Dorsal and ventral fronto-amygdala networks underlie risky decision-making in age-related cognitive decline.

Older adults often have difficulty in making decisions under uncertainty, increasing the risk of financial exploitation. However, it is still under investigation about the extent to which cognitive decline influences risky decision-making and the underlying neural correlates. We hypothesized that the individual differences of risk-taking behavior depend on cognitive integrity, in which the dorsal and ventral fronto-amygdala connectivity would play dissociable roles. In the current study, thirty-six young and 51 older adults were tested with the Iowa gambling task combing resting-state and task-related functional magnetic resonance imaging. The results showed significant changes in behaviors and the fronto-amygdala network in older adults relative to young adults. More importantly, age-effect on risk-taking behaviors was remarkably different in cognitively normal and impaired older adults. In resting-state analysis, task performance was positively correlated with the ventral fronto-amygdala connectivity and negatively correlated with the dorsal fronto-amygdala connectivity in cognitively impaired older adults, compared with cognitively normal individuals. Furthermore, task-related analysis confirmed the relationships between dorsal/ventral fronto-amygdala network and risk-taking behaviors depending on cognitive integrity. These findings indicate that the fronto-amygdala network is crucial for understanding altered risky decision-making in aging, suggesting dissociable contributions of the dorsal and ventral pathways in the context of cognitive decline.

Predictors of smoking cessation outcomes identified by machine learning: A systematic review.

This systematic review aims to characterize the utility of machine learning to identify the predictors of smoking cessation outcomes and identify the machine learning methods applied in this area. In the current study, multiple searches occurred through December 9, 2022 in MEDLINE, Science Citation Index, Social Science Citation Index, EMBASE, CINAHL Plus, APA PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, and the IEEE Xplore were performed. Inclusion criteria included various machine learning techniques, studies reporting cigarette smoking cessation outcomes (smoking status and the number of cigarettes), and various experimental designs (e.g., cross-sectional and longitudinal). Predictors of smoking cessation outcomes were assessed, including behavioral markers, biomarkers, and other predictors. Our systematic review identified 12 papers fitting our inclusion criteria. In this review, we identified gaps in knowledge and innovation opportunities for machine learning research in the field of smoking cessation.

Enhanced putamen functional connectivity underlies altered risky decision-making in age-related cognitive decline.

Risky decision-making is critical to survival and development, which has been compromised in elderly populations. However, the neural substrates of altered financial risk-taking behavior in aging are still under-investigated. Here we examined the intrinsic putamen network in modulating risk-taking behaviors of Balloon Analogue Risk Task in healthy young and older adults using resting-state fMRI. Compared with the young group, the elderly group showed significantly different task performance. Based on the task performance, older adults were further subdivided into two subgroups, showing young-like and over-conservative risk behaviors, regardless of cognitive decline. Compared with young adults, the intrinsic pattern of putamen connectivity was significantly different in over-conservative older adults, but not in young-like older adults. Notably, age-effects on risk behaviors were mediated via the putamen functional connectivity. In addition, the putamen gray matter volume showed significantly different relationships with risk behaviors and functional connectivity in over-conservative older adults. Our findings suggest that reward-based risky behaviors might be a sensitive indicator of brain aging, highlighting the critical role of the putamen network in maintaining optimal risky decision-making in age-related cognitive decline.

Deficiency in the cell-adhesion molecule dscaml1 impairs hypothalamic CRH neuron development and perturbs normal neuroendocrine stress axis function.

The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified Down syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function. In dscaml1 mutant animals, hypothalamic CRH neurons had higher crhb (the CRH homolog in zebrafish) expression, increased cell number, and reduced cell death compared to wild-type controls. Physiologically, dscaml1 mutant animals had higher baseline stress hormone (cortisol) levels and attenuated responses to acute stressors. Together, these findings identify dscaml1 as an essential factor for stress axis development and suggest that HPA axis dysregulation may contribute to the etiology of human DSCAML1-linked neuropsychiatric disorders.

Frontopolar tDCS Induces Frequency-Dependent Changes of Spontaneous Low-Frequency Fluctuations: A Resting-State fMRI Study.

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique that can modulate cortical excitability and behavioral performance. However, its effects on spontaneous low-frequency fluctuations of brain activity are still poorly understood. Here, we systematically investigated the frontopolar tDCS effects on resting-state brain activity and connectivity. Twelve healthy participants were recruited and received anode, cathode, and sham stimulation in a randomized order. Resting-state functional magnetic resonance imaging was performed before and after stimulation. Functional connectivity was calculated to examine tDCS effects within and beyond the frontopolar network. To assess the frequency-dependent changes of brain activity, fractional amplitude of low-frequency fluctuations (fALFF) was computed in the slow-4 (0.027-0.073 Hz) and slow-5 (0.01-0.027 Hz) bands. The results showed anodal tDCS-induced widespread connectivity reduction within and beyond the frontopolar network. Regardless of tDCS polarity, stimulation effect on fALFF was significantly larger in slow-5 band compared with the slow-4. Notably, anodal tDCS-induced connectivity changes were associated with pre-tDCS fALFF in slow-4 band, showing positive correlations in the frontal regions and negative correlations in the temporal regions. Our findings imply that tDCS-induced brain alterations may be frequency-dependent, and pre-tDCS regional brain activity could be used to predict post-tDCS connectivity changes.

Cre-Dependent Anterograde Transsynaptic Labeling and Functional Imaging in Zebrafish Using VSV With Reduced Cytotoxicity.

The small size and translucency of larval zebrafish (Danio rerio) have made it a unique experimental system to investigate whole-brain neural circuit structure and function. Still, the connectivity patterns between most neuronal types remain mostly unknown. This gap in knowledge underscores the critical need for effective neural circuit mapping tools, especially ones that can integrate structural and functional analyses. To address this, we previously developed a vesicular stomatitis virus (VSV) based approach called Tracer with Restricted Anterograde Spread (TRAS). TRAS utilizes lentivirus to complement replication-incompetent VSV (VSVΔG) to allow restricted (monosynaptic) anterograde labeling from projection neurons to their target cells in the brain. Here, we report the second generation of TRAS (TRAS-M51R), which utilizes a mutant variant of VSVΔG [VSV(M51R)ΔG] with reduced cytotoxicity. Within the primary visual pathway, we found that TRAS-M51R significantly improved long-term viability of transsynaptic labeling (compared to TRAS) while maintaining anterograde spread activity. By using Cre-expressing VSV(M51R)ΔG, TRAS-M51R could selectively label excitatory (vglut2a positive) and inhibitory (gad1b positive) retinorecipient neurons. We further show that these labeled excitatory and inhibitory retinorecipient neurons retained neuronal excitability upon visual stimulation at 5-8 days post fertilization (2-5 days post-infection). Together, these findings show that TRAS-M51R is suitable for neural circuit studies that integrate structural connectivity, cell-type identity, and neurophysiology.

Altered complexity of resting-state BOLD activity in Alzheimer's disease-related neurodegeneration: a multiscale entropy analysis.

Brain complexity, which reflects the ability of the brain to adapt to a changing environment, has been found to be significantly changed with age. However, there is less evidence on the alterations of brain complexity in neurodegenerative disorders such as Alzheimer's disease (AD). Here we investigated the altered complexity of resting-state blood oxygen level-dependent signals in AD-related neurodegeneration using multiscale entropy (MSE) analysis. All participants were recruited from the Alzheimer's Disease Neuroimaging Initiative, including healthy controls (HC, n=62), amnestic mild cognitive impairment (aMCI, n =81) patients, and Alzheimer's disease (AD, n=25) patients. Our results showed time scale-dependent MSE differences across the three groups. In scale=1, significantly changed MSE patterns (HC>aMCI>AD) were found in four brain regions, including the hippocampus, middle frontal gyrus, intraparietal lobe, and superior frontal gyrus. In scale=4, reversed MSE patterns (HC

Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development.

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.This article has an associated First Person interview with the first author of the paper.

Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function.

Down syndrome cell adhesion molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.