflexes as minimising prediction errors and may provide a principled explanation for why motor cortex is agranular.
583 citations
TL;DR: It is suggested that the distribution of IFOF fibers within the frontal lobe corresponds to a fine functional segmentation and can be considered as a “multi-function” bundle, with each anatomical subcomponent subserving different brain processing.
Abstract: The anatomy and functional role of the inferior fronto-occipital fascicle (IFOF) remain poorly known. We accurately analyze its course and the anatomical distribution of its frontal terminations. We propose a classification of the IFOF in different subcomponents. Ten hemispheres (5 left, 5 right) were dissected with Klingler's technique. In addition to the IFOF dissection, we performed a 4-T diffusion tensor imaging study on a single healthy subject. We identified two layers of IFOF. The first one is superficial and antero-superiorly directed, terminating in the inferior frontal gyrus. The second is deeper and consists of three portions: posterior, middle and anterior. The posterior component terminates in the middle frontal gyrus (MFG) and dorso-lateral prefrontal cortex. The middle component terminates in the MFG and lateral orbito-frontal cortex. The anterior one is directed to the orbito-frontal cortex and frontal pole. In vivo tractography study confirmed these anatomical findings. We suggest that the distribution of IFOF fibers within the frontal lobe corresponds to a fine functional segmentation. IFOF can be considered as a "multi-function" bundle, with each anatomical subcomponent subserving different brain processing. The superficial layer and the posterior component of the deep layer, which connects the occipital extrastriate, temporo-basal and inferior frontal cortices, might subserve semantic processing. The middle component of the deep layer could play a role in a multimodal sensory-motor integration. Finally, the anterior component of the deep layer might be involved in emotional and behavioral aspects.
284 citations
TL;DR: For the first time, dissections revealed that each component of the perisylvian SLF was connected to a specific cortical area within the frontal, parietal and temporal lobes.
Abstract: The anatomy of the perisylvian component of the superior longitudinal fasciculus (SLF) has recently been reviewed by numerous diffusion tensor imaging tractography (DTI) studies. However, little is known about the exact cortical terminations of this tract. The aim of the present work is to isolate the different subcomponents of this tract with fiber dissection and DTI tractography, and to identify the exact cortical connections. Twelve postmortem human hemispheres (6 right and 6 left) were dissected using the cortex-sparing fiber dissection. In addition, three healthy brains were analyzed using DTI-based tractography software. The different components of the perisylvian SLF were isolated and the fibers were followed until the cortical terminations. Three segments of the perisylvian SLF were identified: (1) anterior segment, connecting the supramarginal gyrus and superior temporal gyrus with the precentral gyrus, (2) posterior segment, connecting the posterior portion of the middle temporal gyrus with the angular gyrus, and (3) long segment of the arcuate fasciculus that connects the middle and inferior temporal gyri with the precentral gyrus and posterior portion of the inferior and middle frontal gyri. In the present study, three different components of the perisylvian SLF were identified. For the first time, our dissections revealed that each component was connected to a specific cortical area within the frontal, parietal and temporal lobes. By accurately depicting not only the trajectory but also cortical connections of this bundle, it is possible to develop new insights into the putative functional role of this tract.
244 citations
TL;DR: There is converging quantitative cytoarchitectonic, receptor architectonic, myeloarchitectonics, hodological, and functional evidence, indicating that the Vogt–Vogt concept is essentially correct, and the problem of relating particular cortical functions, as determined with neuroimaging techniques, to particular cortical structures is solved.
Abstract: The human cerebral cortex contains numerous myelinated fibres, many of which are concentrated in tangentially organized layers and radially oriented bundles. The spatial organization of these fibres is by no means homogeneous throughout the cortex. Local differences in the thickness and compactness of the fibre layers, and in the length and strength of the radial bundles, render it possible to recognize areas with a different myeloarchitecture. The neuroanatomical subdiscipline aimed at the identification and delineation of such areas is known as myeloarchitectonics. There is another, closely related neuroanatomical subdiscipline, named cytoarchitectonics. The aims and scope of this subdiscipline are the same as those of myeloarchitectonics, viz. parcellation. However, this subdiscipline focuses, as its name implies, on the size, shape and arrangement of the neuronal cell bodies in the cortex, rather than on the myelinated fibres.
211 citations
TL;DR: Three different stress models are reported demonstrating that stress-inducible increases in microRNA-132 and consequent decreases in its acetylcholinesterase (AChE) target are causally involved, and cholinergic-mediated induction of miR-132 is suppressed and consequently suppressed ACHE-S, opening venues for intercepting these mi R-132-mediated damages.
Abstract: Diverse stress stimuli induce long-lasting cognitive deficits, but the underlying molecular mechanisms are still incompletely understood. Here, we report three different stress models demonstrating that stress-inducible increases in microRNA-132 (miR-132) and consequent decreases in its acetylcholinesterase (AChE) target are causally involved. In a mild model of predator scent-induced anxiety, we demonstrate long-lasting hippocampal elevation of miR-132, accompanied by and associated with reduced AChE activity. Using lentiviral-mediated suppression of "synaptic" AChE-S mRNA, we quantified footshock stress-inducible changes in miR-132 and AChE and its corresponding cognitive damages. Stressed mice showed long-lasting impairments in the Morris water maze. In contrast, pre-stress injected AChE-suppressing lentivirus, but not a control virus, reduced hippocampal levels of both miR-132 and AChE and maintained similar cognitive performance to that of naive, non-stressed mice. To dissociate between miR-132 and synaptic AChE-S as potential causes for stress-inducible cognitive deficits, we further used engineered TgR mice with enforced over-expression of the soluble "readthrough" AChE-R variant without the 3'-untranslated region binding site for miR-132. TgR mice displayed excess AChE-R in hippocampal neurons, enhanced c-fos labeling and correspondingly intensified reaction to the cholinergic agonist pilocarpine. They further showed excessive hippocampal expression of miR-132, accompanied by reduced host AChE-S mRNA and the GTPase activator p250GAP target of miR-132. At the behavioral level, TgR mice showed abnormal nocturnal locomotion patterns and serial maze mal-performance in spite of their reduced AChE-S levels. Our findings attribute stress-inducible cognitive impairments to cholinergic-mediated induction of miR-132 and consequently suppressed ACHE-S, opening venues for intercepting these miR-132-mediated damages.
164 citations
TL;DR: Two novel cytoarchitectonical areas, FG1 and FG2, were identified on the posterior fusiform gyrus of the human extrastriate cortex and comparison with recent functional imaging studies yielded that both areas are located within the object-related visual cortex.
Abstract: The human extrastriate visual cortex comprises numerous functionally defined areas, which are not identified in the widely used cytoarchitectonical map of Brodmann. The ventral part of the extrastriate cortex is particularly devoted to the identification of visual objects, faces and word forms. We analyzed the region immediately antero-lateral to hOc4v in serially sectioned (20 μm) and cell body-stained human brains using a quantitative observer-independent cytoarchitectonical approach to further identify the anatomical organization of the extrastriate cortex. Two novel cytoarchitectonical areas, FG1 and FG2, were identified on the posterior fusiform gyrus. The results of ten postmortem brains were then registered to their MRI volumes (acquired before histological processing), 3D reconstructed, and spatially normalized to the Montreal Neurological Institute reference brain. Finally, probabilistic maps were generated for each cytoarchitectonical area by superimposing the areas of the individual brains in the reference space. Comparison with recent functional imaging studies yielded that both areas are located within the object-related visual cortex. FG1 fills the gap between the retinotopically mapped area VO-1 and a posterior fusiform face patch. FG2 is probably the correlate of this face patch.
146 citations
TL;DR: Functional correlates of greater deactivation (LF > HF) in the same hippocampal regions in response to noxious stimulation was also accompanied by overall reduction in functional connectivity of the hippocampus with other brain regions involved in pain processing in the HF group, implicate involvement of hippocampus in the pathophysiology of the migraine.
Abstract: The hippocampus is classically involved in memory consolidation, spatial navigation and is involved in the stress response. Migraine is an episodic disorder characterized by intermittent attacks with a number of physiological and emotional stressors associated with or provoking each attack. Given that migraine attacks can be viewed as repeated stressors, alterations in hippocampal function and structure may play an important role in migraine pathophysiology. Using high-resolution magnetic resonance imaging, hippocampal morphometric and functional differences (in response to noxious heat stimulation) were compared in age and gender-matched acute episodic migraineurs with high (HF) versus low (LF) frequency of migraine attacks. Morphometric results were compared with age and gender-matched healthy control (HC) cohort. Significant larger bilateral hippocampal volume was found in LF group relative to the HF and HC groups suggestive of an initial adaptive plasticity that may then become dysfunctional with increased frequency. Functional correlates of greater deactivation (LF > HF) in the same hippocampal regions in response to noxious stimulation was also accompanied by overall reduction in functional connectivity of the hippocampus with other brain regions involved in pain processing in the HF group. The results implicate involvement of hippocampus in the pathophysiology of the migraine.
137 citations
TL;DR: These studies revealed that relatively low levels of transgenic miR-132 expression, paralleling the level of expression in the hippocampus following a spatial memory task, significantly enhanced cognitive capacity and inhibited learning, and indicated that miR -132 expression must be maintained within a limited range to ensure normal learning and memory formation.
Abstract: Within the central nervous system, microRNAs have emerged as important effectors of an array of developmental, physiological, and cognitive processes. Along these lines, the CREB-regulated microRNA miR-132 has been shown to influence neuronal maturation via its effects on dendritic arborization and spinogenesis. In the mature nervous system, dysregulation of miR-132 has been suggested to play a role in a number of neurocognitive disorders characterized by aberrant synaptogenesis. However, little is known about the inducible expression and function of miR-132 under normal physiological conditions in vivo. Here, we begin to explore this question within the context of learning and memory. Using in situ hybridization, we show that the presentation of a spatial memory task induced a significant ~1.5-fold increase in miR-132 expression within the CA1, CA3, and GCL excitatory cell layers of the hippocampus. To examine the role of miR-132 in hippocampal-dependent learning and memory, we employ a doxycycline-regulated miR-132 transgenic mouse strain to drive varying levels of transgenic miR-132 expression. These studies revealed that relatively low levels of transgenic miR-132 expression, paralleling the level of expression in the hippocampus following a spatial memory task, significantly enhanced cognitive capacity. In contrast, higher (supra-physiological) levels of miR-132 (>3-fold) inhibited learning. Interestingly, both the impaired cognition and elevated levels of dendritic spines resulting from supra-physiological levels of transgenic miR-132 were reversed by doxycycline suppression of transgene expression. Together, these data indicate that miR-132 functions as a key activity-dependent regulator of cognition, and that miR-132 expression must be maintained within a limited range to ensure normal learning and memory formation.
125 citations
TL;DR: The A10 region contains dopamine neurons with differential compartmentalization and unique signaling properties, and it is concluded that the majority of TH neurons lacking DAT are TH-VGluT2 neurons, and very few TH-only neurons express DAT without VMAT2.
Abstract: The A10 region contains different neurons: dopamine (expressing tyrosine hydroxylase; TH), GABA, glutamate-only (expressing the vesicular glutamate transporter 2; VGluT2), and TH-VGluT2 (coexpressing TH and VGluT2). We used three methods to investigate proteins necessary for the synthesis (aromatic l-amino acid decarboxylase, AADC) or transport (vesicular monoamine transporter; VMAT2 or dopamine transporter; DAT) of dopamine within TH neurons in the A10 region. By in situ hybridization–immunohistochemistry, we found that all TH neurons in the A10 region had AADC, but not all had VMAT2, DAT or D2 receptors (D2R). To determine whether TH-VGluT2 neurons account for TH neurons lacking these dopamine markers, we implemented an anatomical “mirror technique”, and found that not all TH-VGluT2 neurons lacked VMAT2, DAT or D2R. Next, by quantitative RT-PCR of individual micro-dissected TH neurons, we discovered two classes of TH-VGluT2 and three classes of TH-only neurons with different latero-medial distribution. Some of the TH-VGluT2 neurons had both VMAT2 and DAT (TH-VGluT2 Class 1); others lacked detectable levels of both transporters (TH-VGluT2 Class 2). Most of the TH-only neurons contained VMAT2 and DAT (TH-only Class 1), a few had DAT without detectable VMAT2 (TH-only Class 2), and others lacked detectable levels of both transporters (TH-only Class 3). We concluded that (a) the majority of TH neurons lacking DAT are TH-VGluT2 neurons, (b) very few TH-only neurons express DAT without VMAT2, and (c) TH-VGluT2 neurons lacking DAT also lack VMAT2. Thus, the A10 region contains dopamine neurons with differential compartmentalization and unique signaling properties.
114 citations
TL;DR: In this article, the authors used whole-brain voxel-based morphometry to first assess group differences in regional grey matter volume across age and then investigated the age-related changes of regional GM volumes.
Abstract: Results on grey matter (GM) structural alterations in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about age effects on brain-structure abnormalities in ASD beyond childhood. Here, we aimed to examine regional GM volumes in a large sample of children, adolescents, and adults with ASD. Magnetic resonance imaging scans were obtained in 47 male ASD subjects and 51 matched healthy controls aged 8-50 years. We used whole-brain voxel-based morphometry to first assess group differences in regional GM volume across age. Moreover, taking a cross-sectional approach, group differences in age effects on regional GM volume were investigated. Compared to controls, ASD subjects showed reduced GM volumes in the anterior cingulate cortex, posterior superior temporal sulcus, and middle temporal gyrus. Investigation of group differences in age effects on regional GM volume revealed complex, region-specific alterations in ASD. While GM volumes in the amygdala, temporoparietal junction, septal nucleus and middle cingulate cortex increased in a negative quadratic fashion in both groups, data indicated that GM volume curves in ASD subjects were shifted to the left along the age axis. Moreover, while GM volume in the right precentral gyrus decreased linearly with age in ASD individuals, GM volume development in controls followed a U-shaped pattern. Based on a large sample, our voxel-based morphometry results on group differences in regional GM volumes help to resolve inconclusive findings from previous studies in ASD. Results on age-related changes of regional GM volumes suggest that ASD is characterized by complex alterations in lifetime trajectories of several brain regions that underpin social-cognitive and motor functions.
112 citations
TL;DR: The results show that mPFC inhibitory networks are affected by chronic stress and suggest that structural plasticity may be an important feature of stress-related psychiatric disorders where this cortical region, specially their GABAergic system, is altered.
Abstract: Chronic stress in experimental animals induces dendritic atrophy and decreases spine density in principal neurons of the medial prefrontal cortex (mPFC) This structural plasticity may play a neuroprotective role and underlie stress-induced behavioral changes Different evidences indicate that the prefrontocortical GABA system is also altered by stress and in major depression patients In the amygdala, chronic stress induces dendritic remodeling both in principal neurons and in interneurons However, it is not known whether similar structural changes occur in mPFC interneurons The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these changes, because it is known to influence the dendritic organization of adult cortical interneurons We have analyzed the dendritic arborization and spine density of mPFC interneurons in adult mice after 21 days of restraint stress and have found dendritic hypertrophy in a subpopulation of interneurons identified mainly as Martinotti cells This aversive experience also decreases the number of glutamate decarboxylase enzyme, 67 kDa isoform (GAD67) expressing somata, without affecting different parameters related to apoptosis, but does not alter the number of interneurons expressing PSA-NCAM Quantitative retrotranscription-polymerase chain reaction (qRT-PCR) analysis of genes related to general and inhibitory neurotransmission and of PSA synthesizing enzymes reveals increases in the expression of NCAM, synaptophysin and GABA(A)α1 Together these results show that mPFC inhibitory networks are affected by chronic stress and suggest that structural plasticity may be an important feature of stress-related psychiatric disorders where this cortical region, specially their GABAergic system, is altered
TL;DR: A model in which multiple and parallel frontotemporal circuits between the cortex and the basal ganglia provide the anatomic substrate for supporting action-language processing is proposed and supported by both experimental and clinical evidence.
Abstract: Recent studies suggest that action-verb processing is particularly affected in early stage Parkinson’s disease (PD), highlighting the potential role of subcortical areas in language processing and in the semantic integration of actions. However, this disorder-related language impairment is frequently unrecognized by clinicians and often remains untreated. Early detection of action-language processing deficits could be critical for diagnosing and developing treatment strategies for PD. In this article, we review how action-verb processing is affected in PD and propose a model in which multiple and parallel frontotemporal circuits between the cortex and the basal ganglia provide the anatomic substrate for supporting action-language processing. We hypothesize that contextual coupling of action-language networks are partially dependent on cortical–subcortical integration, and not only on somatotopic motor cortical organization or in a mirror neuron system. This hypothesis is supported by both experimental and clinical evidence. Then, we identify further research steps that would help to determine the reliability of action-language impairments as an early marker of PD. Finally, theoretical implications for clinical assessment and for models of action-language interaction (action–perception cycle theories, mirror system models of language, and embodied cognition approaches to language) are discussed.
TL;DR: It is held that a developmental point of view considering rhombomeres may explain observed differences in connectivity and function, and the reclassification of raphe nuclei may be useful for causal analysis of their differential molecular specification, as well as for studies of differential connectivity andfunction.
Abstract: The raphe nuclei represent the origin of central serotonergic projections. The literature distinguishes seven nuclei grouped into rostral and caudal clusters relative to the pons. The boundaries of these nuclei have not been defined precisely enough, particularly with regard to developmental units, notably hindbrain rhombomeres. We hold that a developmental point of view considering rhombomeres may explain observed differences in connectivity and function. There are twelve rhombomeres characterized by particular genetic profiles, and each develops between one and four distinct serotonergic populations. We have studied the distribution of the conventional seven raphe nuclei among these twelve units. To this aim, we correlated 5-HT-immunoreacted neurons with rhombomeric boundary landmarks in sagittal mouse brain sections at different developmental stages. Furthermore, we performed a partial genoarchitectonic analysis of the developing raphe nuclei, mapping all known serotonergic differentiation markers, and compared these results, jointly with others found in the literature, with our map of serotonin-containing populations, in order to examine regional variations in correspondence. Examples of regionally selective gene patterns were identified. As a result, we produced a rhombomeric classification of some 45 serotonergic populations, and suggested a corresponding modified terminology. Only a minor rostral part of the dorsal raphe nucleus lies in the midbrain. Some serotonergic neurons were found in rhombomere 4, contrary to the conventional assumption that it lacks such neurons. We expect that our reclassification of raphe nuclei may be useful for causal analysis of their differential molecular specification, as well as for studies of differential connectivity and function.
TL;DR: It is suggested that the cortical connections of the MdLF in humans appear to go beyond the superior temporal (STG) and angular (AG) gyri, and might be related to language, high order auditory association, visuospatial and attention functions.
Abstract: Based on high-resolution diffusion tensor magnetic resonance imaging (DTI) tractographic analyses in 39 healthy adult subjects, we derived patterns of connections and measures of volume and biophysical parameters, such as fractional anisotropy (FA) for the human middle longitudinal fascicle (MdLF). Compared to previous studies, we found that the cortical connections of the MdLF in humans appear to go beyond the superior temporal (STG) and angular (AG) gyri, extending to the temporal pole (TP), superior parietal lobule (SPL), supramarginal gyrus, precuneus and the occipital lobe (including the cuneus and lateral occipital areas). Importantly, the MdLF showed a striking lateralized pattern with predominant connections between the TP, STG and AG on the left and TP, STG and SPL on the right hemisphere. In light of the results of the present study, and of the known functional role of the cortical areas interconnected by the MdLF, we suggested that this fiber pathway might be related to language, high order auditory association, visuospatial and attention functions.
TL;DR: The present study demonstrates the presence of major RAS components in dopaminergic neurons, astrocytes and microglia in both the monkey and the human SNc and suggests a major role for the nigral RAS in the normal functioning of the dopamine neurons, and in the progression of the Parkinson’s disease progression.
Abstract: We have previously obtained in rodents a considerable amount of data suggesting a major role for the brain renin–angiotensin system (RAS) in dopaminergic neuron degeneration and potentially in Parkinson’s disease. However, the presence of a local RAS has not been demonstrated in the monkey or the human substantia nigra compacta (SNc). The present study demonstrates the presence of major RAS components in dopaminergic neurons, astrocytes and microglia in both the monkey and the human SNc. Angiotensin type 1 and 2 and renin–prorenin receptors were located at the surface of dopaminergic neurons and glial cells, as expected for a tissular RAS. However, angiotensinogen and receptors for angiotensin and renin–prorenin were also observed at the cytoplasm and nuclear level, which suggests the presence of an intracrine or intracellular RAS in monkey and human SNc. Although astrocytes and microglia were labeled for angiotensin and prorenin receptors in the normal SNc, most glial cells appeared less immunoreactive than the dopaminergic neurons. However, our previous studies in rodent models of PD and studies in other animal models of brain diseases suggest that the RAS activity is significantly upregulated in glial cells in pathological conditions. The present results together with our previous findings in rodents suggest a major role for the nigral RAS in the normal functioning of the dopaminergic neurons, and in the progression of the dopaminergic degeneration.
TL;DR: The observed connections of regions involved in memory for object location and identity clearly demonstrate a distinction into separate pathways that resemble the parietal connectivity patterns of the dorsal and ventral premotor cortex in non-human primates and humans.
Abstract: In a previous meta-analysis across almost 200 neuroimaging experiments, working memory for object location showed significantly stronger convergence on the posterior superior frontal gyrus, whereas working memory for identity showed stronger convergence on the posterior inferior frontal gyrus (dorsal to, but overlapping with Brodmann's area BA 44). As similar locations have been discussed as part of a dorsal frontal-superior parietal reach system and an inferior frontal grasp system, the aim of the present study was to test whether the regions of working-memory related "what" and "where" processing show a similar distinction in parietal connectivity. The regions that were found in the previous meta-analysis were used as seeds for functional connectivity analyses using task-based meta-analytic connectivity modelling and task-independent resting state correlations. While the ventral seed showed significantly stronger connectivity with the bilateral intraparietal sulcus (IPS), the dorsal seed showed stronger connectivity with the bilateral posterior inferior parietal and the medial superior parietal lobule. The observed connections of regions involved in memory for object location and identity thus clearly demonstrate a distinction into separate pathways that resemble the parietal connectivity patterns of the dorsal and ventral premotor cortex in non-human primates and humans. It may hence be speculated that memory for a particular location and reaching towards it as well as object memory and finger positioning for manipulation may rely on shared neural systems. Moreover, the ensuing regions, in turn, featured differential connectivity with the bilateral ventral and dorsal extrastriate cortex, suggesting largely segregated bilateral connectivity pathways from the dorsal visual cortex via the superior and inferior parietal lobules to the dorsal posterior frontal cortex and from the ventral visual cortex via the IPS to the ventral posterior frontal cortex that may underlie action and cognition.
TL;DR: The results support the notion that the role of the auditory cortex in tinnitus is not restricted to perceptual aspects, and the distress observed was dependent on grey matter alterations in the auditory cortical areas, which could reflect reverberations between perceptual and distress networks.
Abstract: Neuroimaging studies of tinnitus suggest the involvement of wide-spread neural networks for perceptual, attentional, memory, and emotional processes encompassing auditory, frontal, parietal, and limbic areas. Despite sparse findings for tinnitus duration and laterality, tinnitus distress has been shown to be related to changes in non-auditory cortical areas. The aim of this study was to correlate tinnitus characteristics with grey matter volume in two large samples of tinnitus patients. High-resolution brain images were obtained using a 1.5 T magnetic resonance imaging scanner and analysed by means of voxel-based morphometry. In sample one (n = 257), tinnitus distress correlated negatively with grey matter volume in bilateral auditory areas including the Heschl's gyrus and insula, that is, the higher the tinnitus distress the lower the grey matter volume. The effects of this correlation were small, but stable after correction for potential confounders such as age, gender, and audiometric parameters. This negative correlation was replicated in a second independent sample (n = 78). Our results support the notion that the role of the auditory cortex in tinnitus is not restricted to perceptual aspects. The distress observed was dependent on grey matter alterations in the auditory cortex, which could reflect reverberations between perceptual and distress networks.
TL;DR: It is suggested that brain structures involving OFC, together with other regions, contribute to the maintenance of effective EFEEs among non-clinical subjects.
Abstract: Executive functions involve control processes such as goal-oriented planning, flexible strategy generation, sustaining set maintenance, self-monitoring, and inhibition. Executive functions during everyday events (EFEEs) are distinct from those measured under laboratory settings; the former can be severely impaired while the latter remain intact. Non-routine everyday problems due to executive dysfunctions affect individual functioning in everyday life and are of great clinical interest. Despite the importance of anatomical bases underlying better EFEEs, such bases have never been investigated among non-clinical samples. Using voxel-based morphometry to measure regional gray matter volume (rGMV) and regional white matter volume (rWMV) and diffusion tensor imaging to determine fractional anisotropy values, we identified the anatomical correlates of better EFEEs using the Dysexecutive Questionnaire in 303 normal young subjects (168 men and 135 women). Better EFEEs were associated with a smaller rGMV in the orbitofrontal cortex (OFC) spread across Brodmann areas (BA) 25, 11, and 12 and larger rWMV in the WM area of OFC adjacent to BA 11. Furthermore, individual EFEEs were positively associated with rWMV in the temporal areas, primarily the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus, the latter of which connects OFC and posterior regions. Thus, our findings suggest that brain structures involving OFC, together with other regions, contribute to the maintenance of effective EFEEs among non-clinical subjects.
TL;DR: Based on their location and neighborhood relationship, areas hOC3d and hOc4d are putative anatomical substrates of functionally defined areas V3dand V3a, a hypothesis that can now be tested by comparing probabilistic cytoarchitectonic maps and activation studies of the living human brain.
Abstract: The dorsal visual stream consists of several functionally specialized areas, but most of their cytoarchitectonic correlates have not yet been identified in the human brain. The cortex adjacent to Brodmann area 18/V2 was therefore analyzed in serial sections of ten human post-mortem brains using morphometrical and multivariate statistical analyses for the definition of areal borders. Two previously unknown cytoarchitectonic areas (hOc3d, hOc4d) were detected. They occupy the medial and, to a smaller extent, lateral surface of the occipital lobe. The larger area, hOc3d, is located dorso-lateral to area V2 in the region of superior and transverse occipital, as well as parieto-occipital sulci. Area hOc4d was identified rostral to hOc3d; it differed from the latter by larger pyramidal cells in lower layer III, thinner layers V and VI, and a sharp cortex-white-matter borderline. The delineated areas were superimposed in the anatomical MNI space, and probabilistic maps were calculated. They show a relatively high intersubject variability in volume and position. Based on their location and neighborhood relationship, areas hOc3d and hOc4d are putative anatomical substrates of functionally defined areas V3d and V3a, a hypothesis that can now be tested by comparing probabilistic cytoarchitectonic maps and activation studies of the living human brain.
TL;DR: The demonstrated similarities and differences in inputs to CEAm and BSTvl provide new anatomical insights into the functional organization of these limbic forebrain regions.
Abstract: The central nucleus of the amygdala (CEA) and lateral bed nucleus of stria terminalis (BST) are highly interconnected limbic forebrain regions that share similar connectivity with other brain regions that coordinate behavioral and physiological responses to internal and environmental stressors. Their similar connectivity is frequently referred to when describing the CEA and lateral BST together as a unified “central extended amygdala”. However, the CEA and BST reportedly play distinct roles in behavioral and physiological responses associated with fear, anxiety, and social defeat, presumably due to differences in connectivity. To identify common and unique sources of input to the CEA and lateral BST, we performed dual retrograde tracing. Fluorogold and cholera toxin β were iontophoresed into the medial CEA (CEAm) and the anterior ventrolateral BST (BSTvl) of adult male rats. The anatomical distribution of tracer-labeled neurons was mapped throughout the brain. Regions with overlapping populations of CEAm- and BSTvl-projecting neurons were further examined for the presence of double-labeled neurons. Although most regions with input to the mCEA also projected to the BSTvl, and vice versa, cortical and sensory system-related regions projected more robustly to the CEAm, while motor system-related regions primarily innervated the BSTvl. The incidence of double-labeled neurons with collateralized axonal inputs to the CEAm and BSTvl was relatively small (~2 to 13%) and varied across regions, suggesting regional differences in the degree of coordinated CEAm and BSTvl input. The demonstrated similarities and differences in inputs to CEAm and BSTvl provide new anatomical insights into the functional organization of these limbic forebrain regions.
TL;DR: Even without significant postnatal medical sequelae, very preterm-born children showed atypical brain structure and developmental patterns in areas related to higher cognitive function, likely due to disruptions of the typical neurodevelopmental trajectory in the third trimester of pregnancy.
Abstract: Individuals born preterm can demonstrate reductions in brain volume, cortical surface area and thickness. However, the extent of these neuroanatomical deficits and the relation among these measures in middle childhood, a critical developmental period, have not been determined. We assessed differences in brain structure by acquiring high-resolution T(1)-weighted scans in 25 children born very preterm (<32 weeks gestational age) without significant post-natal neurological sequelae and 32 age-matched term-born children (7-10 years). Children born very preterm had decreased brain volume, surface area and cortical thickness compared to term-born children. Furthermore, children born preterm did not display the robust relation between total brain volume and basal ganglia and thalamic volume apparent in the term-born children. Cortical thickness analyses revealed that the cortex was thinner for children born preterm than term-born children in the anterior cingulate cortex/supplementary motor area, isthmus of the cingulate gyrus, right superior temporal sulcus, right anterior insula, postcentral gyrus and precuneus. Follow-up analyses revealed that right precuneus thickness was correlated with gestational age. Thus, even without significant postnatal medical sequelae, very preterm-born children showed atypical brain structure and developmental patterns in areas related to higher cognitive function. Disruptions of the typical neurodevelopmental trajectory in the third trimester of pregnancy likely underlie these differences persisting into middle childhood.
TL;DR: A topographically organized neural network implicated in processes such as reward, motivation and cognitive control over behaviour, which mediates social play behaviour in rats is outlined.
Abstract: Positive social interactions during the juvenile and adolescent phases of life are essential for proper social and cognitive development in mammals, including humans. During this developmental period, there is a marked increase in peer-peer interactions, signified by the abundance of social play behaviour. Despite its importance for behavioural development, our knowledge of the neural underpinnings of social play behaviour is limited. Therefore, the purpose of this study was to map the neural circuits involved in social play behaviour in rats. This was achieved by examining cellular activity after social play using the immediate early gene c-Fos as a marker. After a session of social play behaviour, pronounced increases in c-Fos expression were observed in the medial prefrontal cortex, medial and ventral orbitofrontal cortex, dorsal striatum, nucleus accumbens core and shell, lateral amygdala, several thalamic nuclei, dorsal raphe and the pedunculopontine tegmental nucleus. Importantly, the cellular activity patterns after social play were topographically organized in this network, as indicated by play-specific correlations in c-Fos activity between regions with known direct connections. These correlations suggest involvement in social play behaviour of the projections from the medial prefrontal cortex to the striatum, and of amygdala and monoaminergic inputs to frontal cortex and striatum. The analyses presented here outline a topographically organized neural network implicated in processes such as reward, motivation and cognitive control over behaviour, which mediates social play behaviour in rats.
TL;DR: The results show that cortical areas containing VENs form a network of frontoparietal functional connectivity that is primarily involved in functions of saliency detection and self-regulation.
Abstract: Von Economo's neurons (VENs) are large, bipolar or corkscrew-shaped neurons located in layers III and V of the frontoinsular and the anterior cingulate cortices. VENs are reported to be altered in pathologies such as frontotemporal dementia and autism, in which the individual's self control is seriously compromised. To investigate the role of VENs in the active human brain, we have explored the functional connectivity of brain areas containing VENs by analyzing resting state functional connectivity (rsFC) in 20 healthy volunteers. Our results show that cortical areas containing VENs form a network of frontoparietal functional connectivity. With the use of fuzzy clustering techniques, we find that this network comprises four sub-networks: the first network cluster resembles a "saliency detection" attentional network, which includes superior frontal cortex (Brodmann's Area, BA 10), inferior parietal lobe, anterior insula, and dorsal anterior cingulate cortex; the second cluster, part of a "sensory-motor network", comprises the superior temporal, precentral and postcentral areas; the third cluster consists of frontal ventromedial and ventrodorsal areas constituted by parts of the "anterior default mode network"; and the fourth cluster encompasses dorsal anterior cingulate cortex, dorsomedial prefrontal, and superior frontal (BA 10) areas, resembling the anterior part of the "dorsal attentional network". Thus, the network that emerges from analyzing functional connectivity among areas that are known to contain VENs is primarily involved in functions of saliency detection and self-regulation. In addition, parts of this network constitute sub-networks that partially overlap with the default mode, the sensory-motor and the dorsal attentional networks.
TL;DR: The results showed that, on average, microglia densities were highest in the cortex, followed by the limbic area, basal nuclei, diencephalon, brainstem and cerebellum, while the substantia nigra had the highest microglian density.
Abstract: Upon certain stimuli, microglia undergo different degrees of transformation in order to maintain homeostasis of the CNS. However, chronic microglia activation has been suggested to play an active role in the pathogenesis of neurodegenerative diseases. The density of microglia and the degree of microglia activation vary among brain regions; such differences may underlie the brain region-specific characteristics of neurodegenerative diseases. In this study, we aim to characterize the temporal and spatial profiles of microglia activation induced by peripheral inflammation in male C57BL/6J mice. Our results showed that, on average, microglia densities were highest in the cortex, followed by the limbic area, basal nuclei, diencephalon, brainstem and cerebellum. Among the 22 examined brain nuclei/regions, the substantia nigra had the highest microglia density. Microglia morphological changes were evident within 3 h after a single intraperitoneal lipopolysaccharides injection, with the highest degree of changes also in the substantia nigra. The lipopolysaccharide-induced microglia activation, determined by maximal cell size, was positively correlated with density of microglia and levels of TNFα receptor 1; it was not correlated with original microglia cell size or integrity of blood-brain barrier. The differential response of microglia also cannot be explained by different types of neurotransmitters. Our works suggest that the high density of microglia and the high levels of TNFα receptor 1 in the substantia nigra make this brain region the most susceptible area to systemic immunological insults.
TL;DR: Investigation of white matter fibre integrity using diffusion tensor imaging revealed reduced fractional anisotropy in the superior longitudinal fasciculus in children with developmental dyscalculia, and raised the question of whether dyscalculated can be seen as a dysconnection syndrome.
Abstract: Numerical understanding is important for everyday life. For children with developmental dyscalculia (DD), numbers and magnitudes present profound problems which are thought to be based upon neuronal impairments of key regions for numerical understanding. The aim of the present study was to investigate possible differences in white matter fibre integrity between children with DD and controls using diffusion tensor imaging. White matter integrity and behavioural measures were evaluated in 15 children with developmental dyscalculia aged around 10 years and 15 matched controls. The main finding, obtained by a whole brain group comparison, revealed reduced fractional anisotropy in the superior longitudinal fasciculus in children with developmental dyscalculia. In addition, a region of interest analysis exhibited prominent deficits in fibres of the superior longitudinal fasciculus adjacent to the intraparietal sulcus, which is thought to be the core region for number processing. To conclude, our results outline deficient fibre projection between parietal, temporal and frontal regions in children with developmental dyscalculia, and therefore raise the question of whether dyscalculia can be seen as a dysconnection syndrome. Since the superior longitudinal fasciculus is involved in the integration and control of distributed brain processes, the present results highlight the importance of considering broader domain-general mechanisms in the diagnosis and therapy of dyscalculia.
TL;DR: Collateralization patterns of individual axons from VPm, VPl and the rostral extension of VP into the olfactory tubercle are investigated, confirming at the single axon level the parallel organization of functionally different basal ganglia loops.
Abstract: The ventral pallidum (VP) is a key component of the cortico-basal ganglia circuits that process motivational and emotional information, and also a crucial site for reward. Although the main targets of the two VP compartments, medial (VPm) and lateral (VPl) have already been established, the collateralization patterns of individual axons have not previously been investigated. Here we have fully traced eighty-four axons from VPm, VPl and the rostral extension of VP into the olfactory tubercle (VPr), using the anterograde tracer biotinylated dextran amine in the rat. Thirty to fifty percent of axons originating from VPm and VPr collateralized in the mediodorsal thalamic nucleus and lateral habenula, indicating a close association between the ventral basal ganglia-thalamo-cortical loop and the reward network at the single axon level. Additional collateralization of these axons in diverse components of the extended amygdala and corticopetal system supports a multisystem integration that may take place at the basal forebrain. Remarkably, we did not find evidence for a sharp segregation in the targets of axons arising from the two VP compartments, as VPl axons frequently collateralized in the caudal lateral hypothalamus and ventral tegmental area, the well-known targets of VPm, while VPm axons, in turn, also collateralized in typical VPl targets such as the subthalamic nucleus, substantia nigra pars compacta and reticulata, and retrorubral field. Nevertheless, VPl and VPm displayed collateralization patterns that paralleled those of dorsal pallidal components, confirming at the single axon level the parallel organization of functionally different basal ganglia loops.
TL;DR: It is suggested that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations.
Abstract: Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high-resolution T1-weighted structural scan and a 5-min perfusion fMRI scan (a measurement of blood flow), before and after administration of an acute pharmacological manipulation. In a within-subject design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 min before acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra within SPM7, we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM ‘gray matter’ signal in the dorsal rostral anterior cingulate (family wise error corrected at p < 0.04, T = 6.54, extent: 1,460 voxels) that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.
TL;DR: The results indicate that white matter integrity may not stabilize in bilinguals until late adulthood, and advance the understanding of the underlying cortical networks associated with language status and reading skill in monolingual and bilingual adults.
Abstract: Recent studies using diffusion tensor imaging (DTI) have described overall white matter integrity in bilinguals but have not related structural neural pathways to language functions. The current study examined white matter integrity and its relationship to reading skill in monolingual English and bilingual Chinese-English speakers. Eleven monolingual speakers (mean age 28.5 years) and 13 bilingual speakers (mean age 24.2 years; English as a second language was acquired post 5 years of age) participated. Behavioural response times and accuracy rates to name regular and exception words were recorded. Participants were then scanned using a standardized DTI protocol. Fractional anisotropy (FA) and mean diffusivity values were derived from a voxelwise statistical analysis for comparisons between participant groups. Tests for relationships between response time and FA were also conducted. Our results show minimal regions of higher FA for monolinguals when compared to bilinguals and no regions of higher FA for bilinguals when compared to monolinguals, which indicates that white matter integrity may not stabilize in bilinguals until late adulthood. We do show several regions where an increase in FA is associated with faster response times. Interestingly, the FA-response time relationship varies between groups and between word types, which may reflect an increased processing demand for retrieval of difficult words (e.g., exception words). These results provide some support for the interference control and reduced frequency hypotheses outlined by Jones et al. (Cerebr Cortex 22:892-902, 2012). The current findings advance our understanding of the underlying cortical networks associated with language status and reading skill in monolingual and bilingual adults.
TL;DR: The findings show that restricted cortical thinning occurs in RRMS patients with mild disease and that LH superior temporal gyrus atrophy is associated with cognitive dysfunction.
Abstract: Decreased cortical thickness that signifies gray matter pathology and its impact on cognitive performance is a research field with growing interest in relapsing–remitting multiple sclerosis (RRMS) and needs to be further elucidated. Using high-field 3.0 T MRI, three-dimensional T1-FSPGR (voxel size 1 × 1 × 1 mm) cortical thickness was measured in 82 regions in the left hemisphere (LH) and right hemisphere (RH) in 20 RRMS patients with low disease activity and in 20 age-matched healthy subjects that in parallel underwent comprehensive cognitive evaluation. The correlation between local cortical atrophy and cognitive performance was examined. We identified seven regions with cortical tissue loss that differed between RRMS and age-matched healthy controls. These regions were mainly located in the frontal and temporal lobes, specifically within the gyrus rectus, inferior frontal sulcus, orbital gyrus, parahippocampal gyrus, and superior temporal gyrus, with preferential left asymmetry. Increased cortical thickness was identified in two visual sensory regions, the LH inferior occipital gyrus, and the RH cuneus, implicating adaptive plasticity. Correlation analysis demonstrated that only the LH superior temporal gyrus thickness was associated with cognitive performance and its thickness correlated with motor skills (r = 0.65, p = 0.003), attention (r = 0.45, p = 0.042), and information processing speed (r = 0.50, p = 0.025). Our findings show that restricted cortical thinning occurs in RRMS patients with mild disease and that LH superior temporal gyrus atrophy is associated with cognitive dysfunction.
TL;DR: This study searched for age-dependent changes in the number of cells that compose the CNS and the pituitary gland in 4–40-week-old C57BL6 mice and found that all CNS structures, except for the isocortex, increased in mass in the period of 4–15 weeks.
Abstract: The process of development, maturation, and regression in the central nervous system (CNS) are genetically programmed and influenced by environment. Hitherto, most research efforts have focused on either the early development of the CNS or the late changes associated with aging, whereas an important period corresponding to adolescence has been overlooked. In this study, we searched for age-dependent changes in the number of cells that compose the CNS (divided into isocortex, hippocampus, olfactory bulb, cerebellum, ‘rest of the brain’, and spinal cord) and the pituitary gland in 4–40-week-old C57BL6 mice, using the isotropic fractionator method in combination with neuronal nuclear protein as a marker for neuronal cells. We found that all CNS structures, except for the isocortex, increased in mass in the period of 4–15 weeks. Over the same period, the absolute number of neurons significantly increased in the olfactory bulb and cerebellum while non-neuronal cell numbers increased in the ‘rest of the brain’ and isocortex. Along with the gain in body length and weight, the pituitary gland also increased in mass and cell number, the latter correlating well with changes of the brain and spinal cord mass. The majority of the age-dependent alterations (e.g., somatic parameters, relative brain mass, number of pituitary cells, and cellular composition of the cerebellum, isocortex, rest of the brain, and spinal cord) occur rapidly between the 4th and 11th postnatal weeks. This period includes murine adolescence, underscoring the significance of this stage in the postnatal development of the mouse CNS.