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

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

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

The macaque brain serves as a model for the human brain, but its suitability is challenged by unique human features, including connectivity reconfigurations, which emerged during primate evolution. We perform a quantitative comparative analysis of the whole brain macroscale structural connectivity of the two species. Our findings suggest that the human and macaque brain as a whole are similarly wired. A region-wise analysis reveals many interspecies similarities of connectivity patterns, but also lack thereof, primarily involving cingulate regions. We unravel a common structural backbone in both species involving a highly overlapping set of regions. This structural backbone, important for mediating information across the brain, seems to constitute a feature of the primate brain persevering evolution. Our findings illustrate novel evolutionary aspects at the macroscale connectivity level and offer a quantitative translational bridge between macaque and human research.

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

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

Extraordinary neoteny of synaptic spines in the human prefrontal cortex.

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

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

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

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

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

Atrophy of the parietal lobe in preclinical dementia.

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

Glutamine synthetase deficiency in murine astrocytes results in neonatal death.

Glutamine synthetase (GS) is a key enzyme in the "glutamine-glutamate cycle" between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GS(fl/lacZ) or GS(fl/fl) mice with hGFAP-Cre mice resulted in prenatal excision of the GS(fl) allele in astrocytes. "GS-KO/A" mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14-fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6-fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS-KO/A mice. The temporal dissociation between GS(fl) elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS-deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine-glutamate and the associated alanine-lactate cycles.

The major symptom dimensions of obsessive-compulsive disorder are mediated by partially distinct neural systems.

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous disorder characterized by multiple, temporally stable symptom dimensions. Preliminary functional neuroimaging studies suggest that these symptom dimensions may have distinct neural substrates. Whole-brain voxel-based morphometry was used to examine the common and distinct neuroanatomical (structural) substrates of the major symptom dimensions of OCD. First, we compared 55 medication-free patients with OCD and 50 age-matched healthy control subjects. Multiple regression analyses were then used to examine the relationship between global and regional grey matter (GM) and white matter (WM) volumes and symptom dimension scores within the patient group. OCD patients showed decreased GM volume in left lateral orbitofrontal (BA47), left inferior frontal (BA44/45), left dorsolateral prefrontal (BA9) and right medial prefrontal (BA10) cortices and decreased bilateral prefrontal WM volume. Scores on the 'symmetry/ordering' dimension were negatively correlated with 'global' GM and WM volumes. Scores on the 'contamination/washing' dimension were negatively correlated with 'regional' GM volume in bilateral caudate nucleus and WM volume in right parietal region. Scores on the 'harm/checking' dimension were negatively correlated with regional GM and WM volume in bilateral temporal lobes. Scores on the 'symmetry/ordering' dimension were negatively correlated with regional GM volume in right motor cortex, left insula and left parietal cortex and positively correlated with bilateral temporal GM and WM volume. The results remained significant after controlling for age, sex, educational level, overall illness severity, global WM and GM volumes and excluding patients with comorbid depression. The reported symptom dimension-specific GM and WM alterations support the hypothesis that OCD is an etiologically heterogeneous disorder, with both overlapping and distinct neural correlates across symptom dimensions. These results have clear implications for the current neuroanatomical model of OCD and call for a substantial revision of such model which takes into account the heterogeneity of the disorder.

3-D cytoarchitectonic parcellation of human orbitofrontal cortex correlation with postmortem MRI.

The orbitofrontal cortex (OFC) is located on the basal surface of the frontal lobe and is distinguished by its unique anatomical and functional features. Clinical and postmortem studies suggest the involvement of the orbitofrontal cortex in psychiatric disorders. However, the exact parcellation of this cortical region is still a matter of debate. Therefore, the goal of this study is to provide a detailed description of the extent of borders of individual orbitofrontal cortical areas using cytoarchitectonic criteria in a large sample of human brains, which could be applied by independent neuroanatomists. To make this microscopic parcellation useful to neuroimaging studies, magnetic resonance images of postmortem brains in the coronal plane were collected prior to the preparation of coronal histological sections from the same brains. A complete series of coronal sections from 6 normal human brains and partial sections from the frontal cortex of 21 normal human brains were stained with general histological and immunohistochemical methods specific for different cell-types. These sections were examined microscopically by two independent neuroanatomists (HBMU and GR) to achieve reproducible delineations. After the borders were determined, the tissue sections were superimposed on the corresponding magnetic resonance images. Based on our cytoarchitectonical criteria, Brodmann's areas 47 and 11 were included in the human orbitofrontal cortex. Area 47 was further subdivided into three medial (located on the medial, anterior and posterior orbital gyri) and two lateral (located on the lateral orbital gyrus) subareas. In addition, we observed an anterior-posterior gradient in the cytoarchitecture of areas 11 and 47. The transverse orbital sulcus corresponds roughly to the transition between the subregions of the anterior and posterior OFC. Finally, the present delineation is contrasted with an overview of the different published nomenclatures for the OFC parcellation.

A time-saving and facilitating approach for segmentation of anatomically defined cortical regions: MRI volumetry.

In this study, we present an accurate, reliable, robust, and time-efficient technique for a semi-automatic segmentation of neuroanatomically defined cortical structures in Magnetic Resonance Imaging (MRI) scans. It involves manual drawing of the border of a region of interest (ROI), supported by three-dimensional (3D) visualization techniques (rendering), and a subsequent automatic tracing of the gray matter voxels inside the ROI by means of an automatic tissue classifier. The approach has been evaluated on a set of MRI scans of 75 participants selected from the Maastricht Aging Study (MAAS) and applied to cortical brain structures for both the left and right hemispheres, viz., the inferior prefrontal cortex (PFC); the orbital PFC; the dorsolateral PFC; the anterior cingulate cortex; and the posterior cingulate cortex. The use of a 3D surface-rendered brain can be rotated in any direction was invaluable in identifying anatomical landmarks on the basis of gyral and sulcal topography. This resulted in a high accuracy (anatomical correctness) and reliability: the intra-rater intra-class correlation coefficient (ICC) was between 0.96 and 0.99. Furthermore, the obtained time savings were substantial, i.e., up to a factor of 7.5 compared with fully manual segmentations.

The prevalence of cortical gray matter atrophy may be overestimated in the healthy aging brain.

Prevailing opinion holds that normal brain aging is characterized by substantial atrophy of cortical gray matter. However, this conclusion is based on earlier studies whose findings may be influenced by the inclusion of subjects with subclinical cognitive disorders like preclinical dementia. The present magnetic resonance imaging study tested this hypothesis. Cognitively healthy subjects (mean age 72 years, range 52-82) who remained cognitively stable over a 3-year period were compared to subjects with significant cognitive decline. Subjects who developed dementia within 6 years after the scan session were excluded. The gray matter volumes of seven cortical regions were delineated on T1-weighted magnetic resonance imaging scans. Participants without cognitive decline did not exhibit an age effect on the gray matter volume. Conversely, participants with cognitive decline exhibited a significant age effect in all the seven areas. These results suggest that cortical gray matter atrophy may have been overestimated in studies on healthy aging, since most studies were unable to exclude participants with a substantial atypical cognitive decline or preclinical dementia. Our results underscore the importance of establishing stringent inclusion criteria for future studies on normal aging.

Lifespan alterations of basal dendritic trees of pyramidal neurons in the human prefrontal cortex: a layer-specific pattern.

The postnatal development and lifespan alterations in basal dendrites of large layer IIIC and layer V pyramidal neurons were quantitatively studied. Both classes of neurons were characterized by rapid dendritic growth during the first postnatal months. At birth, layer V pyramidal neurons had larger and more complex dendritic trees than those of layer IIIC; however, at 1 postnatal month both classes of neurons displayed a similar extent of dendritic outgrowth. In addition, after a more than year-long "dormant" period of only fine dendritic rearrangement, layer IIIC pyramidal neurons displayed a second period of dendritic growth, starting at the end of the second year and continuing in the third year. During that period, the dendritic tree of layer IIIC pyramidal neurons became more extensive than that of layer V pyramidal neurons. Thus, layer IIIC pyramidal neurons appear to show a biphasic pattern of postnatal dendritic development. Furthermore, the childhood period was characterized by transient increase in size of pyramidal cell somata, which was more pronounced for neurons in layer IIIC. These structural changes occurred during both the period of rapid cognitive development in preschool children and the period of protracted cognitive maturation during the childhood, puberty, and adolescence.

Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson's disease patients.

Gender differences in dopaminergic related neurodegenerative diseases have hardly been studied until now. It is generally accepted that more men than women suffer from Parkinson's disease. One of the most prevalent symptoms in Parkinson's patients, hyposmia, does not show gender differences, while normally the sense of smell is better developed in females. Whether the change in dopamine in the olfactory bulb contributes equally to hyposmia in male and female Parkinson's patients is the subject of the present study. In a stereological study the total number of tyrosine hydroxylase immunoreactive neurons in the olfactory bulbs of male and female Parkinson's patients and age-matched controls has been estimated. The present stereological study shows that the number of tyrosine hydroxylase positive cells in control females is significantly lower than those in control males. The number of dopaminergic cells in the olfactory bulbs of both male and female Parkinson's patients equals that of healthy males of the same age group. We therefore conclude that the hyposmia in Parkinson's disease patients cannot simply be ascribed to dopamine in the olfactory bulb.

The orbital cortex in rats topographically projects to central parts of the caudate-putamen complex.

Disturbances of the orbitofrontal-striatal pathways in humans have been associated with several psychopathologies including obsessive-compulsive disorder and drug addiction. In nonhuman primates, different subareas of the orbitofrontal cortex project topographically to central and ventromedial parts of the striatum. Relatively little is known about the anatomical organization of the rat orbital cortex while there is a growing interest in this cortical area from a functional and behavioral point of view. The aim of the present neuroanatomical tracing study was to determine in rats the striatal target area of the projections of the orbital cortex as well as the topographical organization within these projections. To this end, anterograde tracers were injected in the different cytoarchitectonically distinct subareas of the orbital cortex. The results show that the individual orbital areas, i.e. medial orbital area, ventral orbital area, ventrolateral orbital area and lateral orbital area, project to central parts of the caudate-putamen, exhibiting a mediolateral and, to a lesser degree, rostrocaudal topographical arrangement. Orbital projections avoid the most dorsal, as well as rostral and caudal parts of the caudate-putamen. Terminal fields from cytoarchitectonically different areas show a considerable overlap. Superficial cortical layers project preferentially to the striatal matrix, deep layers to the patch compartment. The projections from the ventrolateral orbital area are strongest and occupy the most extensive striatal area. In addition to projections to the caudate-putamen, the ventrolateral, lateral and dorsolateral orbital areas have a scarce projection to the most lateral part of the nucleus accumbens shell in the ventral striatum. In contrast to nonhuman primates, the remainder of the rat nucleus accumbens is virtually free of orbital projections.

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

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

Medial prefrontal serotonin in the rat is involved in goal-directed behaviour when affect guides decision making.

RATIONALE: Across species, serotonin (5-HT) depletion in the prefrontal cortex (PFC) has been shown to cause impaired performance on tests of cognitive flexibility and the processing of affective information (e.g. information with an 'emotional' content). While recent work has explored the specific role of the orbital PFC herein, the role of the medial PFC remains unclear. OBJECTIVES: The aim of our current experiments was to study the role of medial PFC 5-HT in both the processing of affective information and reversal learning across stimulus modalities. MATERIALS AND METHODS: To this end, we selectively destroyed 5-HT terminals in the medial PFC of male Wistar rats by means of local infusion of the toxin 5,7-dihydroxytryptamine. Both control and lesioned animals were tested in two reversal learning paradigms with either spatial or odour cues and an affective switch from non-preferred to preferred food rewards. RESULTS: Our results indicate that a pellet switch during reversal learning impaired performance in control animals but not in lesioned animals, independent of the stimulus modality. CONCLUSION: These results indicate that lesioned animals are not guided in their behaviour by the affective value of the reward like intact animals and thus that medial prefrontal 5-HT is needed for affective processing in goal-directed behaviour.

Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder.

CONTEXT: The orbitofrontal cortex (OFC)-striatal circuit, which is important for motivational behavior, is assumed to be involved in the pathophysiology of obsessive-compulsive disorder (OCD) according to current neurobiological models of this disorder. However, the engagement of this neural loop in OCD has not been tested directly in a cognitive activation imaging paradigm so far. OBJECTIVE: To determine whether the OFC and the ventral striatum show abnormal neural activity in OCD during cognitive challenge. DESIGN: A reversal learning task was employed in 20 patients with OCD who were not receiving medication and 27 healthy controls during an event-related functional magnetic resonance imaging experiment using a scanning sequence sensitive to OFC signal. This design allowed investigation of the neural correlates of reward and punishment receipt as well as of "affective switching," ie, altering behavior on reversing reinforcement contingencies. RESULTS: Patients with OCD exhibited an impaired task end result reflected by a reduced number of correct responses relative to control subjects but showed adequate behavior on receipt of punishment and with regard to affective switching. On reward outcome, patients showed decreased responsiveness in right medial and lateral OFC as well as in the right caudate nucleus (border zone ventral striatum) when compared with controls. During affective switching, patients recruited the left posterior OFC, bilateral insular cortex, bilateral dorsolateral, and bilateral anterior prefrontal cortex to a lesser extent than control subjects. No areas were found for which patients exhibited increased activity relative to controls, and no differential activations were observed for punishment in a direct group comparison. CONCLUSIONS: These data show behavioral impairments accompanied by aberrant OFC-striatal and dorsal prefrontal activity in OCD on a reversal learning task that addresses this circuit's function. These findings not only confirm previous reports of dorsal prefrontal dysfunction in OCD but also provide evidence for the involvement of the OFC-striatal loop in the pathophysiology of OCD.

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

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