Spatial and temporal heterogeneity of neural responses in human posteromedial cortex.

Neuroimaging evidence supports a role of the default mode network (DMN) in spontaneous thought and goal-driven internally oriented processes, such as recalling an autobiographical event, and has demonstrated its deactivation during focused, externally oriented attention. Recent work suggests that the DMN is not a homogeneous network but rather is composed of at least several subnetworks, which are engaged in distinct functions; however, it is still unclear if these different functions rely on the same neuronal populations. In this study, we used intracranial EEG to record from the posteromedial cortex (PMC), a core hub of the DMN, in 13 human subjects, during autobiographical memory retrieval (internally oriented), arithmetic processing (externally oriented), and cued rest (spontaneous thought), allowing us to measure activity from anatomically precise PMC sites with high temporal resolution. We observed a heterogeneous, yet spatially organized, pattern of activity across tasks. Many sites, primarily in the more ventral portion of PMC, were engaged during autobiographical recall and suppressed during arithmetic processing. Other more dorsal PMC sites were engaged during the cued-rest condition. Of these rest-active sites, some exhibited variable temporal dynamics across trials, possibly reflecting various forms of spontaneous thought, while others showed only transient activity at the beginning of cued-rest trials (i.e., after a switch from a task to cued rest), possibly involved in shifting the brain from a more focused to a more exploratory attentional state. These results suggest heterogeneity of function even within an individual node of the DMN.

The Lifespan Trajectory of the Encoding-Retrieval Flip: A Multimodal Examination of Medial Parietal Cortex Contributions to Episodic Memory.

The formation of episodic memories is associated with deactivation during encoding and activation during retrieval in the posteromedial cortex (PMC). We hypothesized that the encoding/retrieval (E/R) flip is a critical component of episodic memory across the lifespan because structural and metabolic changes in the PMC coincide with the fine tuning of the episodic memory system in development and the reductions of memory performance in aging. The aims of the present study were, first, to describe lifespan trajectories of PMC encoding and retrieval activity in 270 human participants (167 females) from 6 to 80 years of age. Our second goal was to construct a model for episodic memory development in which contributions from brain activity, cortical thickness (CT), and structural connectivity are accounted for. We found that modulation of neural activity in response to memory encoding and retrieval demands was not fully developed until adolescence and decreased from adulthood through old age. The magnitude of the E/R flip was related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence could be accounted for by the E/R flip, CT, and mean diffusivity together. However, only CT and the E/R flip provided unique contributions with which to explain memory performance. The results suggest that neural dynamics in the PMC is related to the development of episodic memory during childhood and adolescence. The similar trajectories of the E/R flip and episodic memory emergence and decline through development and aging further suggests that a lifelong relationship exists.SIGNIFICANCE STATEMENT Modulation of neural activity in the posteromedial cortex (PMC) in response to memory encoding/retrieval (E/R) demands (E/R flip) does not reach its peak until adolescence and decreases from adulthood through old age. The magnitude of the E/R flip is related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence can be accounted for by the E/R flip and brain structure together. The results suggest that neural dynamics in the PMC is related to the development of episodic memory function during childhood and adolescence and the similar trajectories of the E/R flip and episodic memory performance through development and aging suggests that a lifelong relationship exists.

Posterior dopamine D2/3 receptors and brain network functional connectivity.

Recent studies suggest that dopaminergic tone influences resting state activity in multiple brain networks. Although dopamine receptors and transporters have been identified in the posteromedial and parietal cortices, which are linked to functional networks such as the default mode network (DMN), the relationship between dopamine receptor distribution in these posterior regions and resting-state connectivity has yet to be explored. Here, we used a multi-modal neuroimaging strategy, combining resting-state functional magnetic resonance imaging (rsfMRI) and [18 F]-fallypride high-resolution positron emission tomography (PET), to examine the association between within-network functional connectivity and the dopamine D2/3 receptor distribution in the posterior portion of the brain in 13 healthy adults. Our results indicate that the posterior distribution of D2/3 receptors coincides primarily with the posterior portion of the DMN. Furthermore, in the posterior portion of the brain, the level of [18 F]-fallypride binding in the posteromedial cortex correlated positively with the functional connectivity strength of the DMN and sensorimotor network, and negatively with the functional connectivity strength of the dorsal attention network, the salience network, and a network that included the anterior part of the temporo-parietal junction. On the basis of these findings, we propose that posterior brain dopamine influences the configuration of the posterior DMN and several other functional brain networks. The posterior distribution of D2/3 receptors binding (hot colour spectrum) coincides with the functional connectivity of the posterior portion of the default mode network (green colour spectrum). The mean BPND in a posteromedial cortex and the mean ICA-Z score in the precuneus showed significant positive correlation.

Common intrinsic connectivity states among posteromedial cortex subdivisions: Insights from analysis of temporal dynamics.

Perspectives of human brain functional connectivity continue to evolve. Static representations of functional interactions between brain regions are rapidly giving way to dynamic perspectives, which emphasize non-random temporal variations in intrinsic functional connectivity (iFC) patterns. Here, we bring this dynamic perspective to our understanding of iFC patterns for posteromedial cortex (PMC), a cortical hub known for its functional diversity. Previous work has consistently differentiated iFC patterns among PMC subregions, though assumed static iFC over time. Here, we assessed iFC as a function of time utilizing a sliding-window correlation approach, and applied hierarchical clustering to detect representative iFC states from the windowed iFC. Across subregions, five iFC states were detected over time. Although with differing frequencies, each subregion was associated with each of the states, suggesting that these iFC states are "common" to PMC subregions. Importantly, each subregion possessed a unique preferred state(s) and distinct transition patterns, explaining previously observed iFC differentiations. These results resonate with task-based fMRI studies suggesting that large-scale functional networks can be flexibly reconfigured in response to changing task-demands. Additionally, we used retest scans (~1week later) to demonstrate the reproducibility of the iFC states identified, and establish moderate to high test-retest reliability for various metrics used to quantify switching behaviors. We also demonstrate the ability of dynamic properties in the visual PMC subregion to index inter-individual differences in a measure of concept formation and mental flexibility. These findings suggest functional relevance of dynamic iFC and its potential utility in biomarker identification over time, as d-iFC methodologies are refined and mature.

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.

Ventral-Dorsal Subregions in the Posterior Cingulate Cortex Represent Pay and Interest, Two Key Attributes of Job Value.

Career choices affect not only our financial status but also our future well-being. When making these choices, individuals evaluate their willingness to obtain a job (i.e., job values), primarily driven by simulation of future pay and interest. Despite the importance of these decisions, their underlying neural mechanisms remain unclear. In this study, we examined the neural representation of pay and interest. Forty students were presented with 80 job names and asked to evaluate their job values while undergoing functional magnetic resonance imaging (fMRI). Following fMRI, participants rated the jobs in terms of pay and interest. The fMRI data revealed that the ventromedial prefrontal cortex (vmPFC) was associated with job value representation, and the ventral and dorsal regions of the posterior cingulate cortex (PCC) were associated with pay and interest representations, respectively. These findings suggest that the neural computations underlying job valuation conform to a multi-attribute decision-making framework, with overall value signals represented in the vmPFC and the attribute values (i.e., pay and interest) represented in specific regions outside the vmPFC, in the PCC. Furthermore, anatomically distinct representations of pay and interest in the PCC may reflect the differing roles of the two subregions in future simulations.

Effects of risperidone monotherapy on the default-mode network in antipsychotic-naïve first-episode schizophrenia: Posteromedial cortex heterogeneity and relationship with the symptom improvements.

The default mode network (DMN) has been consistently detected abnormally in schizophrenia. However, the effects of antipsychotics on this network are still under debate, and inconsistent findings may be due to the functional heterogeneity within the DMN, especially in the component regions of the posteromedial cortex (PMC). Here, we conducted a longitudinal research on the resting-state functional connectivity of the PMC subdivisions on 33 treatment-naive first-episode patients with schizophrenia at baseline and after 8 weeks of risperidone treatment through resting-state functional magnetic resonance imaging. At baseline, the patients demonstrated decreased connectivity of the three PMC seeds with several brain regions (target regions) compared with healthy controls. We then tested the effect of antipsychotic treatment on the functional connectivity between the three seeds and the target regions. We found that, one of the three seeds encompassed in PMC, namely, posterior cingulate cortex (PCC), was observed to have increased functional connectivity with the bilateral thalamus and the left lingual gyrus (LG). On the contrary, the functional connectivity between the target regions and the two remaining seeds, namely, the retrosplenial cortex and precuneus, was unaffected by risperidone treatment. Correlation analysis revealed a positive correlation between longitudinal change of PCC-LG connectivity and symptom improvement. These findings indicated the heterogeneity of the PMC in response to antipsychotic treatment and suggested the role of PCC as a treatment biomarker for schizophrenia.

Medial Temporal Lobe Disconnection and Hyperexcitability Across Alzheimer's Disease Stages.

 The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer's disease (AD). We have reviewed the spatiotemporal patterns of amyloid-ß and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-ß plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-ß and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-ß pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events.

Neural signature of coma revealed by posteromedial cortex connection density analysis.

Posteromedial cortex (PMC) is a highly segregated and dynamic core, which appears to play a critical role in internally/externally directed cognitive processes, including conscious awareness. Nevertheless, neuroimaging studies on acquired disorders of consciousness, have traditionally explored PMC as a homogenous and indivisible structure. We suggest that a fine-grained description of intrinsic PMC topology during coma, could expand our understanding about how this cortical hub contributes to consciousness generation and maintain, and could permit the identification of specific markers related to brain injury mechanism and useful for neurological prognostication. To explore this, we used a recently developed voxel-based unbiased approach, named functional connectivity density (CD). We compared 27 comatose patients (15 traumatic and 12 anoxic), to 14 age-matched healthy controls. The patients' outcome was assessed 3 months later using Coma Recovery Scale-Revised (CRS-R). A complex pattern of decreased and increased connections was observed, suggesting a network imbalance between internal/external processing systems, within PMC during coma. The number of PMC voxels with hypo-CD positive correlation showed a significant negative association with the CRS-R score, notwithstanding aetiology. Traumatic injury specifically appeared to be associated with a greater prevalence of hyper-connected (negative correlation) voxels, which was inversely associated with patient neurological outcome. A logistic regression model using the number of hypo-CD positive and hyper-CD negative correlations, accurately permitted patient's outcome prediction (AUC = 0.906, 95%IC = 0.795-1). These points might reflect adaptive plasticity mechanism and pave the way for innovative prognosis and therapeutics methods.

Distinct Changes in Functional Connectivity in Posteromedial Cortex Subregions during the Progress of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which causes dementia, especially in the elderly. The posteromedial cortex (PMC), which consists of several subregions involved in distinct functions, is one of the critical regions associated with the progression and severity of AD. However, previous studies always ignored the heterogeneity of the PMC and focused on one stage of AD. Using resting-state functional magnetic resonance imaging, we studied the respective alterations of each subregion within the PMC along the progression of AD. Our data set consisted of 21 healthy controls, 18 patients with mild cognitive impairment (MCI), 17 patients with mild AD (mAD), and 18 patients with severe AD (sAD). We investigated the functional alterations of each subregion within the PMC in different stages of AD. We found that subregions within the PMC have differential vulnerability in AD. Disruptions in functional connectivity began in the transition area between the precuneus and the posterior cingulate cortex (PCC) and then extended to other subregions of the PMC. In addition, each of these subregions was associated with distinct alterations in the functional networks that we were able to relate to AD. Our research demonstrated functional changes within the PMC in the progression of AD and may elucidate potential biomarkers for clinical applications.

Early metabolic development of posteromedial cortex and thalamus in humans analyzed via in vivo quantitative magnetic resonance spectroscopy.

The posteromedial cortex (PMC) including the posterior cingulate, retrosplenial cortex, and medial parietal cortex/precuneus is an epicenter of cortical interactions in a wide spectrum of neural activity. Anatomic connections between PMC and thalamic components have been established in animal studies, but similar studies do not exist for the fetal and neonatal period. Magnetic resonance spectroscopy (MRS) allows for noninvasive measurement of metabolites in early development. Using single-voxel 3-T MRS, healthy term neonates (n = 31, mean postconception age 41.5 weeks ± 3.8 weeks) were compared with control children (n = 23, mean age 9.4 years ± 5.1 years) and young adults (n = 10, mean age 24.1 years ± 2.6 years). LCModel-based calculations compared metabolites within medial parietal gray matter (colocalizing to the PMC), posterior thalamus, and parietal white matter voxels. Common metabolic changes existed for neuronal-axonal maturation and structural markers in the PMC, thalamus, and parietal white matter with increasing NAA and glutamate and decreasing myoinositol and choline with age. Key differences in creatine and glucose metabolism were noted in the PMC, in contrast to the thalamic and parietal white matter locations, suggesting a unique role of energy metabolism. Significant parallel metabolite developmental changes of multiple other metabolites including aspartate, glutamine, and glutathione with age were present between PMC and parietal white matter but not between PMC and thalamus. These findings offer insight into the metabolic architecture of the interface between structural and functional topology of brain networks. Further investigation unifying metabolic changes with functional and anatomic pathways may further enhance the understanding of the PMC in posterior default mode network development.

Involvement of cortical midline structures in the processing of autobiographical information.

The term autobiographical self has been used to refer to a mental state that permits reflection on self-identity and personality and the answer to related questions (Damasio, 1998). It requires the retrieval and integrated assembly of memories of facts and events that define an individual's biography. The neural mechanisms behind this state have not been fully elucidated, but it has been suggested that cortical midline structures (CMSs) are critically involved in processing self-related information. To date, the investigation of the involvement of CMSs in autobiographical-self processes has largely focused on the comparison between self and other in relation to one domain of information, personality traits, and has yielded conflicting results. Here, we investigated how activity in CMSs varies with (1) the target of the information (self versus an acquaintance), (2) the domain of information (personality traits versus facts), and (3) differences across individuals regarding how descriptive and how important/relevant the information targeted by the questions was, and regarding the amount of memory retrieved in order to answer the questions. We used an fMRI block-design in which 19 participants answered questions about traits and biographic facts, in relation to themselves and a distant acquaintance. In addition, the participants rated the descriptiveness and importance of the information targeted by the questions, and estimated the amount of memory retrieved to answer the questions. Our results showed that CMSs were active for both facts and traits and for both self and other, and that the level of activity in the posteromedial cortices was generally higher for other than for self. Moreover, the activity in CMSs also varied with the amount of memory retrieved to answer the questions and with descriptiveness and importance of the information. These findings suggest that involvement of CMSs during the evaluation of information is not specific for self, and depends on varied factors related to memory retrieval prompted by the questions and to processes required to answer them.

Default mode network in childhood autism: posteromedial cortex heterogeneity and relationship with social deficits.

BACKGROUND: The default mode network (DMN), a brain system anchored in the posteromedial cortex, has been identified as underconnected in adults with autism spectrum disorder (ASD). However, to date there have been no attempts to characterize this network and its involvement in mediating social deficits in children with ASD. Furthermore, the functionally heterogeneous profile of the posteromedial cortex raises questions regarding how altered connectivity manifests in specific functional modules within this brain region in children with ASD. METHODS: Resting-state functional magnetic resonance imaging and an anatomically informed approach were used to investigate the functional connectivity of the DMN in 20 children with ASD and 19 age-, gender-, and IQ-matched typically developing (TD) children. Multivariate regression analyses were used to test whether altered patterns of connectivity are predictive of social impairment severity. RESULTS: Compared with TD children, children with ASD demonstrated hyperconnectivity of the posterior cingulate and retrosplenial cortices with predominately medial and anterolateral temporal cortex. In contrast, the precuneus in ASD children demonstrated hypoconnectivity with visual cortex, basal ganglia, and locally within the posteromedial cortex. Aberrant posterior cingulate cortex hyperconnectivity was linked with severity of social impairments in ASD, whereas precuneus hypoconnectivity was unrelated to social deficits. Consistent with previous work in healthy adults, a functionally heterogeneous profile of connectivity within the posteromedial cortex in both TD and ASD children was observed. CONCLUSIONS: This work links hyperconnectivity of DMN-related circuits to the core social deficits in young children with ASD and highlights fundamental aspects of posteromedial cortex heterogeneity.