Ye Ella Tian

Background: Although mental illness is primarily regarded as a disorder of the brain, body system dysfunction is increasingly recognized as a salient biomarker in psychiatry, often emerging before the onset of overt symptoms. Here, we systematically review studies on peripheral organ systems (cardiovascular, metabolic, immune, liver, kidneys, lungs and muskeloskeletal) in schizophrenia, major depressive disorder (MDD), bipolar disorder (BD) and generalized anxiety disorder (GAD), aiming to synthesize findings on the function of multiple body systems in the early stages of mental illness. Methods: EMBASE, MEDLINE and PsycINFO were searched from inception until 19 November 2024, identifying case-control studies comparing physiological markers of peripheral organ systems (i.e., cardiovascular, metabolic, immune, liver, kidney, lung and muskeloskeletal) in adults with one of the four mental illnesses at first-episode and drug naive, with healthy controls. We followed the PRISMA 2020 guidelines (PROSPERO: CRD42023408594). Results: Of 2637 citations retrieved, 138 studies met inclusion criteria for review with 52 markers of immune ( n = 32), metabolic ( n = 11), cardiovascular ( n = 6), liver ( n = 2) and musculoskeletal ( n = 1) function identified. 105 studies were eligible for meta-analysis, including 80, 26, 4 and 0 studies on schizophrenia, MDD, BD and GAD respectively. Meta-analysis revealed increased waist-hip-circumference ratio, triglycerides, insulin, insulin resistance, 2-hr glucose, neutrophil, monocyte, white blood cell, IL-4 and systolic blood pressure, and reduced albumin in schizophrenia; increased TNF-α and IL-10 in MDD; and increased IL-6 and IFN-γ in both schizophrenia and MDD. Other results were narratively discussed. Conclusions: Alterations in peripheral organ function across multiple systems characterizes the onset of psychiatric disorders. However, research on peripheral organ function in psychiatry is limited and primarily focusses on the immune and metabolic systems.

Frontolimbic circuits connecting the frontal cortex with the amygdala and the hippocampus are critical for emotion and learning. These connections undergo major changes throughout childhood and adolescence, yet the principles guiding their maturation remain unclear. Analyzing large developmental cohorts, we show that fronto-hippocampus connectivity develops rapidly in early childhood and stabilizes thereafter. In contrast, fronto-amygdala connectivity becomes progressively differentiated from fronto-hippocampus connectivity, with development most pronounced during adolescence. This entailed hippocampus and amygdala respectively becoming preferentially tethered to association-related regions and sensorimotor-related regions. Greater adversity exposure was associated with more differentiated fronto-amygdala connectivity for a given age. Higher cognitive ability was associated with less differentiated fronto-hippocampus connectivity. These findings suggest that frontolimbic connectivity development follows a principle of differentiation, with circuit-specific timing and sensitivity to stress and learning. This work provides a foundation for understanding typical and atypical frontolimbic circuitry development from birth to emerging adulthood.

Background Although mental illness is primarily regarded as a disorder of the brain, body system dysfunction is increasingly recognized as a salient biomarker in psychiatry, often emerging before the onset of overt symptoms. Here, we systematically review studies on peripheral organ systems (cardiovascular, metabolic, immune, liver, kidneys, lungs and muskeloskeletal) in schizophrenia, major depressive disorder (MDD), bipolar disorder (BD) and generalized anxiety disorder (GAD), aiming to synthesize findings on the function of multiple body systems in the early stages of mental illness. Methods EMBASE, MEDLINE and PsycINFO were searched from inception until 19 November 2024, identifying case-control studies comparing physiological markers of peripheral organ systems (i.e., cardiovascular, metabolic, immune, liver, kidney, lung and muskeloskeletal) in adults with one of the four mental illnesses at first-episode and drug naive, with healthy controls. We followed the PRISMA 2020 guidelines (PROSPERO: CRD42023408594). Results Of 2,637 citations retrieved, 138 studies met inclusion criteria for review with 52 markers of immune (n=32), metabolic (n=11), cardiovascular (n=6), liver (n=2) and musculoskeletal (n=1) function identified. 105 studies were eligible for meta-analysis, including 80, 26, 4 and 0 studies on schizophrenia, MDD, BD and GAD respectively. Meta-analysis revealed increased HDL-cholesterol, waist-hip-circumference ratio, triglycerides, insulin, insulin resistance, 2-hr glucose, neutrophil, monocyte, white blood cell, IL-4 and systolic blood pressure, and reduced albumin in schizophrenia; increased TNF-α and IL-10 in MDD; and increased IL-6 and IFN-γ in both schizophrenia and MDD. Other results were narratively discussed. Conclusions Alterations in peripheral organ function across multiple systems characterizes the onset of psychiatric disorders. However, research on peripheral organ function in psychiatry is limited and primarily focusses on the immune and metabolic systems.

Frontolimbic circuits connecting the frontal cortex with the amygdala and the hippocampus are critical for emotion and learning. These connections undergo major changes throughout childhood and adolescence, yet the principles guiding their maturation remain unclear. Analyzing large developmental cohorts, we show that fronto-hippocampus connectivity develops rapidly in early childhood and stabilizes thereafter. In contrast, fronto-amygdala connectivity becomes progressively differentiated from fronto-hippocampus connectivity, with development most pronounced during adolescence. This entailed hippocampus and amygdala respectively becoming preferentially tethered to association-related regions and sensorimotor-related regions. Greater adversity exposure was associated with more differentiated fronto-amygdala connectivity for a given age. Higher cognitive ability was associated with less differentiated fronto-hippocampus connectivity. These findings suggest that frontolimbic connectivity development follows a principle of differentiation, with circuit-specific timing and sensitivity to stress and learning. This work provides a foundation for understanding typical and atypical frontolimbic circuitry development from birth to emerging adulthood. Significance Statement: The frontolimbic circuit, especially the fronto-hippocampus and fronto-amygdala circuitry, is integral for cognitive and affective processes. Yet its maturation has been challenging to characterize due to variable connectivity growth across the frontal cortex. Here, we reveal that this variability follows a principle of differentiation, where the hippocampus and the amygdala acquire respectively unique connectivity profiles with the frontal cortex at disparate developmental stages. Deviations from these normative trajectories were linked to cognitive ability and cumulative adversity, respectively. This approach provides a framework to unify inconsistent findings while serving as a foundation for identifying circuit-specific windows of plasticity and vulnerability.

Recent work leveraging omics and imaging data now enables the estimation of aging at the level of individual organs. Emerging findings suggest that organs age at different rates, which may be linked to environmental exposures and genetic factors. However, premature aging in one organ may also drive aging in connected organs within multi-organ aging networks. Here, we outline methods for measuring organ-specific biological age and discuss insights derived from recent progress in multi-organ aging research. We put forward recommendations, best practices and research priorities, including the importance of longitudinal tracking, biomarkers with high organ specificity and reference ranges for organ age gaps. We envision routine organ-specific biological age assessments as tools for developing personalized organ aging maps and tracking organ aging across the life course, thereby facilitating early, targeted interventions to delay organ-specific decline and interorgan consequences.

Optimal sleep has a vital role in promoting healthy ageing and enhancing longevity. Here we propose Sleep Chart to assess the relationship between self-reported sleep duration and 23 biological ageing clocks derived from in vivo imaging¹, plasma proteomics² and metabolomics³. First, a systemic, U-shaped pattern emerges between sleep duration and biological age gaps across nine brain and body systems and three omics technologies. The sample-specific lowest biological age gaps are achieved between 6.4 and 7.8 h of sleep duration, varying by organ and sex in the UK Biobank (aged 37–84 years). Furthermore, short (8 h) sleep duration, compared with a normal sleep duration (6–8 h), are associated with increased risk of systemic diseases beyond the brain and all-cause mortality, with evidence from genetic correlations and time-to-incident survival predictions, such as depression and diabetes. Finally, the pathways by which long and short sleep duration are associated with late-life depression differ: ageing clocks may partially mediate the pathway for long sleep duration, while short sleep duration shows a more direct link. Although Mendelian randomization does not provide strong evidence that disease causally affects sleep, it cannot completely exclude such reverse causality. Our findings suggest a cross-organ, multi-omics U-shaped relationship between sleep duration and biological ageing clocks, highlighting the potential of sleep optimization to promote healthy ageing, lower disease risk and extend longevity.