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Fung, H.

Publications and source records attributed to Fung, H..

10 recordsLinked to original sources

Zero-shot evaluations expose structured generalization limits in predictive models of the brain

Artificial neural networks (ANNs) can predict neural responses to natural images with remarkable accuracy, making them promising models of human vision. However, prediction scores alone reveal little about what computations these models have captured or how well they generalize beyond the images on which they are trained. Here, we introduce a principled zero-shot model evaluation framework in which ANN-based encoding models are frozen before being tested on not just held out images but entirely new datasets. Our strongest tests repurpose decades of cognitive neuroscience experiments as diagnostic benchmarks for identifying which computations current models capture and where they fail. To implement this framework we built encoding models of human category-selective regions (FFA, PPA, and EBA) using several pretrained ANNs and evaluated these fixed models across 7 independent fMRI datasets and 31 cognitive experiments from 10 published studies. This framework revealed three broad patterns. First, zero-shot evaluations exposed systematic limits to model predictivity that were largely hidden by standard within-dataset cross-validation. These limits were structured varying across brain regions and model classes and depending strongly on the similarity between the images used to build and test the models. Second, current models reproduced some, but not all, classical findings from cognitive neuroscience, providing a diagnosis of the computations that current models have yet to capture. Finally, models that performed well on prediction tests also tended to succeed at reproducing cognitive neuroscience findings, suggesting that prediction and explanation are closely linked. Unlike prediction scores however, cognitive tests help diagnose where and why models fail. Together, the zero-shot evaluation framework provides a scalable and unified approach for evaluating brain models across prediction and cognitive neuroscience tests, which can help us better understand what current models capture and what still remains to be explained.

neuroscience↗

Symptom Dimension-Specific Neurotransmitter Correlates of Psychopathology and Cognition in Early Psychosis

Extended duration of under-treated psychosis (DUP) is among the strongest predictors of poor outcome, yet diagnostic heterogeneity impedes treatment matching, with approximately 50% of patients failing to respond to first-line antipsychotics. Negative symptoms and cognitive impairment are particularly refractory, lacking effective pharmacological treatments. Identifying neurotransmitter systems associated with specific symptom dimensions could accelerate targeted therapeutic development and reduce DUP. We applied Partial Least Squares correlation (PLSc) to derive whole-brain resting-state functional connectivity (RSFC) and anatomical (cortical thickness and subcortical volume) signatures associated with five psychopathology dimensions (positive symptoms, negative symptoms, general psychopathology, mania, and cognition) in a transdiagnostic sample from the Human Connectome Project-Early Psychosis (HCP-EP; n=124). We tested associations with potential confounds including antipsychotic medication dosage and substance use. Signatures were spatially correlated with 21 Positron Emission Tomography (PET)-derived receptor and transporter maps across 9 neurotransmitter systems using the neuromaps toolbox. Significant RSFC signatures emerged for positive symptoms, negative symptoms, general psychopathology, and cognition, but not mania. The negative symptom RSFC signature correlated with norepinephrine transporter (NET; {rho}=.40, q=.030) and vesicular acetylcholine transporter (VAChT; {rho}=.38, q=.048) distributions. The cognition signature similarly correlated with VAChT ({rho}=.48, q=.025). Anatomical signatures were associated with positive symptoms, general psychopathology, and cognition, but were more susceptible to confounding by medication and substance use. No significant receptor associations were detected for anatomical signatures. These findings implicate cholinergic and noradrenergic systems as molecular targets for negative symptoms and cognitive impairment, supporting prioritization of these systems in pharmacotherapy development in early psychosis.

neuroscience↗

Individual differences in artificial neural networks capture individual differences in human behavior

Human behavior differs substantially across individuals. While artificial neural networks (ANNs) are regarded as promising models of human perception, they are often assumed to lack such individual differences. Here, we demonstrate that multiple instances of the same ANN architecture exhibit substantial individual differences in behavior that mimic those observed in humans. We trained and tested 60 ANN instances from three architectures on a digit recognition task and found notable individual differences in overall accuracy, confidence, and response time (RT). Critically, these individual differences in ANN instances mapped consistently onto the individual differences produced by 60 humans performing the same task, with the mapping strength often approaching the human-to-human benchmark across all three behavioral metrics (accuracy, confidence, RT). The mapping generalized even across behavioral metrics: an ANN instance that aligned with an individual human on accuracy also aligned with the same individual on confidence and RT. These findings generalized to a more complex, 10-choice blurry object recognition task, though the human-ANN mapping was generally less robust than the human-human benchmark. Overall, these findings open the possibility of using ANN ensembles as computational proxies for probing the mechanisms underlying human variability.

neuroscience↗

Human-like individual differences emerge from random weight initializations in neural networks

Much of AI research targets the behavior of an average human, a focus that traces to Turings imitation game. Yet, no two human individuals behave exactly alike. In this study, we show that artificial neural networks (ANNs) trained with different random initializations exhibit substantial individual differences that resemble those in humans. Using a large dataset (N = 60) of human responses (accuracy, confidence, & response time) in a digit recognition task, we trained multiple instances of three ANN architectures on the same task, creating as many ANN instances as human subjects. We found that these ANN instances vary significantly from one another. Critically, ANN instances showed consistent variation in their alignment with specific human subjects. This consistency in alignment between ANN instances and humans extended across behavioral metrics, indicating that an ANN instance mimicking an individual on one metric also does so on others. Finally, we showed that leveraging these alignments improves predictions of individual human responses. Our findings highlight the potential of ANNs to capture human variability, opening new directions to develop models that go beyond aligning the average human and instead aligning the idiosyncratic behavior of specific individuals.

neuroscience↗

Convergent and Divergent Cerebellar Alterations in 22q11.2 Copy Number Variants

BackgroundIndividuals with copy number variants (CNVs) at 22q11.2 are at elevated risk for neurodevelopmental and psychiatric disorders, including autism spectrum disorder and intellectual disability. For psychosis, effects diverge, with 22q11.2 deletion (22qDel) conferring one of the highest known risks for schizophrenia, while duplication (22qDup) may be protective. Prior investigations of neurobiological mechanisms in 22q11.2 CNVs have predominantly focused on the cerebrum, whereas the cerebellum--a region increasingly recognized for its contributions to cognitive, affective, and social processes--remains underexplored and represents a promising target for investigation. Although alterations in cerebellar structure have been reported in 22qDel, they remain largely unexplored in 22qDup. This study provides the first characterization of regional cerebellar volumes in 22qDup and the first direct comparison of cerebellar structure across 22q11.2 CNVs, offering a unique opportunity to identify shared and distinct neurobiological mechanisms with implications for understanding cerebellar contributions to brain-behavior relationships in CNV carriers. MethodsWe analyzed 514 longitudinally collected structural Magnetic Resonance Imaging (MRI) scans of 111 individuals with 22qDel, 37 individuals with 22qDup, and 167 typically developing (TD) controls. Total and regional cerebellar volumes were quantified using ACAPULCO, a deep-learning-based parcellation method that segments the cerebellum into 28 subregions. Group differences in cerebellar volumes, as well as their associations with cognition, autism-related traits, and psychosis-risk symptoms, were examined using linear mixed-effects models. False discovery rate (FDR) correction was applied to control for multiple comparisons where appropriate. ResultsIn relation to TD controls, cerebellar volumes were broadly reduced in 22qDel, whereas cerebellar alterations in 22qDup were more modest and variable. Regional analyses revealed both linear (22qDel < TD < 22qDup) and nonlinear (22qDel {approx} 22qDup < TD; 22qDel < 22qDup < TD) gene-dosage patterns, though not all reached significance. Vermis VII was significantly reduced in both CNVs but showed no relationship to behavioral differences. In contrast, reduction of Right Lobule VIIIA was associated with greater social impairment in 22qDup. Unlike TD controls, this region was not associated with IQ in 22qDup, suggesting CNV-specific alterations in cerebellar-behavior relationships. ConclusionThese findings indicate that reciprocal CNVs at the 22q11.2 locus both affect cerebellar structure, yet their functional consequences diverge, suggesting overlapping but distinct pathways to clinical risk. They underscore the cerebellums multifaceted role in neurodevelopment and highlight the need for studies examining broader cognitive and socio-affective domains, as well as cerebellar-cortical connectivity, to clarify links to clinical outcomes.

neuroscience↗

Gene dosage effects of 22q11.2 copy number variants on in-vivo measures of white matter axonal density and dispersion

22q11.2 deletion (22qDel) and duplication (22qDup) carriers have an increased risk of neurodevelopmental disorders and exhibit altered brain structure, including white matter microstructure. However, the underlying cellular architecture and age-related changes contributing to these white matter alterations remain poorly understood. Neurite orientation dispersion and density imaging (NODDI) was used on mixed cross-sectional and longitudinal data to examine group differences and age-related trajectories in measures of axonal density (i.e., intracellular volume fraction; ICVF), axonal orientation (orientation dispersion index; ODI) and free water diffusion (isotropic volume fraction; ISO) in 50 22qDel (n scans = 69, mean age = 20.7, age range = 7.4-51.1, 64.0% female) and 24 22qDup (n scans = 34, mean age = 21.6, age range = 8.3-49.4, 54.2% female) carriers, and 890 controls (n scans = 901, mean age = 21.9, age range = 7.8-51.1, 54.5% female). The results showed widespread gene dosage effects, with higher ICVF in 22qDel and lower ICVF in 22qDup compared to controls, and region-specific effects of the 22qDel and 22qDup on ODI and ISO measures. However, 22qDel and 22qDup carriers did not exhibit altered age-related trajectories relative to controls. Observed differences in ICVF suggest higher white matter axonal density in 22qDel and lower axonal density in 22qDup compared to controls. Conversely, differences in ODI are highly localized, indicating region-specific effects on axonal dispersion in white matter. We do not find evidence for altered developmental trajectories of axonal density or dispersion among 22q11.2 CNV carriers, suggesting stable disruptions to neurodevelopmental events before childhood.

neuroscience↗

Unique functional neuroimaging signatures of genetic versus clinical high risk for psychosis

Background22q11.2 Deletion Syndrome (22qDel) is a copy number variant (CNV) associated with psychosis and other neurodevelopmental disorders. Adolescents at clinical high risk for psychosis (CHR) have subthreshold psychosis symptoms without known genetic risk factors. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped results to biological pathways. MethodsWe analyzed two large multi-site cohorts with resting-state functional MRI (rs-fMRI): 1) 22qDel (n=164, 47% female) and typically developing (TD) controls (n=134, 56% female); 2) CHR individuals (n=244, 41% female) and TD controls (n=151, 46% female) from the North American Prodrome Longitudinal Study-2. We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions, testing case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation. ResultsBSV, LC, and GBC are significantly disrupted in 22qDel compared with TD controls (False Discovery Rate q<0.05). Spatial maps of BSV and LC differences are highly correlated with each other, unlike GBC. In CHR, only LC is significantly altered versus controls, with a different spatial pattern compared to 22qDel. Group differences map onto biological gradients, with 22qDel effects strongest in regions with high predicted blood flow and metabolism. Conclusion22qDel and CHR exhibit divergent effects on fMRI temporal variability and multi-scale functional connectivity. In 22qDel, strong and convergent disruptions in BSV and LC not seen in CHR individuals suggest distinct functional brain alterations.

neuroscience↗

Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in 22qDel (n=96, 53.1% female), 22qDup (n=37, 45.9% female), and TD controls (n=80, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the effect of 22q11.2 gene dosage was examined using linear mixed models. Age-related changes were characterized with general additive mixed models (GAMMs). Positive gene dosage effects (22qDel < TD < 22qDup) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age- related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

neuroscience↗

Insights into a viral motor: the structure of the HK97 packaging termination assembly

Double-stranded DNA viruses utilise machinery, made of terminase proteins, to package viral DNA into the capsid. For cos bacteriophage, a defined signal, recognised by small terminase, flanks each genome unit. Here we present the first structural data for a cos virus DNA packaging motor, assembled from the bacteriophage HK97 terminase proteins, procapsids encompassing the portal protein, and DNA containing a cos site. The cryo-EM structure is consistent with the packaging termination state adopted after DNA cleavage, with DNA density within the large terminase assembly ending abruptly at the portal protein entrance. Retention of the large terminase complex after cleavage of the short DNA substrate suggests that motor dissociation from the capsid requires headful pressure, in common with pac viruses. Interestingly, the clip domain of the 12-subunit portal protein does not adhere to C12 symmetry, indicating asymmetry induced by binding of the large terminase/DNA. The motor assembly is also highly asymmetric, showing a ring of 5 large terminase monomers, tilted against the portal. Variable degrees of extension between N- and C-terminal domains of individual subunits suggest a mechanism of DNA translocation driven by inter-domain contraction and relaxation.

molecular biology↗

Engineering of Chimeric Antigen Receptor T Cells with integrin αEβ7 Results in Augmented Therapeutic Efficacy against E-cadherin positive tumor

Integrin E{beta}7 (CD103) can interact with E-cadherin and promote T cell retention in epithelial tissue. However, whether the expression of CD103 on chimeric antigen receptor (CAR)-T cells may augment T cell anti-tumor activity remains unknown. Using a preclinical model, we demonstrate that CD103 engineering of human CAR-T cells significantly improves their therapeutic effects on eliminating pre-established E-cadherin expressing tumor cells in immune deficient NOD.scid.Il2R{gamma}cnull (NSG) mice. Human T cells that were engineered with CAR containing 4-1BB and CD3zeta intracellular signaling domains (named BBz) expressed reduced level of CD103 in mice model. Ex vivo assays confirmed the effect of 4-1BB on repressing CD103 expression in CAR-T cells. On the other hand, we generated CD103 expressing CAR-T cells by introducing the E gene into the CAR structure (named CD103-BBz CAR-T cells). As compared to BBz CAR-T cells, CD103-BBz CAR-T cells produced higher levels of IL-2 and underwent greater expansion in cultures and acquired greater capacity to control the growth and metastasis of E-cadherin expressing lymphoma cells in NSG mice. This effect of CD103-BBz CAR-T cells was associated with their increased capacity to infiltrate into the tumor and persist in vivo, leading to significantly improved overall survival of lymphoma mice. Our findings suggest that engineering tumor-reactive T cells with CD103 may represent a novel strategy to improve adoptive T cells anti-tumor efficacy, and this strategy may have broad implication in the epithelial solid tumor treatment.\n\nHighlightsO_LICAR-T cells with 4-1BB costimulatory domain express reduced level of CD103\nC_LIO_LI4-1BB signaling antagonist TGF-{beta}1 induced CD103 expression\nC_LIO_LIEctopically expression of CD103 on CAR-T cells enhanced their anti-E-cadherin positive tumor capacity\nC_LI\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC=\"FIGDIR/small/727446v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (19K):\norg.highwire.dtl.DTLVardef@d32377org.highwire.dtl.DTLVardef@1bd841corg.highwire.dtl.DTLVardef@12c5c98org.highwire.dtl.DTLVardef@173382d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract:\n\nGraphic Summary: The co-stimulatory molecule 4-1BB within the CAR protein potently suppresses CD103 expression. Engineering CAR-T cells with CD103 significantly enhances their capacity to proliferate and infiltrate into the solid tumor, leading to augmented anti-tumor immunity.\n\nC_FIG

immunology↗