Muscone abrogates breast cancer progression through tumor angiogenic suppression via VEGF/PI3K/Akt/MAPK signaling pathways.

BACKGROUND: Angiogenesis strongly reflects poor breast cancer outcome and an important contributor to breast cancer (BC) metastasis; therefore, anti-angiogenic intervention is a potential tool for cancer treatment. However, currently used antibodies against vascular endothelial growth factor A (VEGFA) or inhibitors that target the VEGFA receptor are not effective due to weak penetration and low efficiency. Herein, we assessed the anti-BC angiogenic role of muscone, a natural bioactive musk constituent, and explored possible anti-cancer mechanisms of this compound. METHODS: CCK-8, EdU, scratch and Transwell assessments were employed to detect the muscone-mediated regulation of breast cancer (BC) and human umbilical vein endothelial cells (HUVECs) proliferation and migration. Tube formation, matrigel plug assay and zebrafish assay were employed for assessment of regulation of tumor angiogenesis by muscone. In vivo xenograft mouse model was constructed to compare microvessel density (MVD), vascular leakage, vascular maturation and function in muscone-treated or untreated mice. RNA sequencing was performed for gene screening, and Western blot verified the effect of the VEGFA-VEGFR2 pathway on BC angiogenic inhibition by muscone. RESULTS: Based on our findings, muscone suppressed BC progression via tumor angiogenic inhibition in cellular and animal models. Functionally, muscone inhibited BC cell proliferation and migration as well as tumor cell-conditioned medium-based endothelial cell proliferation and migration. Muscone exhibited a strong suppressive influence on tumor vasculature in cellular and animal models. It abrogated tumor cell growth in a xenograft BC mouse model and minimized tumor microvessel density and hypoxia, and increased vascular wall cell coverage and perfusion. Regarding the mechanism of action, we found that muscone suppressed phosphorylation of members of the VEGF/PI3K/Akt/MAPK axis, and it worked synergistically with a VEGFR2 inhibitor, an Akt inhibitor, and a MAPK inhibitor to further inhibit tube formation. CONCLUSION: Overall, our results demonstrate that muscone may proficiently suppress tumor angiogenesis via modulation of the VEGF/PI3K/Akt/MAPK axis, facilitating its candidacy as a natural small molecule drug for BC treatment.

Precisely Tuning Band Gaps of Hexabenzocoronene-Based MOFs Toward Enhanced Photocatalysis.

Precise adjusting the band gaps in metal-organic frameworks (MOFs) is crucial for improving their visible-light absorption capacity during photocatalysis, presenting both a formidable challenge and a charming opportunity. This present study employed a symmetry-reduction strategy to pre-design six novel 4-connected ligands with systematic substituents (-NO2, -H, -tBu, -OCH3, -OH and -NH2) and synthesized the corresponding pillared-layer Zr-MOFs (NKM-668) retaining the hexaphenylbenzene fragment. Subsequently, the NKM-668 MOFs were transformed into large-π-conjugated hexabenzocoronene-based MOFs (pNKM-668) via the Scholl reaction. These twelve MOFs exhibited broad and tunable band gaps over 1.41 eV (ranging from 3.25 eV to 1.84 eV), and the photocatalytic CO2 conversion rate raised by 33.2-fold. This study not only enriches the type of hexaphenylbenzene-based MOFs, but also paves the way for nanographene-containing MOFs in the further application of photocatalysis.

Gut microbiome causal impacts on the prognosis of breast cancer: a Mendelian randomization study.

BACKGROUND: Growing evidence has shown that gut microbiome composition is associated with breast cancer (BC), but the causality remains unknown. We aimed to investigate the link between BC prognosis and the gut microbiome at various oestrogen receptor (ER) statuses. METHODS: We performed a genome-wide association study (GWAS) to analyse the gut microbiome of BC patients, the dataset for which was collected by the Breast Cancer Association Consortium (BCAC). The analysis was executed mainly via inverse variance weighting (IVW); the Mendelian randomization (MR) results were verified by heterogeneity tests, sensitivity analysis, and pleiotropy analysis. RESULTS: Our findings identified nine causal relationships between the gut microbiome and total BC cases, with ten and nine causal relationships between the gut microbiome and ER-negative (ER-) and ER-positive (ER+) BC, respectively. The family Ruminococcaceae and genus Parabacteroides were most apparent among the three categories. Moreover, the genus Desulfovibrio was expressed in ER- BC and total BC, whereas the genera Sellimonas, Adlercreutzia and Rikenellaceae appeared in the relationship between ER + BC and total BC. CONCLUSION: Our MR inquiry confirmed that the gut microbiota is causally related to BC. This further explains the link between specific bacteria for prognosis of BC at different ER statuses. Considering that potential weak instrument bias impacts the findings and that the results are limited to European females due to data constraints, further validation is crucial.

Personalized fMRI Delineates Functional Regions Preserved within Brain Tumors.

OBJECTIVE: Accumulating evidence from invasive cortical stimulation mapping and noninvasive neuroimaging studies indicates that brain function may be preserved within brain tumors. However, a noninvasive approach to accurately and comprehensively delineate individual-specific functional networks in the whole brain, especially in brain tissues within and surrounding tumors, is still lacking. The purpose of the study is to develop a clinically useful technique that can map functional regions within tumoral brains. METHODS: We developed an individual-specific functional network parcellation approach using resting state functional magnetic resonance imaging (rsfMRI) that effectively captured functional networks within and nearby tumors in 20 patients. We examined the accuracy of the functional maps using invasive cortical stimulation and task response. RESULTS: We found that approximately 33.2% of the tumoral mass appeared to be functionally active and demonstrated robust functional connectivity with non-tumoral brain regions. Functional networks nearby tumors were validated by invasive cortical stimulation mapping. Intratumoral sensorimotor networks mapped by our technique could be distinguished by their distinct cortico-cerebellar connectivity patterns and were consistent with hand movement evoked fMRI task activations. Furthermore, in some patients, cognitive networks that were detected in the tumor mass showed long-distance and distributed functional connectivity. INTERPRETATION: Our noninvasive approach to mapping individual-specific functional networks using rsfMRI represents a promising new tool for identifying regions with preserved functional connectivity within and surrounding brain tumors, and could be used as a complement to presurgical planning for patients undergoing tumor resection surgery. ANN NEUROL 2022;91:353-366.

A survey on the current status of Helicobacter pylori infection in households in Hainan Province, China.

OBJECTIVE: This study aims to assess the prevalence of Helicobacter pylori (Hp) infection at the household level in Hainan Province in China and identify the factors that contribute to its spread. The findings of this study have significant implications for public health prevention strategies in the Hainan region. METHODS: A total of 421 families, comprising 1355 individuals, were tested for Hp infection across five cities in Hainan Province between July 2021 and April 2022. The study utilized questionnaires that included questions about personal characteristics, household shared lifestyle and dietary habits, and potential pathways of Hp infection in children to identify potential factors linked to household Hp infection and transmission patterns. RESULTS: The prevalence of Hp infection on an individual basis was 46.72% (629/1355), with age ≥ 20 years, being married and having junior secondary education and above as risk factors for Hp infection. The prevalence of Hp infection in households was 80.29% (338/421), household size of 5, 6 and above were risk factors for Hp infection with Odds Ratios (ORs) of 4.09 (1.17-14.33) and 15.19 (2.01-114.73), respectively, household income ≥ 100,000 yuan and drinking boiled water from a tap source were protective factors for Hp infection with ORs of 0.52 (0.31-0.89) and 0.51 (0.28-0.95), respectively. The prevalence of Hp infection among minors in the household was 24.89% (58/233), with paternal infection and maternal infection as risk factors for child infection, with ORs of 2.93 (1.29-6.62) and 2.51 (1.07-5.89), respectively. CONCLUSION: Hp infection was prevalent among Hainan families, and interaction with infected family members may be the primary cause of transmission.

B3S2 monolayer as an anode material for Na/K-ion batteries: a first-principles study.

Two-dimensional (2D) materials used as anodes in metal-ion batteries have attracted increased attention due to their high specific surface area, abundant active sites and good electronic properties. Searching for 2D materials with high storage capacities and low diffusion energy barriers is one of the most effective ways to design novel anode materials. In this work, based on first-principles calculations, we design a new 2D B3S2 monolayer with high thermodynamic and dynamic stability. The obtained B3S2 monolayer has a high cohesive energy, ensuring the feasibility of experimental synthesis. These characteristics of the B3S2 monolayer prompt us to explore its application as an anode material. The B3S2 monolayer exhibits not only a metallic nature but also a low diffusion energy barrier (0.037 eV) and open-circuit voltage (0.09 V). More importantly, the B3S2 monolayer shows a very high theoretical capacity of 1658 mA h g-1 as an anode material for sodium-ion batteries, which is comparable to other similar or common 2D materials. All of these intriguing properties make the B3S2 monolayer a promising 2D anode material for sodium-ion batteries.

Distinct doorway states lead to triplet excited state generation in epigenetic RNA nucleosides.

N 6-Hydroxymethyladenosine (hm6A) and N6-formyladenosine (f6A) are two important intermediates during the demethylation process of N6-methyladenosine (m6A), which has been proven to show epigenetic function in mRNA. However, there is no knowledge about how the chemical integrity and stability could be altered when these two nucleosides are exposed to ultraviolet (UV) radiation. Herein, we report the first study on excited state dynamics of hm6A and f6A in solutions by using femtosecond time-resolved spectroscopy and quantum chemistry calculations. Surprisingly, triplet excited species are clearly identified in both hm6A and f6A after UV excitation, which is in sharp contrast to the 10-3 level triplet yield of adenosine scaffolds. Moreover, the doorway states leading to triplet states are found to be an intramolecular charge transfer state and a lower-lying dark nπ* state in hm6A and f6A, respectively. These discoveries pave the way to further study their effects on RNA strands and provide insight for understanding RNA photochemistry.

Pan-cancer Analysis Identifies AIMP2 as a Potential Biomarker for Breast Cancer.

Introduction: Aminoacyl tRNA synthetase complex interacting with multifunctional protein 2 (AIMP2) is a significant regulator of cell proliferation and apoptosis. Despite its abnormal expression in various tumor types, the specific functions and effects of AIMP2 on tumor immune cell infiltration, proliferation, and migration remain unclear. Materials and Methods: To assess AIMP2's role in tumor immunity, we conducted a pan-cancer multi-database analysis using the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Lines Encyclopedia (CCLE) datasets, examining expression levels, prognosis, tumor progression, and immune microenvironment. Additionally, we investigated AIMP2's impact on breast cancer (BRCA) proliferation and migration using cell counting kit 8 (CCK-8) assay, transwell assays, and western blot analysis. Results: Our findings revealed that AIMP2 was overexpressed in 24 tumor tissue types compared to normal tissue and was associated with four tumor stages. Survival analysis indicated that AIMP2 expression was strongly correlated with overall survival (OS) in certain cancer patients, with high AIMP2 expression linked to poorer prognosis in five cancer types. Conclusion: Finally, siRNA-mediated AIMP2 knockdown inhibited BRCA cell proliferation and migration in vitro. In conclusion, our pan-cancer analysis suggests that AIMP2 may play a crucial role in tumor immunity and could serve as a potential prognostic marker, particularly in BRCA.

Variable functional connectivity architecture of the preterm human brain: Impact of developmental cortical expansion and maturation.

Functional connectivity (FC) is known to be individually unique and to reflect cognitive variability. Although FC can serve as a valuable correlate and potential predictor of (patho-) physiological nervous function in high-risk constellations, such as preterm birth, templates for individualized FC analysis are lacking, and knowledge about the capacity of the premature brain to develop FC variability is limited. In a cohort of prospectively recruited, preterm-born infants undergoing magnetic resonance imaging close to term-equivalent age, we show that the overall pattern could be reliably detected with a broad range of interindividual FC variability in regions of higher-order cognitive functions (e.g., association cortices) and less interindividual variability in unimodal regions (e.g., visual and motor cortices). However, when comparing the preterm and adult brains, some brain regions showed a marked shift in variability toward adulthood. This shift toward greater variability was strongest in cognitive networks like the attention and frontoparietal networks and could be partially predicted by developmental cortical expansion. Furthermore, FC variability was reflected by brain tissue characteristics indicating cortical maturation. Brain regions with high functional variability (e.g., the inferior frontal gyrus and temporoparietal junction) displayed lower cortical maturation at birth compared with somatosensory cortices. In conclusion, the overall pattern of interindividual variability in FC is already present preterm; however, some brain regions show increased variability toward adulthood, identifying characteristic patterns, such as in cognitive networks. These changes are related to postnatal cortical expansion and maturation, allowing for environmental and developmental factors to translate into marked individual differences in FC.

ZnF2 -Riched Inorganic/Organic Hybrid SEI: in situ-Chemical Construction and Performance-Improving Mechanism for Aqueous Zinc-ion Batteries.

Uncontrolled dendrites growth and serious parasitic reactions in aqueous electrolytes, greatly hinder the practical application of aqueous zinc-ion battery. On the basis of in situ-chemical construction and performance-improving mechanism, multifunctional fluoroethylene carbonate (FEC) is introduced into aqueous electrolyte to construct a high-quality and ZnF2 -riched inorganic/organic hybrid SEI (ZHS) layer on Zn metal anode (ZMA) surface. Notably, FEC additive can regulate the solvated structure of Zn2+ to reduce H2 O molecules reactivity. Additionally, the ZHS layer with strong Zn2+ affinity can avoid dendrites formation and hinder the direct contact between the electrolyte and anode. Therefore, the dendrites growth, Zn corrosion, and H2 evolution reaction on ZMA in FEC-included ZnSO4 electrolyte are highly suppressed. Thus, ZMA in such electrolyte realize a long cycle life over 1000 h and deliver a stable coulombic efficiency of 99.1 % after 500 cycles.

Altered temporal, but intact spatial, features of transient network dynamics in psychosis.

Contemporary models of psychosis suggest that a continuum of severity of psychotic symptoms exists, with subthreshold psychotic experiences (PEs) potentially reflecting some genetic and environmental risk factors shared with clinical psychosis. Thus, identifying abnormalities in brain activity that manifest across this continuum can shed new light on the pathophysiology of psychosis. Here, we investigated the moment-to-moment engagement of brain networks ("states") in individuals with schizophrenia (SCZ) and PEs and identified features of these states that are associated with psychosis-spectrum symptoms. Transient brain states were defined by clustering "single snapshots" of blood oxygen level-dependent images, based on spatial similarity of the images. We found that individuals with SCZ (n = 35) demonstrated reduced recruitment of three brain states compared to demographically matched healthy controls (n = 35). Of these three illness-related states, one specific state, involving primarily the visual and salience networks, also occurred at a lower rate in individuals with persistent PEs (n = 22), compared to demographically matched healthy youth (n = 22). Moreover, the occurrence rate of this marker brain state was negatively correlated with the severity of PEs (r = -0.26, p = 0.003, n = 130). In contrast, the spatial map of this state appeared to be unaffected in the SCZ or PE groups. Thus, reduced engagement of a brain state involving the visual and salience networks was demonstrated across the psychosis continuum, suggesting that early disruptions of perceptual and affective function may underlie some of the core symptoms of the illness.

Performing group-level functional image analyses based on homologous functional regions mapped in individuals.

Functional MRI (fMRI) studies have traditionally relied on intersubject normalization based on global brain morphology, which cannot establish proper functional correspondence between subjects due to substantial intersubject variability in functional organization. Here, we reliably identified a set of discrete, homologous functional regions in individuals to improve intersubject alignment of fMRI data. These functional regions demonstrated marked intersubject variability in size, position, and connectivity. We found that previously reported intersubject variability in functional connectivity maps could be partially explained by variability in size and position of the functional regions. Importantly, individual differences in network topography are associated with individual differences in task-evoked activations, suggesting that these individually specified regions may serve as the "localizer" to improve the alignment of task-fMRI data. We demonstrated that aligning task-fMRI data using the regions derived from resting state fMRI may lead to increased statistical power of task-fMRI analyses. In addition, resting state functional connectivity among these homologous regions is able to capture the idiosyncrasies of subjects and better predict fluid intelligence (gF) than connectivity measures derived from group-level brain atlases. Critically, we showed that not only the connectivity but also the size and position of functional regions are related to human behavior. Collectively, these findings suggest that identifying homologous functional regions across individuals can benefit a wide range of studies in the investigation of connectivity, task activation, and brain-behavior associations.

Dissociable Auditory Cortico-Cerebellar Pathways in the Human Brain Estimated by Intrinsic Functional Connectivity.

The cerebellum, a structure historically associated with motor control, has more recently been implicated in several higher-order auditory-cognitive functions. However, the exact functional pathways that mediate cerebellar influences on auditory cortex (AC) remain unclear. Here, we sought to identify auditory cortico-cerebellar pathways based on intrinsic functional connectivity magnetic resonance imaging. In contrast to previous connectivity studies that principally consider the AC as a single functionally homogenous unit, we mapped the cerebellar connectivity across different parts of the AC. Our results reveal that auditory subareas demonstrating different levels of interindividual functional variability are functionally coupled with distinct cerebellar regions. Moreover, auditory and sensorimotor areas show divergent cortico-cerebellar connectivity patterns, although sensorimotor areas proximal to the AC are often functionally grouped with the AC in previous connectivity-based network analyses. Lastly, we found that the AC can be functionally segmented into highly similar subareas based on either cortico-cerebellar or cortico-cortical functional connectivity, suggesting the existence of multiple parallel auditory cortico-cerebellar circuits that involve different subareas of the AC. Overall, the present study revealed multiple auditory cortico-cerebellar pathways and provided a fine-grained map of AC subareas, indicative of the critical role of the cerebellum in auditory processing and multisensory integration.

Individual Variability in Functional Organization of the Human and Monkey Auditory Cortex.

Accumulating evidence shows that auditory cortex (AC) of humans, and other primates, is involved in more complex cognitive processes than feature segregation only, which are shaped by experience-dependent plasticity and thus likely show substantial individual variability. However, thus far, individual variability of ACs has been considered a methodological impediment rather than a phenomenon of theoretical importance. Here, we examined the variability of ACs using intrinsic functional connectivity patterns in humans and macaques. Our results demonstrate that in humans, interindividual variability is greater near the nonprimary than primary ACs, indicating that variability dramatically increases across the processing hierarchy. ACs are also more variable than comparable visual areas and show higher variability in the left than in the right hemisphere, which may be related to the left lateralization of auditory-related functions such as language. Intriguingly, remarkably similar modality differences and lateralization of variability were also observed in macaques. These connectivity-based findings are consistent with a confirmatory task-based functional magnetic resonance imaging analysis. The quantification of variability in auditory function, and the similar findings in both humans and macaques, will have strong implications for understanding the evolution of advanced auditory functions in humans.

Recent developments in representations of the connectome.

Research into the human connectome (i.e., all connections in the human brain) with the use of resting state functional MRI has rapidly increased in popularity in recent years, especially with the growing availability of large-scale neuroimaging datasets. The goal of this review article is to describe innovations in functional connectome representations that have come about in the past 8 years, since the 2013 NeuroImage special issue on 'Mapping the Connectome'. In the period, research has shifted from group-level brain parcellations towards the characterization of the individualized connectome and of relationships between individual connectomic differences and behavioral/clinical variation. Achieving subject-specific accuracy in parcel boundaries while retaining cross-subject correspondence is challenging, and a variety of different approaches are being developed to meet this challenge, including improved alignment, improved noise reduction, and robust group-to-subject mapping approaches. Beyond the interest in the individualized connectome, new representations of the data are being studied to complement the traditional parcellated connectome representation (i.e., pairwise connections between distinct brain regions), such as methods that capture overlapping and smoothly varying patterns of connectivity ('gradients'). These different connectome representations offer complimentary insights into the inherent functional organization of the brain, but challenges for functional connectome research remain. Interpretability will be improved by future research towards gaining insights into the neural mechanisms underlying connectome observations obtained from functional MRI. Validation studies comparing different connectome representations are also needed to build consensus and confidence to proceed with clinical trials that may produce meaningful clinical translation of connectome insights.

Functional connectome reorganization relates to post-stroke motor recovery and structural and functional disconnection.

Motor recovery following ischemic stroke is contingent on the ability of surviving brain networks to compensate for damaged tissue. In rodent models, sensory and motor cortical representations have been shown to remap onto intact tissue around the lesion site, but remapping to more distal sites (e.g. in the contralesional hemisphere) has also been observed. Resting state functional connectivity (FC) analysis has been employed to study compensatory network adaptations in humans, but mechanisms and time course of motor recovery are not well understood. Here, we examine longitudinal FC in 23 first-episode ischemic pontine stroke patients and utilize a graph matching approach to identify patterns of functional connectivity reorganization during recovery. We quantified functional reorganization between several intervals ranging from 1 week to 6 months following stroke, and demonstrated that the areas that undergo functional reorganization most frequently are in cerebellar/subcortical networks. Brain regions with more structural and functional connectome disruption due to the stroke also had more remapping over time. Finally, we show that functional reorganization is correlated with the extent of motor recovery in the early to late subacute phases, and furthermore, individuals with greater baseline motor impairment demonstrate more extensive early subacute functional reorganization (from one to two weeks post-stroke) and this reorganization correlates with better motor recovery at 6 months. Taken together, these results suggest that our graph matching approach can quantify recovery-relevant, whole-brain functional connectivity network reorganization after stroke.

Co-activation patterns across multiple tasks reveal robust anti-correlated functional networks.

Whether antagonistic brain states constitute a fundamental principle of human brain organization has been debated over the past decade. Some argue that intrinsically anti-correlated brain networks in resting-state functional connectivity are an artifact of preprocessing. Others argue that anti-correlations are biologically meaningful predictors of how the brain will respond to different stimuli. Here, we investigated the co-activation patterns across the whole brain in various tasks and test whether brain regions demonstrate anti-correlated activity similar to those observed at rest. We examined brain activity in 47 task contrasts from the Human Connectome Project (N = 680) and found robust antagonistic interactions between networks. Regions of the default network exhibited the highest degree of cortex-wide negative connectivity. The negative co-activation patterns across tasks showed good correspondence to that derived from resting-state data processed with global signal regression (GSR). Interestingly, GSR-processed resting-state data was a significantly better predictor of task-induced modulation than data processed without GSR. Finally, in a cohort of 25 patients with depression, we found that task-based anti-correlations between the dorsolateral prefrontal cortex (DLPFC) and subgenual anterior cingulate cortex were associated with clinical efficacy of transcranial magnetic stimulation therapy targeting the DLPFC. Overall, our findings indicate that anti-correlations are a biologically meaningful phenomenon and may reflect an important principle of functional brain organization.

Subthalamic Nucleus Deep Brain Stimulation Modulates 2 Distinct Neurocircuits.

OBJECTIVE: Current understanding of the neuromodulatory effects of deep brain stimulation (DBS) on large-scale brain networks remains elusive, largely due to the lack of techniques that can reveal DBS-induced activity at the whole-brain level. Using a novel 3T magnetic resonance imaging (MRI)-compatible stimulator, we investigated whole-brain effects of subthalamic nucleus (STN) stimulation in patients with Parkinson disease. METHODS: Fourteen patients received STN-DBS treatment and participated in a block-design functional MRI (fMRI) experiment, wherein stimulations were delivered during "ON" blocks interleaved with "OFF" blocks. fMRI responses to low-frequency (60Hz) and high-frequency(130Hz) STN-DBS were measured 1, 3, 6, and 12 months postsurgery. To ensure reliability, multiple runs (48 minutes) of fMRI data were acquired at each postsurgical visit. Presurgical resting-state fMRI (30 minutes) data were also acquired. RESULTS: Two neurocircuits showed highly replicable, but distinct responses to STN-DBS. A circuit involving the globus pallidus internus (GPi), thalamus, and deep cerebellar nuclei was significantly activated, whereas another circuit involving the primary motor cortex (M1), putamen, and cerebellum showed DBS-induced deactivation. These 2 circuits were dissociable in terms of their DBS-induced responses and resting-state functional connectivity. The GPi circuit was frequency-dependent, selectively responding to high-frequency stimulation, whereas the M1 circuit was responsive in a time-dependent manner, showing enhanced deactivation over time. Finally, activation of the GPi circuit was associated with overall motor improvement, whereas M1 circuit deactivation was related to reduced bradykinesia. INTERPRETATION: Concurrent DBS-fMRI using 3T revealed 2 distinct circuits that responded differentially to STN-DBS and were related to divergent symptoms, a finding that may provide novel insights into the neural mechanisms underlying DBS. ANN NEUROL 2020;88:1178-1193.

Correction: Individual-specific functional connectivity markers track dimensional and categorical features of psychotic illness.

The original version of this article omitted the author "Roscoe O. Brady Jr." from the "Psychotic Disorders Division, McLean Hospital, Harvard Medical School, Belmont, MA, USA" and the "Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA". This has been corrected in both the PDF and HTML versions of the article.

Individual-specific functional connectivity markers track dimensional and categorical features of psychotic illness.

Neuroimaging studies of psychotic disorders have demonstrated abnormalities in structural and functional connectivity involving widespread brain networks. However, these group-level observations have failed to yield any biomarkers that can provide confirmatory evidence of a patient's current symptoms, predict future symptoms, or predict a treatment response. Lack of precision in both neuroanatomical and clinical boundaries have likely contributed to the inability of even well-powered studies to resolve these key relationships. Here, we employed a novel approach to defining individual-specific functional connectivity in 158 patients diagnosed with schizophrenia (n = 49), schizoaffective disorder (n = 37), or bipolar disorder with psychosis (n = 72), and identified neuroimaging features that track psychotic symptoms in a dimension- or disorder-specific fashion. Using individually specified functional connectivity, we were able to estimate positive, negative, and manic symptoms that showed correlations ranging from r = 0.35 to r = 0.51 with the observed symptom scores. Comparing optimized estimation models among schizophrenia spectrum patients, positive and negative symptoms were associated with largely non-overlapping sets of cortical connections. Comparing between schizophrenia spectrum and bipolar disorder patients, the models for positive symptoms were largely non-overlapping between the two disorder classes. Finally, models derived using conventional region definition strategies performed at chance levels for most symptom domains. Individual-specific functional connectivity analyses revealed important new distinctions among cortical circuits responsible for the positive and negative symptoms, as well as key new information about how circuits underlying symptom expressions may vary depending on the underlying etiology and illness syndrome from which they manifest.