Defining Overlooked Structures Reveals New Associations between the Cortex and Cognition in Aging and Alzheimer's Disease.

Recent work suggests that indentations of the cerebral cortex, or sulci, may be uniquely vulnerable to atrophy in aging and Alzheimer's disease (AD) and that the posteromedial cortex (PMC) is particularly vulnerable to atrophy and pathology accumulation. However, these studies did not consider small, shallow, and variable tertiary sulci that are located in association cortices and are often associated with human-specific aspects of cognition. Here, we manually defined 4,362 PMC sulci in 432 hemispheres in 216 human participants (50.5% female) and found that these smaller putative tertiary sulci showed more age- and AD-related thinning than larger, more consistent sulci, with the strongest effects for two newly uncovered sulci. A model-based approach relating sulcal morphology to cognition identified that a subset of these sulci was most associated with memory and executive function scores in older adults. These findings lend support to the retrogenesis hypothesis linking brain development and aging and provide new neuroanatomical targets for future studies of aging and AD.

Development of Human Lateral Prefrontal Sulcal Morphology and Its Relation to Reasoning Performance.

Previous findings show that the morphology of folds (sulci) of the human cerebral cortex flatten during postnatal development. However, previous studies did not consider the relationship between sulcal morphology and cognitive development in individual participants. Here, we fill this gap in knowledge by leveraging cross-sectional morphologic neuroimaging data in the lateral PFC (LPFC) from individual human participants (6-36 years old, males and females; N = 108; 3672 sulci), as well as longitudinal morphologic and behavioral data from a subset of child and adolescent participants scanned at two time points (6-18 years old; N = 44; 2992 sulci). Manually defining thousands of sulci revealed that LPFC sulcal morphology (depth, surface area, and gray matter thickness) differed between children (6-11 years old)/adolescents (11-18 years old) and young adults (22-36 years old) cross-sectionally, but only cortical thickness showed differences across childhood and adolescence and presented longitudinal changes during childhood and adolescence. Furthermore, a data-driven approach relating morphology and cognition identified that longitudinal changes in cortical thickness of four left-hemisphere LPFC sulci predicted longitudinal changes in reasoning performance, a higher-level cognitive ability that relies on LPFC. Contrary to previous findings, these results suggest that sulci may flatten either after this time frame or over a longer longitudinal period of time than previously presented. Crucially, these results also suggest that longitudinal changes in the cortex within specific LPFC sulci are behaviorally meaningful, providing targeted structures, and areas of the cortex, for future neuroimaging studies examining the development of cognitive abilities.SIGNIFICANCE STATEMENT Recent work has shown that individual differences in neuroanatomical structures (indentations, or sulci) within the lateral PFC are behaviorally meaningful during childhood and adolescence. Here, we describe how specific lateral PFC sulci develop at the level of individual participants for the first time: from both cross-sectional and longitudinal perspectives. Further, we show, also for the first time, that the longitudinal morphologic changes in these structures are behaviorally relevant. These findings lay the foundation for a future avenue to precisely study the development of the cortex and highlight the importance of studying the development of sulci in other cortical expanses and charting how these changes relate to the cognitive abilities those areas support at the level of individual participants.

Neuroanatomical and Functional Dissociations between Variably Present Anterior Lateral Prefrontal Sulci.

The lateral prefrontal cortex (LPFC) is an evolutionarily expanded region in humans that is critical for numerous complex functions, many of which are largely hominoid specific. Although recent work shows that the presence or absence of specific sulci in anterior LPFC is associated with cognitive performance across age groups, it is unknown whether the presence of these structures relates to individual differences in the functional organization of LPFC. To fill this gap in knowledge, we leveraged multimodal neuroimaging data from two samples encompassing 82 young adult humans (aged 22-36 years) and show that the dorsal and ventral components of the paraintermediate frontal sulcus, or pimfs, present distinct morphological (surface area), architectural (thickness and myelination), and functional (resting-state connectivity networks) properties. We further contextualize the pimfs components within classic and modern cortical parcellations. Taken together, the dorsal and ventral pimfs components mark transitions in LPFC anatomy and function, across metrics and parcellations. These results emphasize that the pimfs is a critical structure to consider when examining individual differences in the anatomical and functional organization of LPFC and suggest that future individual-level parcellations could benefit from incorporating sulcal anatomy when delineating LPFC cortical regions.

Individual differences, missing sulci, and nomenclature: A comment on "On presentation of the human cerebral sulci from inside the cerebrum".

An average hemisphere of the human cerebral cortex contains over 100 individual folds (sulci). Many of these sulci have been overlooked by classic and modern atlases and neuroimaging tools. These sulci also show prominent individual differences: They can be broken into variable "complexes" and some sulci may not be present altogether.

Updating the sulcal landscape of the human lateral parieto-occipital junction provides anatomical, functional, and cognitive insights.

Recent work has uncovered relationships between evolutionarily new small and shallow cerebral indentations, or sulci, and human behavior. Yet, this relationship remains unexplored in the lateral parietal cortex (LPC) and the lateral parieto-occipital junction (LPOJ). After defining thousands of sulci in a young adult cohort, we revised the previous LPC/LPOJ sulcal landscape to include four previously overlooked, small, shallow, and variable sulci. One of these sulci (ventral supralateral occipital sulcus, slocs-v) is present in nearly every hemisphere and is morphologically, architecturally, and functionally dissociable from neighboring sulci. A data-driven, model-based approach, relating sulcal depth to behavior further revealed that the morphology of only a subset of LPC/LPOJ sulci, including the slocs-v, is related to performance on a spatial orientation task. Our findings build on classic neuroanatomical theories and identify new neuroanatomical targets for future "precision imaging" studies exploring the relationship among brain structure, brain function, and cognitive abilities in individual participants.

Emotion-related impulsivity is related to orbitofrontal cortical sulcation.

Background: Emotion-related impulsivity (ERI) describes the trait-like tendency toward poor self-control when experiencing strong emotions. ERI has been shown to be elevated across psychiatric disorders and predictive of the onset and worsening of psychiatric syndromes. Recent work has correlated ERI scores with the neuroanatomy of the orbitofrontal cortex (OFC). Informed by a growing body of research indicating that the morphology of cortical folds (sulci) can produce insights into behavioral outcomes, the present study modeled the association between ERI and the sulcal morphology of OFC at a finer scale than previously conducted. Methods: Analyses were conducted in a transdiagnostic sample of 118 individuals with a broad range of psychiatric syndromes. We first manually defined over 2000 sulci across the 118 participants. We then implemented a model-based LASSO regression to relate OFC sulcal morphology to ERI and test whether effects were specific to ERI as compared to non-emotion-related impulsivity. Results: The LASSO regression revealed bilateral associations of ERI with the depth of eight OFC sulci. These effects were specific to ERI and were not observed in non-emotion-related impulsivity. In addition, we identified a new transverse component of the olfactory sulcus in every hemisphere that is dissociable from the longitudinal component based on anatomical features and correlation with behavior, which could serve as a new transdiagnostic biomarker. Conclusions: The results of this data-driven investigation provide greater neuroanatomical and neurodevelopmental specificity on how OFC is related to ERI. As such, findings link neuroanatomical characteristics to a trait that is highly predictive of psychopathology.

Ventral temporal and posteromedial sulcal morphology in autism spectrum disorder.

Two parallel research tracks link the morphology of small and shallow indentations, or sulci, of the cerebral cortex with functional features of the cortex and human cognition, respectively. The first track identified a relationship between the mid-fusiform sulcus (MFS) in ventral temporal cortex (VTC) and cognition in individuals with Autism Spectrum Disorder (ASD). The second track identified a new sulcus, the inframarginal sulcus (IFRMS), that serves as a tripartite landmark within the posteromedial cortex (PMC). As VTC and PMC are structurally and functionally different in ASD, here, we integrated these two tracks and tested if there are morphological differences in VTC and PMC sulci in a sample of young (5-17 years old) male participants (50 participants with ASD and 50 neurotypical controls). Our approach replicates and extends recent findings in four ways. First, regarding replication, the standard deviation (STD) of MFS cortical thickness (CT) was increased in ASD. Second, MFS length was shorter in ASD. Third, the CT STD effect extended to other VTC and to PMC sulci. Fourth, additional morphological features of VTC sulci (depth, surface area, gray matter volume) and PMC sulci (mean CT) were decreased in ASD, including putative tertiary sulci, which emerge last in gestation and continue to develop after birth. To our knowledge, this study is the most extensive comparison of the sulcal landscape (including putative tertiary sulci) in multiple cortical expanses between individuals with ASD and NTs based on manually defined sulci at the level of individual hemispheres, providing novel targets for future studies of neurodevelopmental disorders more broadly.

Sulcal variability in anterior lateral prefrontal cortex contributes to variability in reasoning performance among young adults.

Identifying structure-function correspondences is a major goal among biologists, cognitive neuroscientists, and brain mappers. Recent studies have identified relationships between performance on cognitive tasks and the presence or absence of small, shallow indentations, or sulci, of the human brain. Building on the previous finding that the presence of the ventral para-intermediate frontal sulcus (pimfs-v) in the left anterior lateral prefrontal cortex (aLPFC) was related to reasoning task performance in children and adolescents, we tested whether this relationship extended to a different sample, age group, and reasoning task. As predicted, the presence of this aLPFC sulcus was also associated with higher reasoning scores in young adults (ages 22-36). These findings have not only direct developmental, but also evolutionary relevance-as recent work shows that the pimfs-v is exceedingly rare in chimpanzees. Thus, the pimfs-v is a key developmental, cognitive, and evolutionarily relevant feature that should be considered in future studies examining how the complex relationships among multiscale anatomical and functional features of the brain give rise to abstract thought.

Lateral frontoparietal functional connectivity based on individual sulcal morphology.

A salient neuroanatomical feature of the human brain is its pronounced cortical folding, and there is mounting evidence that sulcal morphology is relevant to functional brain architecture and cognition. Recent studies have emphasized putative tertiary sulci (pTS): small, shallow, late-developing, and evolutionarily new sulci that have been posited to serve as functional landmarks in association cortices. A fruitful approach to characterizing brain architecture has been to delineate regions based on transitions in fMRI-based functional connectivity profiles; however, exact regional boundaries can change depending on the data used to generate the parcellation. As sulci are fixed neuroanatomical structures, here, we propose to anchor functional connectivity to individual-level sulcal anatomy. We characterized fine-grained patterns of functional connectivity across 42 sulci in lateral prefrontal (LPFC) and lateral parietal cortices (LPC) in a pediatric sample (N = 43; 20 female; ages 7-18). Further, we test for relationships between pTS morphology and functional network architecture, focusing on depth as a defining characteristic of these shallow sulci, and one that has been linked to variability in cognition. We find that 1) individual sulci have distinct patterns of connectivity, but nonetheless cluster together into groups with similar patterns - in some cases with distant rather than neighboring sulci, 2) there is moderate agreement in cluster assignments at the group and individual levels, underscoring the need for individual-level analyses, and 3) across individuals, greater depth was associated with higher network centrality for several pTS. These results highlight the importance of considering individual sulcal morphology for understanding functional brain organization. Significance Statement: A salient, and functionally relevant, feature of the human brain is its pronounced cortical folding. However, the links between sulcal anatomy and brain function are still poorly understood - particularly for small, shallow, individually variable sulci in association cortices. Here, we explore functional connectivity among individually defined sulci in lateral prefrontal and parietal regions. We find that individual sulci have distinct patterns of connectivity but nonetheless cluster together into groups with similar connectivity - in some cases spanning lateral prefrontal and parietal sulci. We further show that the network centrality of specific sulci is positively associated with their depth, thereby helping to bridge the gap between individual differences in brain anatomy and functional networks leveraging the sulcal anatomy of the individual.

Neuroanatomical and functional dissociations between variably present anterior lateral prefrontal sulci.

The lateral prefrontal cortex (LPFC) is an evolutionarily expanded region in humans that is critical for numerous complex functions, many of which are largely hominoid-specific. While recent work shows that the presence or absence of specific sulci in anterior LPFC is associated with cognitive performance across age groups, it is unknown whether the presence of these structures relates to individual differences in the functional organization of LPFC. To fill this gap in knowledge, we leveraged multimodal neuroimaging data from 72 young adult humans aged 22-36 and show that dorsal and ventral components of the paraintermediate frontal sulcus (pimfs) present distinct morphological (surface area), architectural (thickness and myelination), and functional (resting-state connectivity networks) properties. We further contextualize the pimfs components within classic and modern cortical parcellations. Taken together, the dorsal and ventral pimfs components mark transitions in anatomy and function in LPFC, across metrics and parcellations. These results emphasize that the pimfs is a critical structure to consider when examining individual differences in the anatomical and functional organization of LPFC and highlight the importance of considering individual anatomy when investigating structural and functional features of the cortex.

Defining overlooked structures reveals new associations between cortex and cognition in aging and Alzheimer's disease.

Recent work suggests that indentations of the cerebral cortex, or sulci, may be uniquely vulnerable to atrophy in aging and Alzheimer's disease (AD) and that posteromedial cortex (PMC) is particularly vulnerable to atrophy and pathology accumulation. However, these studies did not consider small, shallow, and variable tertiary sulci that are located in association cortices and are often associated with human-specific aspects of cognition. Here, we first manually defined 4,362 PMC sulci in 432 hemispheres in 216 participants. Tertiary sulci showed more age- and AD-related thinning than non-tertiary sulci, with the strongest effects for two newly uncovered tertiary sulci. A model-based approach relating sulcal morphology to cognition identified that a subset of these sulci were most associated with memory and executive function scores in older adults. These findings support the retrogenesis hypothesis linking brain development and aging, and provide new neuroanatomical targets for future studies of aging and AD.

Hominoid-specific sulcal variability is related to face perception ability.

The relationship among brain structure, brain function, and behavior is of major interest in neuroscience, evolutionary biology, and psychology. This relationship is especially intriguing when considering hominoid-specific brain structures because they cannot be studied in widely examined models in neuroscience such as mice, marmosets, and macaques. The fusiform gyrus (FG) is a hominoid-specific structure critical for face processing that is abnormal in individuals with developmental prosopagnosia (DPs)-individuals who have severe deficits recognizing the faces of familiar people in the absence of brain damage. While previous studies have found anatomical and functional differences in the FG between DPs and NTs, no study has examined the shallow tertiary sulcus (mid-fusiform sulcus, MFS) within the FG that is a microanatomical, macroanatomical, and functional landmark in humans, as well as was recently shown to be present in non-human hominoids. Here, we implemented pre-registered analyses of neuroanatomy and face perception in NTs and DPs. Results show that the MFS was shorter in DPs than NTs. Furthermore, individual differences in MFS length in the right, but not left, hemisphere predicted individual differences in face perception. These results support theories linking brain structure and function to perception, as well as indicate that individual differences in MFS length can predict individual differences in face processing. Finally, these findings add to growing evidence supporting a relationship between morphological variability of late developing, tertiary sulci and individual differences in cognition.

Sulcal morphology of posteromedial cortex substantially differs between humans and chimpanzees.

Recent studies identify a surprising coupling between evolutionarily new sulci and the functional organization of human posteromedial cortex (PMC). Yet, no study has compared this modern PMC sulcal patterning between humans and non-human hominoids. To fill this gap in knowledge, we first manually defined 918 sulci in 120 chimpanzee ( Pan Troglodytes ) hemispheres and 1619 sulci in 144 human hemispheres. We uncovered four new PMC sulci, and quantitatively identified species differences in incidence, depth, and surface area. Interestingly, some PMC sulci are more common in humans and others, in chimpanzees. Further, we found that the prominent marginal ramus of the cingulate sulcus differs significantly between species. Contrary to classic observations, the present results reveal that the surface anatomy of PMC substantially differs between humans and chimpanzees â€" findings which lay a foundation for better understanding the evolution of neuroanatomical-functional and neuroanatomical-behavioral relationships in this highly expanded region of the human cerebral cortex.

Sulcal variability in anterior lateral prefrontal cortex contributes to variability in reasoning performance among young adults.

Identifying structure-function correspondences is a major goal among biologists, cognitive neuroscientists, and brain mappers. Recent studies have identified relationships between performance on cognitive tasks and the presence or absence of small, shallow indentations, or sulci, of the human brain. Building on the previous finding that the presence of one such sulcus in the left anterior lateral prefrontal cortex (aLPFC) was related to reasoning task performance in children and adolescents, we tested whether this relationship extended to a different sample, age group, and reasoning task. As predicted, the presence of this aLPFC sulcus-the ventral para-intermediate frontal sulcus-was also associated with higher reasoning scores in young adults (ages 22-36). These findings have not only direct developmental, but also evolutionary relevance-as recent work shows that the pimfs-v is exceedingly rare in chimpanzees. Thus, the pimfs-v is a novel developmental, cognitive, and evolutionarily relevant feature that should be considered in future studies examining how the complex relationships among multiscale anatomical and functional features of the brain give rise to abstract thought.

Sulcal morphology of posteromedial cortex substantially differs between humans and chimpanzees.

Recent studies identify a surprising coupling between evolutionarily new sulci and the functional organization of human posteromedial cortex (PMC). Yet, no study has compared this modern PMC sulcal patterning between humans and non-human hominoids. To fill this gap in knowledge, we first manually defined over 2500 PMC sulci in 120 chimpanzee (Pan Troglodytes) hemispheres and 144 human hemispheres. We uncovered four new sulci, and quantitatively identified species differences in sulcal incidence, depth, and surface area. Interestingly, some sulci are more common in humans and others, in chimpanzees. Further, we found that the prominent marginal ramus of the cingulate sulcus differs significantly between species. Contrary to classic observations, the present results reveal that the surface anatomy of PMC substantially differs between humans and chimpanzees-findings which lay a foundation for better understanding the evolution of neuroanatomical-functional and neuroanatomical-behavioral relationships in this highly expanded region of the human cerebral cortex.

Presence or absence of a prefrontal sulcus is linked to reasoning performance during child development.

The relationship between structural variability in late-developing association cortices like the lateral prefrontal cortex (LPFC) and the development of higher-order cognitive skills is not well understood. Recent findings show that the morphology of LPFC sulci predicts reasoning performance; this work led to the observation of substantial individual variability in the morphology of one of these sulci, the para-intermediate frontal sulcus (pimfs). Here, we sought to characterize this variability and assess its behavioral significance. To this end, we identified the pimfs in a developmental cohort of 72 participants, ages 6-18. Subsequent analyses revealed that the presence or absence of the ventral component of the pimfs was associated with reasoning, even when controlling for age. This finding shows that the cortex lining the banks of sulci can support the development of complex cognitive abilities and highlights the importance of considering individual differences in local morphology when exploring the neurodevelopmental basis of cognition.

Uncovering a tripartite landmark in posterior cingulate cortex.

Understanding brain structure-function relationships, and their development and evolution, is central to neuroscience research. Here, we show that morphological differences in posterior cingulate cortex (PCC), a hub of functional brain networks, predict individual differences in macroanatomical, microstructural, and functional features of PCC. Manually labeling 4511 sulci in 572 hemispheres, we found a shallow cortical indentation (termed the inframarginal sulcus; ifrms) within PCC that is absent from neuroanatomical atlases yet colocalized with a focal, functional region of the lateral frontoparietal network implicated in cognitive control. This structural-functional coupling generalized to meta-analyses consisting of hundreds of studies and thousands of participants. Additional morphological analyses showed that unique properties of the ifrms differ across the life span and between hominoid species. These findings support a classic theory that shallow, tertiary sulci serve as landmarks in association cortices. They also beg the question: How many other cortical indentations have we missed?