Neuroimaging epicenters as potential sites of onset of the neuroanatomical pathology in schizophrenia.

Schizophrenia lacks a clear definition at the neuroanatomical level, capturing the sites of origin and progress of this disorder. Using a network-theory approach called epicenter mapping on cross-sectional magnetic resonance imaging from 1124 individuals with schizophrenia, we identified the most likely "source of origin" of the structural pathology. Our results suggest that the Broca's area and adjacent frontoinsular cortex may be the epicenters of neuroanatomical pathophysiology in schizophrenia. These epicenters can predict an individual's response to treatment for psychosis. In addition, cross-diagnostic similarities based on epicenter mapping over of 4000 individuals diagnosed with neurological, neurodevelopmental, or psychiatric disorders appear to be limited. When present, these similarities are restricted to bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. We provide a comprehensive framework linking schizophrenia-specific epicenters to multiple levels of neurobiology, including cognitive processes, neurotransmitter receptors and transporters, and human brain gene expression. Epicenter mapping may be a reliable tool for identifying the potential onset sites of neural pathophysiology in schizophrenia.

The aging trajectories of brain functional hierarchy and its impact on cognition across the adult lifespan.

Introduction: The hierarchical network architecture of the human brain, pivotal to cognition and behavior, can be explored via gradient analysis using restingstate functional MRI data. Although it has been employed to understand brain development and disorders, the impact of aging on this hierarchical architecture and its link to cognitive decline remains elusive. Methods: This study utilized resting-state functional MRI data from 350 healthy adults (aged 20-85) to investigate the functional hierarchical network using connectome gradient analysis with a cross-age sliding window approach. Gradient-related metrics were estimated and correlated with age to evaluate trajectory of gradient changes across lifespan. Results: The principal gradient (unimodal-to-transmodal) demonstrated a significant non-linear relationship with age, whereas the secondary gradient (visual-to-somatomotor) showed a simple linear decreasing pattern. Among the principal gradient, significant age-related changes were observed in the somatomotor, dorsal attention, limbic and default mode networks. The changes in the gradient scores of both the somatomotor and frontal-parietal networks were associated with greater working memory and visuospatial ability. Gender differences were found in global gradient metrics and gradient scores of somatomotor and default mode networks in the principal gradient, with no interaction with age effect. Discussion: Our study delves into the aging trajectories of functional connectome gradient and its cognitive impact across the adult lifespan, providing insights for future research into the biological underpinnings of brain function and pathological models of atypical aging processes.

Changes in microstructural similarity of hippocampal subfield circuits in pathological cognitive aging.

The hippocampal networks support multiple cognitive functions and may have biological roles and functions in pathological cognitive aging (PCA) and its associated diseases, which have not been explored. In the current study, a total of 116 older adults with 39 normal controls (NC) (mean age: 52.3 ± 13.64 years; 16 females), 39 mild cognitive impairment (MCI) (mean age: 68.15 ± 9.28 years, 14 females), and 38 dementia (mean age: 73.82 ± 8.06 years, 8 females) were included. The within-hippocampal subfields and the cortico-hippocampal circuits were assessed via a micro-structural similarity network approach using T1w/T2w ratio and regional gray matter tissue probability maps, respectively. An analysis of covariance was conducted to identify between-group differences in structural similarities among hippocampal subfields. The partial correlation analyses were performed to associate changes in micro-structural similarities with cognitive performance in the three groups, controlling the effect of age, sex, education, and cerebral small-vessel disease. Compared with the NC, an altered T1w/T2w ratio similarity between left CA3 and left subiculum was observed in the mild cognitive impairment (MCI) and dementia. The left CA3 was the most impaired region correlated with deteriorated cognitive performance. Using these regions as seeds for GM similarity comparisons between hippocampal subfields and cortical regions, group differences were observed primarily between the left subiculum and several cortical regions. By utilizing T1w/T2w ratio as a proxy measure for myelin content, our data suggest that the imbalanced synaptic weights within hippocampal CA3 provide a substrate to explain the abnormal firing characteristics of hippocampal neurons in PCA. Furthermore, our work depicts specific brain structural characteristics of normal and pathological cognitive aging and suggests a potential mechanism for cognitive aging heterogeneity.

SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.