Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

Identifying Game-Based Digital Biomarkers of Cognitive Risk for Adolescent Substance Misuse: Protocol for a Proof-of-Concept Study.

BACKGROUND: Adolescents at risk for substance misuse are rarely identified early due to existing barriers to screening that include the lack of time and privacy in clinic settings. Games can be used for screening and thus mitigate these barriers. Performance in a game is influenced by cognitive processes such as working memory and inhibitory control. Deficits in these cognitive processes can increase the risk of substance use. Further, substance misuse affects these cognitive processes and may influence game performance, captured by in-game metrics such as reaction time or time for task completion. Digital biomarkers are measures generated from digital tools that explain underlying health processes and can be used to predict, identify, and monitor health outcomes. As such, in-game performance metrics may represent digital biomarkers of cognitive processes that can offer an objective method for assessing underlying risk for substance misuse. OBJECTIVE: This is a protocol for a proof-of-concept study to investigate the utility of in-game performance metrics as digital biomarkers of cognitive processes implicated in the development of substance misuse. METHODS: This study has 2 aims. In aim 1, using previously collected data from 166 adolescents aged 11-14 years, we extracted in-game performance metrics from a video game and are using machine learning methods to determine whether these metrics predict substance misuse. The extraction of in-game performance metrics was guided by literature review of in-game performance metrics and gameplay guidebooks provided by the game developers. In aim 2, using data from a new sample of 30 adolescents playing the same video game, we will test if metrics identified in aim 1 correlate with cognitive processes. Our hypothesis is that in-game performance metrics that are predictive of substance misuse in aim 1 will correlate with poor cognitive function in our second sample. RESULTS: This study was funded by National Institute on Drug Abuse through the Center for Technology and Behavioral Health Pilot Core in May 2022. To date, we have extracted 285 in-game performance metrics. We obtained institutional review board approval on October 11, 2022. Data collection for aim 2 is ongoing and projected to end in February 2024. Currently, we have enrolled 12 participants. Data analysis for aim 2 will begin once data collection is completed. The results from both aims will be reported in a subsequent publication, expected to be published in late 2024. CONCLUSIONS: Screening adolescents for substance use is not consistently done due to barriers that include the lack of time. Using games that provide an objective measure to identify adolescents at risk for substance misuse can increase screening rates, early identification, and intervention. The results will inform the utility of in-game performance metrics as digital biomarkers for identifying adolescents at high risk for substance misuse. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46990.

GuaRD: Guaranteed robustness of image retrieval system under data distortion turbulence.

Image search systems could be endangered by adversarial attacks and data perturbations. The image retrieval system can be compromised either by distorting the query or hacking the ranking system. However, existing literature primarily discusses attack methods, whereas the research on countermeasures to defend against such adversarial attacks is rare. As a defense mechanism against the intrusions, quality assessment can complement existing image retrieval systems. "GuaRD" is proposed as an end-to-end framework that uses the quality metric as a weighted-regularization term. Proper utilization and balance of the two features could lead to reliable and robust ranking; the original image is assigned a higher rank while the distorted image is assigned a relatively lower rank. Meanwhile, the primary goal of the image retrieval system is to prioritize searching the relevant images. Therefore, the use of leveraged features should not compromise the accuracy of the system. To evaluate the generality of the framework, we conducted three experiments on two image quality assessment(IQA) benchmarks (Waterloo and PieAPP). For the first two tests, GuaRD achieved enhanced performance than the existing model: the mean reciprocal rank(mRR) value of the original image predictions increased by 61%, and the predictions for the distorted input query decreased by 18%. The third experiment was conducted to analyze the mean average precision (mAP) score of the system to verify the accuracy of the retrieval system. The results indicated little deviation in performance between the tested methods, and the score was not effected or slightly decreased by 0.9% after the GuaRD was applied. Therefore, GuaRD is a novel and robust framework that can act as a defense mechanism for data distortions.

Individual differences in spatial working memory strategies differentially reflected in the engagement of control and default brain networks.

Spatial locations can be encoded and maintained in working memory using high-precision, fine-grained representations that are cognitively demanding, or coarse and less demanding categorical representations. In this study, we employed an individual differences approach to identify brain activity correlates of the use of fine-grained and categorical representations in spatial working memory. We combined data from six fMRI studies, resulting in a sample of 153 (77 women, 25 ± 6 years) healthy participants performing a spatial working memory task. Our results showed that individual differences in the use of spatial representations in working memory were associated with distinct patterns of brain activation, with fine-grained representations requiring greater engagement of attentional and control brain systems, while categorical representations were associated with decreased inhibition of the default network. These findings may indicate a greater need for ongoing maintenance and protection against interference for fine-grained compared to categorical representations.

The spatial extent of anatomical connections within the thalamus varies across the cortical hierarchy in humans and macaques.

Each cortical area has a distinct pattern of anatomical connections within the thalamus, a central subcortical structure composed of functionally and structurally distinct nuclei. Previous studies have suggested that certain cortical areas may have more extensive anatomical connections that target multiple thalamic nuclei, which potentially allows them to modulate distributed information flow. However, there is a lack of quantitative investigations into anatomical connectivity patterns within the thalamus. Consequently, it remains unknown if cortical areas exhibit systematic differences in the extent of their anatomical connections within the thalamus. To address this knowledge gap, we used diffusion magnetic resonance imaging (dMRI) to perform brain-wide probabilistic tractography for 828 healthy adults from the Human Connectome Project. We then developed a framework to quantify the spatial extent of each cortical area's anatomical connections within the thalamus. Additionally, we leveraged resting-state functional MRI, cortical myelin, and human neural gene expression data to test if the extent of anatomical connections within the thalamus varied along the cortical hierarchy. Our results revealed two distinct corticothalamic tractography motifs: 1) a sensorimotor cortical motif characterized by focal thalamic connections targeting posterolateral thalamus, associated with fast, feed-forward information flow; and 2) an associative cortical motif characterized by diffuse thalamic connections targeting anteromedial thalamus, associated with slow, feed-back information flow. These findings were consistent across human subjects and were also observed in macaques, indicating cross-species generalizability. Overall, our study demonstrates that sensorimotor and association cortical areas exhibit differences in the spatial extent of their anatomical connections within the thalamus, which may support functionally-distinct cortico-thalamic information flow.

Illness Phase as a Key Assessment and Intervention Window for Psychosis.

The phenotype of schizophrenia, regardless of etiology, represents the most studied psychotic disorder with respect to neurobiology and distinct phases of illness. The early phase of illness represents a unique opportunity to provide effective and individualized interventions that can alter illness trajectories. Developmental age and illness stage, including temporal variation in neurobiology, can be targeted to develop phase-specific clinical assessment, biomarkers, and interventions. We review an earlier model whereby an initial glutamate signaling deficit progresses through different phases of allostatic adaptation, moving from potentially reversible functional abnormalities associated with early psychosis and working memory dysfunction, and ending with difficult-to-reverse structural changes after chronic illness. We integrate this model with evidence of dopaminergic abnormalities, including cortical D1 dysfunction, which develop during adolescence. We discuss how this model and a focus on a potential critical window of intervention in the early stages of schizophrenia impact the approach to research design and clinical care. This impact includes stage-specific considerations for symptom assessment as well as genetic, cognitive, and neurophysiological biomarkers. We examine how phase-specific biomarkers of illness phase and brain development can be incorporated into current strategies for large-scale research and clinical programs implementing coordinated specialty care. We highlight working memory and D1 dysfunction as early treatment targets that can substantially affect functional outcome.

Changes to Gut Microbiota Following Systemic Antibiotic Administration in Infants.

Long-term antibiotic use can have consequences on systemic diseases, such as obesity, allergy, and depression, implicating the causal role of gut microbiome imbalance. However, the evaluation of the effect of antibiotics in early infancy on alterations to the gut microbiome remains poorly understood. This study aimed to evaluate the gut microbiome state in infancy following systemic antibiotic treatment. Twenty infants under 3 months of age who had received antibiotics for at least 3 days were enrolled, and their fecal samples were collected 4 weeks after antibiotic administration finished. Thirty-four age-matched healthy controls without prior exposure to antibiotics were also assessed. The relative bacterial abundance in feces was obtained via sequencing of 16 S rRNA genes, and alpha and beta diversities were evaluated. At the genus level, the relative abundance of Escherichia/Shigella and Bifidobacterium increased (p = 0.03 and p = 0.017, respectively) but that of Bacteroides decreased (p = 0.02) in the antibiotic treatment group. The microbiome of the antibiotic treatment group exhibited an alpha diversity lower than that of the control group. Thus, systemic antibiotic administration in early infancy affects the gut microbiome composition even after a month has passed; long-term studies are needed to further evaluate this.

Reward and loss incentives improve spatial working memory by shaping trial-by-trial posterior frontoparietal signals.

Integrating motivational signals with cognition is critical for goal-directed activities. The mechanisms that link neural changes with motivated working memory continue to be understood. Here, we tested how externally cued and non-cued (internally represented) reward and loss impact spatial working memory precision and neural circuits in human subjects using fMRI. We translated the classic delayed-response spatial working memory paradigm from non-human primate studies to take advantage of a continuous numeric measure of working memory precision, and the wealth of translational neuroscience yielded by these studies. Our results demonstrated that both cued and non-cued reward and loss improved spatial working memory precision. Visual association regions of the posterior prefrontal and parietal cortices, specifically the precentral sulcus (PCS) and intraparietal sulcus (IPS), had increased BOLD signal during incentivized spatial working memory. A subset of these regions had trial-by-trial increases in BOLD signal that were associated with better working memory precision, suggesting that these regions may be critical for linking neural signals with motivated working memory. In contrast, regions straddling executive networks, including areas in the dorsolateral prefrontal cortex, anterior parietal cortex and cerebellum displayed decreased BOLD signal during incentivized working memory. While reward and loss similarly impacted working memory processes, they dissociated during feedback when money won or avoided in loss was given based on working memory performance. During feedback, the trial-by-trial amount and valence of reward/loss received was dissociated amongst regions such as the ventral striatum, habenula and periaqueductal gray. Overall, this work suggests motivated spatial working memory is supported by complex sensory processes, and that the IPS and PCS in the posterior frontoparietal cortices may be key regions for integrating motivational signals with spatial working memory precision.

Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia.

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.

Mapping brain-behavior space relationships along the psychosis spectrum.

Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlight a need to develop a stable neurobiologically grounded mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 PSD patients spanning several diagnoses, we derived and replicated a dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits. In turn, these symptom axes mapped onto distinct, reproducible brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) do not produce stable results with current sample sizes. However, we show that a univariate brain-behavioral space (BBS) can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and neural gene expression maps derived from the Allen Human Brain Atlas. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable path that can be iteratively optimized for personalized clinical biomarker endpoints.

Refining the Empirical Constraints on Computational Models of Spatial Working Memory in Schizophrenia.

BACKGROUND: Impairments in spatial working memory (sWM) have been well documented in schizophrenia. Here we provide a comprehensive test of a microcircuit model of WM performance in schizophrenia that predicts enhanced effects of increasing delay duration and distractors based on a hypothesized imbalance of excitatory and inhibitory processes. METHODS: Model predictions were tested in 41 people with schizophrenia (PSZ) and 32 healthy control subjects (HCS) performing an sWM task. In one condition, a single target location was followed by delays of 0, 2, 4, or 8 seconds. In a second condition, distractors were presented during the 4-second delay interval at 20°, 30°, 40°, 50°, or 90° from the original target location. RESULTS: PSZ showed less precise sWM representations than HCS, and the rate of memory drift over time was greater in PSZ than in HCS. Relative to HCS, the spatial recall responses of PSZ were more repelled by distractors presented close to the target location and more attracted by distractors presented far from the target location. The degree of attraction to distant distractors was correlated with the rate of memory drift in the absence of distractors. CONCLUSIONS: Consistent with the microcircuit model, PSZ exhibited both a greater rate of drift and greater attraction to distant distractors relative to HCS. These two effects were correlated, consistent with the proposal that they arise from a single underlying mechanism. However, the repulsion effects produced by nearby distractors were not predicted by the model and thus require an updated modeling framework.

Epidemiological Investigation of Tick Species from Near Domestic Animal Farms and Cattle, Goat, and Wild Boar in Korea.

This study aimed to investigate the tick species and give background for tick-borne investigations in Korea. Ticks were collected from the area within 2 km radius of the 4 domestic animal farms, where they were located in mountainous areas and raising animals on pasture, and from animal bodies in 2014 and 2015. In total, 7,973 nymphal and adult ticks were collected from the farms - 7,758 Haemaphysalis longicornis, 198 Haemaphysalis flava, and 17 Ixodes nipponensis, and 1,763 were collected from animals - 729 H. longicornis from cattle; 569 H. longicornis from goats; and 297 H. longicornis, 118 H. flava, 1 I. nipponensis, and 49 Amblyomma testudinarium from wild boars. As more species of ticks were collected from wild boars than domesticated animals and their habitats, various animal hosts should be considered while investigating tick species.

Association of the Vitamin D Level and Quality of School Life in Adolescents with Irritable Bowel Syndrome.

There is no treatment of choice for irritable bowel syndrome, which affects up to 20% of school-aged children. This cross-sectional study evaluated the difference in the average vitamin D level between subtypes of irritable bowel syndrome, and the relationship between the vitamin D level as well as the severity of irritable bowel syndrome symptoms. We included 124 adolescents aged 10⁻17 years (68 boys, 56 girls; mean age 12.29 ± 1.92 years) from 2014 to 2016. Patients with irritable bowel syndrome were diagnosed by Rome III criteria and classified by clinical manifestation: irritable bowel syndrome with constipation (n = 29), irritable bowel syndrome with diarrhea (n = 63), and irritable bowel syndrome with constipation and diarrhea (n = 32). The severity of irritable bowel syndrome symptoms and school absence were evaluated. Vitamin D levels were measured by serum 25-hydroxyvitamin D. The chi-square test and analysis of variance were used. The patients' average vitamin D level was 16.25 ± 6.58 ng/mL. There was a significant negative association of the 25-hydroxyvitamin D level with symptom severity and school absence (p = 0.022 and p < 0.001, respectively). Vitamin D supplementation could be considered as a choice of therapeutic method.

Effects of reward on spatial working memory in schizophrenia.

Reward processing and cognition are disrupted in schizophrenia (SCZ), yet how these processes interface is unknown. In SCZ, deficits in reward representation may affect motivated, goal-directed behaviors. To test this, we examined the effects of monetary reward on spatial working memory (WM) performance in patients with SCZ. To capture complimentary effects, we tested biophysically grounded computational models of neuropharmacologic manipulations onto a canonical fronto-parietal association cortical microcircuit capable of WM computations. Patients with SCZ (n = 33) and healthy control subjects (HCS; n = 32) performed a spatial WM task with 2 reward manipulations: reward cues presented prior to each trial, or contextually prior to a block of trials. WM performance was compared with cortical circuit models of WM subjected to feed-forward glutamatergic excitation, feed-forward GABAergic inhibition, or recurrent modulation strengthening local connections. Results demonstrated that both groups improved WM performance to reward cues presented prior to each trial (HCS d = -0.62; SCZ d = -1.0), with percent improvement correlating with baseline WM performance (r = .472, p < .001). However, rewards presented contextually before a block of trials did not improve WM performance in patients with SCZ (d = 0.01). Modeling simulations achieved improved WM precision through strengthened local connections via neuromodulation, or feed-forward inhibition. Taken together, this work demonstrates that patients with SCZ can improve WM performance to short-term, but not longer-term rewards-thus, motivated behaviors may be limited by strength of reward representation. A potential mechanism for transiently improved WM performance may be strengthening of local fronto-parietal microcircuit connections via neuromodulation or feed-forward inhibitory drive. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The natural history of fetal diagnosed isolated ventricular septal defect.

OBJECTIVE: This study was undertaken to clarify the natural course of ventricular septal defect, and to find an index that would help in prenatal counseling. METHODS: Between January 2010 and December 2014, 18 188 fetuses underwent echocardiographic examinations. Of these, 228 isolated ventricular septal defect cases were retrospectively reviewed. RESULTS: In this retrospective study, the incidence of isolated ventricular septal defect was 1.25% (228/18 188). There were 146 patients who underwent echocardiography after delivery in order to confirm the natural course of patients with isolated ventricular septal defect. Of the 146 cases, 64 cases (43.84%) had the ventricular septal defect naturally closed in the fetal period. Of the 82 patients with ventricular septal defect at birth, 25 patients showed natural closure during follow-up. However, four patients (2.74%) required surgical treatment for ventricular septal defect. In case of perimembranous defects, natural closure is more frequent in the fetal period than in the postnatal period. CONCLUSION: Our results indicate that 60.96% (89/146) of isolated ventricular septal defects diagnosed during the fetal life are closed naturally. Perimembranous type defect, small defect (<2 mm) and maternal age less than 35 years are the good prognostic factors for the natural closure during fetal life. © 2017 John Wiley & Sons, Ltd.

Molecular detection of severe fever with thrombocytopenia syndrome virus (SFTSV) in feral cats from Seoul, Korea.

This study tested serum samples of feral cats from a highly urbanized habitat, Seoul, Korea to determine the infection to severe fever with thrombocytopenia syndrome virus (SFTSV). From 126 samples tested, SFTSV was detected by RT-PCR in 22 (17.5%) cats from various sites of Seoul. Sequences identified from this study were grouped with clusters from China and Japan. Our result provides data that SFTSV may have been circulating in settings that were suspected to have relatively low risk, such as highly urbanized habitats. Thus it warrants further study to investigate the ecology of SFTSV in urban-dwelling animals including ticks, human and other potential host species.

Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition.

Schizophrenia is associated with severe cognitive deficits, including impaired working memory (WM). A neural mechanism that may contribute to WM impairment is the disruption in excitation-inhibition (E/I) balance in cortical microcircuits. It remains unknown, however, how these alterations map onto quantifiable behavioral deficits in patients. Based on predictions from a validated microcircuit model of spatial WM, we hypothesized two key behavioral consequences: i) increased variability of WM traces over time, reducing performance precision; and ii) decreased ability to filter out distractors that overlap with WM representations. To test model predictions, we studied N=27 schizophrenia patients and N=28 matched healthy comparison subjects (HCS) who performed a spatial WM task designed to test the computational model. Specifically, we manipulated delay duration and distractor distance presented during the delay. Subjects used a high-sensitivity joystick to indicate the remembered location, yielding a continuous response measure. Results largely followed model predictions, whereby patients exhibited increased variance and less WM precision as the delay period increased relative to HCS. Schizophrenia patients also exhibited increased WM distractibility, with reports biased toward distractors at specific spatial locations, as predicted by the model. Finally, the magnitude of the WM drift and distractibility were significantly correlated, indicating a possibly shared underlying mechanism. Effects are consistent with elevated E/I ratio in schizophrenia, establishing a framework for translating neural circuit computational model of cognition to human experiments, explicitly testing mechanistic behavioral hypotheses of cellular-level neural deficits in patients.