The specialised regional functionality of the mature human cortex partly emerges through experience-dependent specialisation during early development. Our existing understanding of functional specialisation in the infant brain is based on evidence from unitary imaging modalities and has thus focused on isolated estimates of spatial or temporal selectivity of neural or haemodynamic activation, giving an incomplete picture. We speculate that functional specialisation will be underpinned by better coordinated haemodynamic and metabolic changes in a broadly orchestrated physiological response. To enable researchers to track this process through development, we develop new tools that allow the simultaneous measurement of coordinated neural activity (EEG), metabolic rate, and oxygenated blood supply (broadband near-infrared spectroscopy) in the awake infant. In 4- to 7-month-old infants, we use these new tools to show that social processing is accompanied by spatially and temporally specific increases in coupled activation in the temporal-parietal junction, a core hub region of the adult social brain. During non-social processing, coupled activation decreased in the same region, indicating specificity to social processing. Coupling was strongest with high-frequency brain activity (beta and gamma), consistent with the greater energetic requirements and more localised action of high-frequency brain activity. The development of simultaneous multimodal neural measures will enable future researchers to open new vistas in understanding functional specialisation of the brain.

Neuroimaging stands to benefit from emerging ultrahigh-resolution 3D histological atlases of the human brain; the first of which is 'BigBrain'. Here, we review recent methodological advances for the integration of BigBrain with multi-modal neuroimaging and introduce a toolbox, 'BigBrainWarp', that combines these developments. The aim of BigBrainWarp is to simplify workflows and support the adoption of best practices. This is accomplished with a simple wrapper function that allows users to easily map data between BigBrain and standard MRI spaces. The function automatically pulls specialised transformation procedures, based on ongoing research from a wide collaborative network of researchers. Additionally, the toolbox improves accessibility of histological information through dissemination of ready-to-use cytoarchitectural features. Finally, we demonstrate the utility of BigBrainWarp with three tutorials and discuss the potential of the toolbox to support multi-scale investigations of brain organisation.

Both healthy aging and Alzheimer's disease (AD) are characterized by concurrent alterations in several biological factors. However, generative brain models of aging and AD are limited in incorporating the measures of these biological factors at different spatial resolutions. Here, we propose a personalized bottom-up spatiotemporal brain model that accounts for the direct interplay between hundreds of RNA transcripts and multiple macroscopic neuroimaging modalities (PET, MRI). In normal elderly and AD participants, the model identifies top genes modulating tau and amyloid-β burdens, vascular flow, glucose metabolism, functional activity, and atrophy to drive cognitive decline. The results also revealed that AD and healthy aging share specific biological mechanisms, even though AD is a separate entity with considerably more altered pathways. Overall, this personalized model offers novel insights into the multiscale alterations in the elderly brain, with important implications for identifying effective genetic targets for extending healthy aging and treating AD progression.

Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically induced effects. Previously, using pharmacological neuroimaging, we found that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to agonism of the serotonin-2A receptor (Preller et al., 2018). Here, we integrate brain-wide transcriptomics with biophysically based circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical large-scale spatiotemporal dynamics. Our model captures the inter-areal topography of LSD-induced changes in cortical blood oxygen level-dependent (BOLD) functional connectivity. These findings suggest that serotonin-2A-mediated modulation of pyramidal-neuronal gain is a circuit mechanism through which LSD alters cortical functional topography. Individual-subject model fitting captures patterns of individual neural differences in pharmacological response related to altered states of consciousness. This work establishes a framework for linking molecular-level manipulations to systems-level functional alterations, with implications for precision medicine.

Social isolation has been suggested to increase the risk to develop cognitive decline. However, our knowledge on causality and neurobiological underpinnings is still limited.

Influential accounts claim that violent video games (VVGs) decrease players' emotional empathy by desensitizing them to both virtual and real-life violence. However, scientific evidence for this claim is inconclusive and controversially debated. To assess the causal effect of VVGs on the behavioral and neural correlates of empathy and emotional reactivity to violence, we conducted a prospective experimental study using functional magnetic resonance imaging (fMRI). We recruited 89 male participants without prior VVG experience. Over the course of two weeks, participants played either a highly violent video game or a non-violent version of the same game. Before and after this period, participants completed an fMRI experiment with paradigms measuring their empathy for pain and emotional reactivity to violent images. Applying a Bayesian analysis approach throughout enabled us to find substantial evidence for the absence of an effect of VVGs on the behavioral and neural correlates of empathy. Moreover, participants in the VVG group were not desensitized to images of real-world violence. These results imply that short and controlled exposure to VVGs does not numb empathy nor the responses to real-world violence. We discuss the implications of our findings regarding the potential and limitations of experimental research on the causal effects of VVGs. While VVGs might not have a discernible effect on the investigated subpopulation within our carefully controlled experimental setting, our results cannot preclude that effects could be found in settings with higher ecological validity, in vulnerable subpopulations, or after more extensive VVG play.

Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-β, more advanced stages (AT) of AD pathology and APOE-ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury.

Participant-specific, functionally defined brain areas are usually mapped with functional localizers and estimated by making contrasts between responses to single categories of input. Naturalistic stimuli engage multiple brain systems in parallel, provide more ecologically plausible estimates of real-world statistics, and are friendly to special populations. The current study shows that cortical functional topographies in individual participants can be estimated with high fidelity from naturalistic stimuli. Importantly, we demonstrate that robust, individualized estimates can be obtained even when participants watched different movies, were scanned with different parameters/scanners, and were sampled from different institutes across the world. Our results create a foundation for future studies that allow researchers to estimate a broad range of functional topographies based on naturalistic movies and a normative database, making it possible to integrate high-level cognitive functions across datasets from laboratories worldwide.

Despite extensive research on the role of the rodent medial and lateral entorhinal cortex (MEC/LEC) in spatial navigation, memory and related disease, their human homologues remain elusive. Here, we combine high-field functional magnetic resonance imaging at 7 T with novel data-driven and model-based analyses to identify corresponding subregions in humans based on the well-known global connectivity fingerprints in rodents and sensitivity to spatial and non-spatial information. We provide evidence for a functional division primarily along the anteroposterior axis. Localising the human homologue of the rodent MEC and LEC has important implications for translating studies on the hippocampo-entorhinal memory system from rodents to humans.

The entorhinal cortex (EC) is the primary site of interactions between the neocortex and hippocampus. Studies in rodents and nonhuman primates suggest that EC can be divided into subregions that connect differentially with perirhinal cortex (PRC) vs parahippocampal cortex (PHC) and with hippocampal subfields along the proximo-distal axis. Here, we used high-resolution functional magnetic resonance imaging at 7 Tesla to identify functional subdivisions of the human EC. In two independent datasets, PRC showed preferential intrinsic functional connectivity with anterior-lateral EC and PHC with posterior-medial EC. These EC subregions, in turn, exhibited differential connectivity with proximal and distal subiculum. In contrast, connectivity of PRC and PHC with subiculum followed not only a proximal-distal but also an anterior-posterior gradient. Our data provide the first evidence that the human EC can be divided into functional subdivisions whose functional connectivity closely parallels the known anatomical connectivity patterns of the rodent and nonhuman primate EC.

Brain connectivity is often considered in terms of the communication between functionally distinct brain regions. Many studies have investigated the extent to which patterns of coupling strength between multiple neural populations relates to behaviour. For example, studies have used 'functional connectivity fingerprints' to characterise individuals' brain activity. Here, we investigate the extent to which the exact spatial arrangement of cortical regions interacts with measures of brain connectivity. We find that the shape and exact location of brain regions interact strongly with the modelling of brain connectivity, and present evidence that the spatial arrangement of functional regions is strongly predictive of non-imaging measures of behaviour and lifestyle. We believe that, in many cases, cross-subject variations in the spatial configuration of functional brain regions are being interpreted as changes in functional connectivity. Therefore, a better understanding of these effects is important when interpreting the relationship between functional imaging data and cognitive traits.

The human brain supports social cognitive functions, including Theory of Mind, empathy, and compassion, through its intrinsic hierarchical organization. However, it remains unclear how the learning and refinement of social skills shapes brain function and structure. We studied if different types of social mental training induce changes in cortical function and microstructure, investigating 332 healthy adults (197 women, 20-55 years) with repeated multimodal neuroimaging and behavioral testing. Our neuroimaging approach examined longitudinal changes in cortical functional gradients and myelin-sensitive T1 relaxometry, two complementary measures of cortical hierarchical organization. We observed marked changes in intrinsic cortical function and microstructure, which varied as a function of social training content. In particular, cortical function and microstructure changed as a result of attention-mindfulness and socio-cognitive training in regions functionally associated with attention and interoception, including insular and parietal cortices. Conversely, socio-affective and socio-cognitive training resulted in differential microstructural changes in regions classically implicated in interoceptive and emotional processing, including insular and orbitofrontal areas, but did not result in functional reorganization. Notably, longitudinal changes in cortical function and microstructure predicted behavioral change in attention, compassion and perspective-taking. Our work demonstrates functional and microstructural plasticity after the training of social-interoceptive functions, and illustrates the bidirectional relationship between brain organisation and human social skills.

The inferior parietal lobe (IPL) is a key neural substrate underlying diverse mental processes, from basic attention to language and social cognition, that define human interactions. Its putative domain-global role appears to tie into poorly understood differences between cognitive domains in both hemispheres. Across attentional, semantic, and social cognitive tasks, our study explored functional specialization within the IPL. The task specificity of IPL subregion activity was substantiated by distinct predictive signatures identified by multivariate pattern-learning algorithms. Moreover, the left and right IPL exerted domain-specific modulation of effective connectivity among their subregions. Task-evoked functional interactions of the anterior and posterior IPL subregions involved recruitment of distributed cortical partners. While anterior IPL subregions were engaged in strongly lateralized coupling links, both posterior subregions showed more symmetric coupling patterns across hemispheres. Our collective results shed light on how under-appreciated hemispheric specialization in the IPL supports some of the most distinctive human mental capacities.

Previously we showed that network-based modelling of brain connectivity interacts strongly with the shape and exact location of brain regions, such that cross-subject variations in the spatial configuration of functional brain regions are being interpreted as changes in functional connectivity (Bijsterbosch et al., 2018). Here we show that these spatial effects on connectivity estimates actually occur as a result of spatial overlap between brain networks. This is shown to systematically bias connectivity estimates obtained from group spatial ICA followed by dual regression. We introduce an extended method that addresses the bias and achieves more accurate connectivity estimates.

Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these 'resting state networks' is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies. DOI: http://dx.doi.org/10.7554/eLife.01465.001.

Resting-state functional MRI (rs-fMRI) is widely used to examine the dynamic brain functional development of infants, but these studies typically require precise cortical parcellation maps, which cannot be directly borrowed from adult-based functional parcellation maps due to the substantial differences in functional brain organization between infants and adults. Creating infant-specific cortical parcellation maps is thus highly desired but remains challenging due to difficulties in acquiring and processing infant brain MRIs. In this study, we leveraged 1064 high-resolution longitudinal rs-fMRIs from 197 typically developing infants and toddlers from birth to 24 months who participated in the Baby Connectome Project to develop the first set of infant-specific, fine-grained, surface-based cortical functional parcellation maps. To establish meaningful cortical functional correspondence across individuals, we performed cortical co-registration using both the cortical folding geometric features and the local gradient of functional connectivity (FC). Then we generated both age-related and age-independent cortical parcellation maps with over 800 fine-grained parcels during infancy based on aligned and averaged local gradient maps of FC across individuals. These parcellation maps reveal complex functional developmental patterns, such as changes in local gradient, network size, and local efficiency, especially during the first 9 postnatal months. Our generated fine-grained infant cortical functional parcellation maps are publicly available at https://www.nitrc.org/projects/infantsurfatlas/ for advancing the pediatric neuroimaging field.

Previous studies have related pair-bonding in Microtus ochrogaster, the prairie vole, with plastic changes in several brain regions. However, the interactions between these socially relevant regions have yet to be described. In this study, we used resting-state magnetic resonance imaging to explore bonding behaviors and functional connectivity of brain regions previously associated with pair-bonding. Thirty-two male and female prairie voles were scanned at baseline, 24 hr, and 2 weeks after the onset of cohabitation. By using network-based statistics, we identified that the functional connectivity of a corticostriatal network predicted the onset of affiliative behavior, while another predicted the amount of social interaction during a partner preference test. Furthermore, a network with significant changes in time was revealed, also showing associations with the level of partner preference. Overall, our findings revealed the association between network-level functional connectivity changes and social bonding.

We previously demonstrated that network level functional connectivity in the human brain could be related to levels of inhibition in a major network node at baseline (Stagg et al., 2014). In this study, we build upon this finding to directly investigate the effects of perturbing M1 GABA and resting state functional connectivity using transcranial direct current stimulation (tDCS), a neuromodulatory approach that has previously been demonstrated to modulate both metrics. FMRI data and GABA levels, as assessed by Magnetic Resonance Spectroscopy, were measured before and after 20 min of 1 mA anodal or sham tDCS. In line with previous studies, baseline GABA levels were negatively correlated with the strength of functional connectivity within the resting motor network. However, although we confirm the previously reported findings that anodal tDCS reduces GABA concentration and increases functional connectivity in the stimulated motor cortex; these changes are not correlated, suggesting they may be driven by distinct underlying mechanisms.

The mesiotemporal lobe (MTL) is implicated in many cognitive processes, is compromised in numerous brain disorders, and exhibits a gradual cytoarchitectural transition from six-layered parahippocampal isocortex to three-layered hippocampal allocortex. Leveraging an ultra-high-resolution histological reconstruction of a human brain, our study showed that the dominant axis of MTL cytoarchitectural differentiation follows the iso-to-allocortical transition and depth-specific variations in neuronal density. Projecting the histology-derived MTL model to in-vivo functional MRI, we furthermore determined how its cytoarchitecture underpins its intrinsic effective connectivity and association to large-scale networks. Here, the cytoarchitectural gradient was found to underpin intrinsic effective connectivity of the MTL, but patterns differed along the anterior-posterior axis. Moreover, while the iso-to-allocortical gradient parametrically represented the multiple-demand relative to task-negative networks, anterior-posterior gradients represented transmodal versus unimodal networks. Our findings establish that the combination of micro- and macrostructural features allow the MTL to represent dominant motifs of whole-brain functional organisation.

The human cerebral cortex is symmetrically organized along large-scale axes but also presents inter-hemispheric differences in structure and function. The quantified contralateral homologous difference, that is asymmetry, is a key feature of the human brain left-right axis supporting functional processes, such as language. Here, we assessed whether the asymmetry of cortical functional organization is heritable and phylogenetically conserved between humans and macaques. Our findings indicate asymmetric organization along an axis describing a functional trajectory from perceptual/action to abstract cognition. Whereas language network showed leftward asymmetric organization, frontoparietal network showed rightward asymmetric organization in humans. These asymmetries were heritable in humans and showed a similar spatial distribution with macaques, in the case of intra-hemispheric asymmetry of functional hierarchy. This suggests (phylo)genetic conservation. However, both language and frontoparietal networks showed a qualitatively larger asymmetry in humans relative to macaques. Overall, our findings suggest a genetic basis for asymmetry in intrinsic functional organization, linked to higher order cognitive functions uniquely developed in humans.