Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

Associations between COVID-19 and putative markers of neuroinflammation: A diffusion basis spectrum imaging study.

COVID-19 remains a significant international public health concern. Yet, the mechanisms through which symptomatology emerges remain poorly understood. While SARS-CoV-2 infection may induce prolonged inflammation within the central nervous system, the evidence primarily stems from limited small-scale case investigations. To address this gap, our study capitalized on longitudinal UK Biobank neuroimaging data acquired prior to and following COVID-19 testing (N = 416 including n = 224 COVID-19 cases; Mage = 58.6). Putative neuroinflammation was assessed in gray matter structures and white matter tracts using non-invasive Diffusion Basis Spectrum Imaging (DBSI), which estimates inflammation-related cellularity (DBSI-restricted fraction; DBSI-RF) and vasogenic edema (DBSI-hindered fraction; DBSI-HF). We hypothesized that COVID-19 case status would be associated with increases in DBSI markers after accounting for potential confound (age, sex, race, body mass index, smoking frequency, and data acquisition interval) and multiple testing. COVID-19 case status was not significantly associated with DBSI-RF (|ß|'s < 0.28, pFDR >0.05), but with greater DBSI-HF in left pre- and post-central gyri and right middle frontal gyrus (ß's > 0.3, all pFDR = 0.03). Intriguingly, the brain areas exhibiting increased putative vasogenic edema had previously been linked to COVID-19-related functional and structural alterations, whereas brain regions displaying subtle differences in cellularity between COVID-19 cases and controls included regions within or functionally connected to the olfactory network, which has been implicated in COVID-19 psychopathology. Nevertheless, our study might not have captured acute and transitory neuroinflammatory effects linked to SARS-CoV-2 infection, possibly due to symptom resolution before the imaging scan. Future research is warranted to explore the potential time- and symptom-dependent neuroinflammatory relationship with COVID-19.

The brainstem's red nucleus was evolutionarily upgraded to support goal-directed action.

The red nucleus is a large brainstem structure that coordinates limb movement for locomotion in quadrupedal animals (Basile et al., 2021). The humans red nucleus has a different pattern of anatomical connectivity compared to quadrupeds, suggesting a unique purpose (Hatschek, 1907). Previously the function of the human red nucleus remained unclear at least partly due to methodological limitations with brainstem functional neuroimaging (Sclocco et al., 2018). Here, we used our most advanced resting-state functional connectivity (RSFC) based precision functional mapping (PFM) in highly sampled individuals (n = 5) and large group-averaged datasets (combined N ~ 45,000), to precisely examine red nucleus functional connectivity. Notably, red nucleus functional connectivity to motor-effector networks (somatomotor hand, foot, and mouth) was minimal. Instead, red nucleus functional connectivity along the central sulcus was specific to regions of the recently discovered somato-cognitive action network (SCAN; (Gordon et al., 2023)). Outside of primary motor cortex, red nucleus connectivity was strongest to the cingulo-opercular (CON) and salience networks, involved in action/cognitive control (Dosenbach et al., 2007; Newbold et al., 2021) and reward/motivated behavior (Seeley, 2019), respectively. Functional connectivity to these two networks was organized into discrete dorsal-medial and ventral-lateral zones. Red nucleus functional connectivity to the thalamus recapitulated known structural connectivity of the dento-rubral thalamic tract (DRTT) and could prove clinically useful in functionally targeting the ventral intermediate (VIM) nucleus. In total, our results indicate that far from being a 'motor' structure, the red nucleus is better understood as a brainstem nucleus for implementing goal-directed behavior, integrating behavioral valence and action plans.

A high-density diffuse optical tomography dataset of naturalistic viewing.

Traditional laboratory tasks offer tight experimental control but lack the richness of our everyday human experience. As a result many cognitive neuroscientists have been motivated to adopt experimental paradigms that are more natural, such as stories and movies. Here we describe data collected from 58 healthy adult participants (aged 18-76 years) who viewed 10 minutes of a movie (The Good, the Bad, and the Ugly, 1966). Most (36) participants viewed the clip more than once, resulting in 106 sessions of data. Cortical responses were mapped using high-density diffuse optical tomography (first- through fourth nearest neighbor separations of 1.3, 3.0, 3.9, and 4.7 cm), covering large portions of superficial occipital, temporal, parietal, and frontal lobes. Consistency of measured activity across subjects was quantified using intersubject correlation analysis. Data are provided in both channel format (SNIRF) and projected to standard space (NIfTI), using an atlas-based light model. These data are suitable for methods exploration as well as investigating a wide variety of cognitive phenomena.

Effect of Peanut Paste-based Ready-to-use School Meals With and Without Milk on Fluid Cognition in Northern Ghana: A Randomized Controlled Trial.

BACKGROUND: Few studies have investigated the role of school feeding in low- and middle-income countries as a means of improving childhood cognition. Peanut/milk ready-to-use food (PM-RUF) or cowpea offers an affordable, scalable option that might improve cognition. OBJECTIVES: To determine whether micronutrient-fortified PM-RUF or peanut/cowpea ready-to-use food (PC-RUF) would improve fluid cognition as assessed by 4 tests from the National Institutes of Health Toolbox Cognitive Battery when compared with a micronutrient-fortified millet porridge (FP) after a year of school feeding. METHODS: An individually randomly assigned, investigator-blinded, controlled clinical trial was conducted at 6 schools in Mion District in rural northern Ghana. Eight hundred seventy-one school children aged 5-12 y were randomly assigned and allocated to receive PM-RUF (n = 282), PC-RUF (n = 292), or FP (n = 297), each providing ∼400 kcal/d. The primary outcomes were 4 fluid cognition test scores: Dimensional Change Card Sort test, Flanker Inhibitory Control and Attention test, Pattern Comparison Processing Speed test, and a modified List Sorting Working Memory test. Secondary outcomes included a composite median ranking of the 4 primary outcomes and anthropometry changes. RESULTS: Among the 871 participants (median age, 8.8 y; 47% female), 795 (91%) completed endline cognitive testing. Median attendance rates exceeded 87% in all groups. PM-RUF group demonstrated better fluid cognition on the Dimensional Change Card Sort test [odds ratio (OR): 1.5; 95% CI: 1.1, 2.0; P = 0.016] and Pattern Comparison Processing Speed test (OR: 1.4; 95% CI: 1.0, 1.9; P = 0.026) than FP, whereas there were no significant differences on Flanker Inhibitory Control and Attention or List Sorting Working Memory tests. PC-RUF group demonstrated no improvement over FP on any cognitive tests. PM-RUF group had superior fluid cognition composite median rankings (OR: 1.5; 95% CI: 1.1, 2.0; P = 0.007). CONCLUSIONS: Among rural Ghanaian children aged 5-12 y, PM-RUF compared with FP resulted in superior fluid cognition. This trial was registered at clinicaltrials.gov as NCT04349007.

Associations between COVID-19 and putative markers of neuroinflammation: A diffusion basis spectrum imaging study.

COVID-19 remains a significant international public health concern. Yet, the mechanisms through which symptomatology emerges remain poorly understood. While SARS-CoV-2 infection may induce prolonged inflammation within the central nervous system, the evidence primarily stems from limited small-scale case investigations. To address this gap, our study capitalized on longitudinal UK Biobank neuroimaging data acquired prior to and following COVID-19 testing (N=416 including n=224 COVID-19 cases; Mage=58.6). Putative neuroinflammation was assessed in gray matter structures and white matter tracts using non-invasive Diffusion Basis Spectrum Imaging (DBSI), which estimates inflammation-related cellularity (DBSI-restricted fraction; DBSI-RF) and vasogenic edema (DBSI-hindered fraction; DBSI-HF).We hypothesized that COVID-19 case status would be associated with increases in DBSI markers after accounting for potential confound (age, sex, race, body mass index, smoking frequency, and data acquisition interval) and multiple testing. COVID-19 case status was not significantly associated with DBSI-RF (|ß|'s<0.28, pFDR >0.05), but with greater DBSI-HF in left pre- and post-central gyri and right middle frontal gyrus (ß's>0.3, all pFDR=0.03). Intriguingly, the brain areas exhibiting increased putative vasogenic edema had previously been linked to COVID-19-related functional and structural alterations, whereas brain regions displaying subtle differences in cellularity between COVID-19 cases and controls included regions within or functionally connected to the olfactory network, which has been implicated in COVID-19 psychopathology. Nevertheless, our study might not have captured acute and transitory neuroinflammatory effects linked to SARS-CoV-2 infection, possibly due to symptom resolution before the imaging scan. Future research is warranted to explore the potential time- and symptom-dependent neuroinflammatory relationship with COVID-19.

Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders.

Objective: Wolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately. Approach: Patient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants. Missense/in-frame variants were further classified as transmembrane or non-transmembrane based on whether they affected amino acid residues predicted to be in transmembrane domains of WFS1. Statistical analysis was performed using Wilcoxon rank-sum tests with multiple test adjustment applied via the Bonferonni correction. Results: A greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by diabetes mellitus and optic atrophy emerging significantly earlier in patients with two nonsense/frameshift variants compared with zero or one nonsense/frameshift variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy among patients with either one or two in-frame variants. Summary/Conclusion: The results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

Dorsal striatal response to taste is modified by obesity and insulin resistance.

OBJECTIVE: In preclinical models, insulin resistance in the dorsal striatum (DS) contributes to overeating. Although human studies support the concept of central insulin resistance, they have not investigated its effect on consummatory reward-induced brain activity. METHODS: Taste-induced activation was assessed in the caudate and putamen of the DS with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Three phenotypically distinct groups were studied: metabolically healthy lean, metabolically healthy obesity, and metabolically unhealthy obesity (MUO; presumed to have central insulin resistance). Participants with MUO also completed a weight loss intervention followed by a second functional magnetic resonance imaging session. RESULTS: The three groups were significantly different at baseline consistent with the design. The metabolically healthy lean group had a primarily positive BOLD response, the MUO group had a primarily negative BOLD response, and the metabolically healthy obesity group had a response in between the two other groups. Food craving was predicted by taste-induced activation. After weight loss in the MUO group, taste-induced activation increased in the DS. CONCLUSIONS: These data support the hypothesis that insulin resistance and obesity contribute to aberrant responses to taste in the DS, which is only partially attenuated by weight loss. Aberrant responses to food exposure may be a barrier to weight loss.

Associations Between Socioeconomic Status, Obesity, Cognition, and White Matter Microstructure in Children.

Importance: Lower neighborhood and household socioeconomic status (SES) are associated with negative health outcomes and altered brain structure in children. It is unclear whether such findings extend to white matter and via what mechanisms. Objective: To assess whether and how neighborhood and household SES are independently associated with children's white matter microstructure and examine whether obesity and cognitive performance (reflecting environmental cognitive and sensory stimulation) are plausible mediators. Design, Setting, and Participants: This cross-sectional study used baseline data from participants in the Adolescent Brain Cognitive Development (ABCD) study. Data were collected at 21 US sites, and school-based recruitment was used to represent the US population. Children aged 9 to 11 years and their parents or caregivers completed assessments between October 1, 2016, and October 31, 2018. After exclusions, 8842 of 11 875 children in the ABCD study were included in the analyses. Data analysis was conducted from July 11 to December 19, 2022. Exposures: Neighborhood disadvantage was derived from area deprivation indices at participants' primary residence. Household SES factors were total income and highest parental educational attainment. Main Outcomes and Measures: A restriction spectrum imaging (RSI) model was used to quantify restricted normalized directional (RND; reflecting oriented myelin organization) and restricted normalized isotropic (RNI; reflecting glial and neuronal cell bodies) diffusion in 31 major white matter tracts. The RSI measurements were scanner harmonized. Obesity was assessed through body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), age- and sex-adjusted BMI z scores, and waist circumference, and cognition was assessed through the National Institutes of Health Toolbox Cognition Battery. Analyses were adjusted for age, sex, pubertal development stage, intracranial volume, mean head motion, and twin or siblingship. Results: Among 8842 children, 4543 (51.4%) were boys, and the mean (SD) age was 9.9 (0.7) years. Linear mixed-effects models revealed that greater neighborhood disadvantage was associated with lower RSI-RND in the left superior longitudinal fasciculus (ß = -0.055; 95% CI, -0.081 to -0.028) and forceps major (ß = -0.040; 95% CI, -0.067 to -0.013). Lower parental educational attainment was associated with lower RSI-RND in the bilateral superior longitudinal fasciculus (eg, right hemisphere: ß = 0.053; 95% CI, 0.025-0.080) and bilateral corticospinal or pyramidal tract (eg, right hemisphere: ß = 0.042; 95% CI, 0.015-0.069). Structural equation models revealed that lower cognitive performance (eg, lower total cognition score and higher neighborhood disadvantage: ß = -0.012; 95% CI, -0.016 to -0.009) and greater obesity (eg, higher BMI and higher neighborhood disadvantage: ß = -0.004; 95% CI, -0.006 to -0.001) partially accounted for the associations between SES and RSI-RND. Lower household income was associated with higher RSI-RNI in most tracts (eg, right inferior longitudinal fasciculus: ß = -0.042 [95% CI, -0.073 to -0.012]; right anterior thalamic radiations: ß = -0.045 [95% CI, -0.075 to -0.014]), and greater neighborhood disadvantage had similar associations in primarily frontolimbic tracts (eg, right fornix: ß = 0.046 [95% CI, 0.019-0.074]; right anterior thalamic radiations: ß = 0.045 [95% CI, 0.018-0.072]). Lower parental educational attainment was associated with higher RSI-RNI in the forceps major (ß = -0.048; 95% CI, -0.077 to -0.020). Greater obesity partially accounted for these SES associations with RSI-RNI (eg, higher BMI and higher neighborhood disadvantage: ß = 0.015; 95% CI, 0.011-0.020). Findings were robust in sensitivity analyses and were corroborated using diffusion tensor imaging. Conclusions and Relevance: In this cross-sectional study, both neighborhood and household contexts were associated with white matter development in children, and findings suggested that obesity and cognitive performance were possible mediators in these associations. Future research on children's brain health may benefit from considering these factors from multiple socioeconomic perspectives.

Neuroinflammation: A Modifiable Pathway Linking Obesity, Alzheimer's disease, and Depression.

Obesity, depression and Alzheimer's disease (AD) are three major interrelated modern health conditions with complex relationships. Early-life depression may serve as a risk factor for AD, while late-life depression may be a prodrome of AD. Depression affects approximately 23% of obese individuals, and depression itself raises the risk of obesity by 37%. Mid-life obesity independently increases AD risk, while late-life obesity, particularly metabolically healthy obesity, may offer protection against AD pathology. Chronic inflammation serves as a key mechanism linking obesity, AD, and depression, encompassing systemic inflammation from metabolic disturbances, immune dysregulation through the gut microbiome, and direct interactions with amyloid pathology and neuroinflammation. In this review, we explore the biological mechanisms of neuroinflammation in relation to obesity, AD, and depression. We assess the efficacy of therapeutic interventions targeting neuroinflammation and discuss current and future radiological imaging initiatives for studying neuroinflammation. By comprehending the intricate interplay among depression, obesity, and AD, especially the role of neuroinflammation, we can advance our understanding and develop innovative strategies for prevention and treatment.

Neuroinflammation in the Amygdala Is Associated With Recent Depressive Symptoms.

BACKGROUND: Converging evidence suggests that elevated inflammation may contribute to depression. Yet, the link between peripheral inflammation and neuroinflammation in depression is unclear. Here, using data from the UK Biobank, we estimated associations among depression, C-reactive protein (CRP) as a measure of peripheral inflammation, and neuroinflammation as indexed by diffusion basis spectral imaging-based restricted fraction (DBSI-RF). METHODS: DBSI-RF was derived from diffusion-weighted imaging data (N = 11,512) for whole-brain gray matter (global-RF), and regions of interest in the bilateral amygdala (amygdala-RF) and hippocampus (hippocampus-RF), and CRP was estimated from blood (serum) samples. Self-reported recent depression symptoms were measured using a 4-item assessment. Linear regressions were used to estimate associations between CRP and DBSI-RFs with depression while adjusting for the following covariates: age, sex, body mass index, smoking, drinking, and medical conditions. RESULTS: Elevated CRP was associated with higher depression symptoms (ß = 0.04, false discovery rate-corrected p < .005) and reduced global-RF (ß = -0.03, false discovery rate-corrected p < .001). Higher amygdala-RF was associated with elevated depression-an effect resilient to added covariates and CRP (ß = 0.02, false discovery rate-corrected p < .05). Interestingly, this association was stronger in individuals with a lifetime history of depression (ß = 0.07, p < .005) than in those without (ß = 0.03, p < .05). Associations between global-RF or hippocampus-RF with depression were not significant, and no DBSI-RF indices indirectly linked CRP with depression (i.e., mediation effect). CONCLUSIONS: Peripheral inflammation and DBSI-RF neuroinflammation in the amygdala are independently associated with depression, consistent with animal studies suggesting distinct pathways of peripheral inflammation and neuroinflammation in the pathophysiology of depression and with investigations highlighting the role of the amygdala in stress-induced inflammation and depression.

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum.

Neuroinflammation is both a consequence and driver of overfeeding and weight gain in rodent obesity models. Advances in magnetic resonance imaging (MRI) enable investigations of brain microstructure that suggests neuroinflammation in human obesity. To assess the convergent validity across MRI techniques and extend previous findings, we used diffusion basis spectrum imaging (DBSI) to characterize obesity-associated alterations in brain microstructure in 601 children (age 9-11 years) from the Adolescent Brain Cognitive DevelopmentSM Study. Compared with children with normal-weight, greater DBSI restricted fraction (RF), reflecting neuroinflammation-related cellularity, was seen in widespread white matter in children with overweight and obesity. Greater DBSI-RF in hypothalamus, caudate nucleus, putamen, and, in particular, nucleus accumbens, correlated with higher baseline body mass index and related anthropometrics. Comparable findings were seen in the striatum with a previously reported restriction spectrum imaging (RSI) model. Gain in waist circumference over 1 and 2 years related, at nominal significance, to greater baseline RSI-assessed restricted diffusion in nucleus accumbens and caudate nucleus, and DBSI-RF in hypothalamus, respectively. Here we demonstrate that childhood obesity is associated with microstructural alterations in white matter, hypothalamus, and striatum. Our results also support the reproducibility, across MRI methods, of findings of obesity-related putative neuroinflammation in children.

Genotype and Clinical Characteristics of Patients with Wolfram Syndrome and WFS1-related Disorders.

Objective: Wolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately. Approach: Patient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants and statistical analysis was performed using unpaired and paired t-tests and one- and two-way ANOVA with Tukey's or Dunnett's tests. Results: A greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by optic atrophy emerging significantly earlier in patients with 2 nonsense/frameshift alleles compared with 0 missense transmembrane variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy. Summary / Conclusions: The results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

Enhancement of taste by retronasal odors in patients with Wolfram syndrome and decreased olfactory function.

Wolfram syndrome is a rare disease characterized by diabetes, neurodegeneration, loss of vision, and audition. We recently found, in a young sample of participants (mean age 15 years), that Wolfram syndrome was associated with impairment in smell identification with normal smell sensitivity and whole-mouth taste function. However, these senses were assessed separately, and it is unknown whether smell-taste interactions are altered in Wolfram syndrome, which was the focus of this study. Participants with Wolfram syndrome (n = 36; 18.2 ± 6.8 years) and sex-age-equivalent healthy controls (n = 34) were assessed with a battery of sensory tests. Using sip-and-spit methods, participants tasted solutions containing gustatory and olfactory stimuli (sucrose with strawberry extract, citric acid with lemon extract, sodium chloride in vegetable broth, and coffee) with and without nose clips, and rated perceived taste and retronasal smell intensities using the generalized Labeled Magnitude Scale. Participants also completed n-butanol detection thresholds and the University of Pennsylvania Smell Identification Test (UPSIT). Retronasal smell increased taste intensity of sucrose, sodium chloride, and coffee solutions similarly in both groups (P values <0.03). Compared with the control group, participants in the Wolfram group had lower UPSIT scores and reduced smell sensitivity, retronasal intensity, and saltiness (P values <0.03), but rated other taste intensities similarly when wearing the nose clip. Despite impairments in orthonasal smell identification, odor-induced taste enhancement was preserved in participants with Wolfram syndrome who still had some peripheral olfactory function. This finding suggests that odor-induced taste enhancement may be preserved in the presence of reduced olfactory intensity.

Associations between socioeconomic status and white matter microstructure in children: indirect effects via obesity and cognition.

Importance: Both neighborhood and household socioeconomic disadvantage relate to negative health outcomes and altered brain structure in children. It is unclear whether such findings extend to white matter development, and via what mechanisms socioeconomic status (SES) influences the brain. Objective: To test independent associations between neighborhood and household SES indicators and white matter microstructure in children, and examine whether body mass index and cognitive function (a proxy of environmental cognitive/sensory stimulation) may plausibly mediate these associations. Design: This cross-sectional study used baseline data from the Adolescent Brain Cognitive Development (ABCD) Study, an ongoing 10-year cohort study tracking child health. Setting: School-based recruitment at 21 U.S. sites. Participants: Children aged 9 to 11 years and their parents/caregivers completed baseline assessments between October 1 st , 2016 and October 31 st , 2018. Data analysis was conducted from July to December 2022. Exposures: Neighborhood disadvantage was derived from area deprivation indices at primary residence. Household SES indicators were total income and the highest parental education attainment. Main Outcomes and Measures: Thirty-one major white matter tracts were segmented from diffusion-weighted images. The Restriction Spectrum Imaging (RSI) model was implemented to measure restricted normalized directional (RND; reflecting oriented myelin organization) and isotropic (RNI; reflecting glial/neuronal cell bodies) diffusion in each tract. Obesity-related measures were body mass index (BMI), BMI z -scores, and waist circumference, and cognitive performance was assessed using the NIH Toolbox Cognition Battery. Linear mixed-effects models tested the associations between SES indicators and scanner-harmonized RSI metrics. Structural equation models examined indirect effects of obesity and cognitive performance in the significant associations between SES and white mater microstructure summary principal components. Analyses were adjusted for age, sex, pubertal development stage, intracranial volume, and head motion. Results: The analytical sample included 8842 children (4299 [48.6%] girls; mean age [SD], 9.9 [0.7] years). Greater neighborhood disadvantage and lower parental education were independently associated with lower RSI-RND in forceps major and corticospinal/pyramidal tracts, and had overlapping associations in the superior longitudinal fasciculus. Lower cognition scores and greater obesity-related measures partially accounted for these SES associations with RSI-RND. Lower household income was related to higher RSI-RNI in almost every tract, and greater neighborhood disadvantage had similar effects in primarily frontolimbic tracts. Lower parental education was uniquely linked to higher RSI-RNI in forceps major. Greater obesity-related measures partially accounted for these SES associations with RSI-RNI. Findings were robust in sensitivity analyses and mostly corroborated using traditional diffusion tensor imaging (DTI). Conclusions and Relevance: These cross-sectional results demonstrate that both neighborhood and household contexts are relevant to white matter development in children, and suggest cognitive performance and obesity as possible pathways of influence. Interventions targeting obesity reduction and improving cognition from multiple socioeconomic angles may ameliorate brain health in low-SES children. Key Points: Question: Are neighborhood and household socioeconomic levels associated with children’s brain white matter microstructure, and if so, do obesity and cognitive performance (reflecting environmental stimulation) mediate the associations?Findings: In a cohort of 8842 children, higher neighborhood disadvantage, lower household income, and lower parental education had independent and overlapping associations with lower restricted directional diffusion and greater restricted isotropic diffusion in white matter. Greater body mass index and poorer cognitive performance partially mediated these associations.Meaning: Both neighborhood and household poverty may contribute to altered white matter development in children. These effects may be partially explained by obesity incidence and poorer cognitive performance.

Longitudinal associations between weight indices, cognition, and mental health from childhood to early adolescence.

Childhood obesity has been associated with lower cognitive performance and worse mental health in cross-sectional studies. However, it is unclear whether these findings extend longitudinally and in what causal direction. Using data from the Adolescent Brain Cognitive Development (ABCD) Study (maximum analytical n = 6671, 48.3% girls, 42.8% non-White), we examined how body mass index (BMI) at baseline (ages 9-11) relate prospectively to changes in cognition or psychopathology across the 2 years thereafter, and vice versa. Cognitive tests included the National Institutes of Health Toolbox Cognition Battery, Little Man Task of mental rotation, and Rey Auditory Verbal Learning Test. Psychopathology was assessed using caregiver-reported Child Behavior Checklist. Linear mixed models adjusted for sociodemographic and developmental covariates indicated that lower baseline performance on most cognitive tests was associated with greater longitudinal BMI gain (eg, 1 point lower than median on Picture Vocabulary corresponded to 0.012 kg/m2 [1.6%; 95% CI, 0.008 to 0.016 kg/m2] more annual BMI gain, PFDR < .001), whereas baseline BMI was unrelated to longitudinal changes in cognition (PFDR ≥ .12; including after considering practice effects). Greater broad-spectrum psychopathology at baseline was associated with increased BMI gain (eg, each endorsement of externalizing problems than none corresponded to 0.015 kg/m2 [2.2%; 95% CI, 0.009 to 0.021 kg/m2] more annual BMI gain, PFDR < .001) and, reciprocally, greater baseline BMI was linked specifically to more longitudinal withdrawn/depressed and depression problems (0.010 [22%; 95% CI, 0.004 to 0.016] and 0.011 [15%; 95% CI, 0.004 to 0.017] more problems annually per 1 kg/m2 above median BMI, PFDR = .003 and .008). The associations did not differ in boys vs. girls (PFDR ≥ .40), and remained stable with waist circumference as the weight index and in subgroups of participants without weight-altering medications or common baseline psychiatric diagnoses. Our longitudinal findings expand previous cross-sectional works and highlight the importance of cognitive and mental health to children's weight development and links between weight and depression.

Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults: A Randomized Clinical Trial.

Importance: Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. Objective: To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Interventions: Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. Main Outcomes and Measures: The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Results: Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Conclusions and Relevance: Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. Trial Registration: ClinicalTrials.gov Identifier: NCT02665481.

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Longitudinal Changes in Vision and Retinal Morphology in Wolfram Syndrome.

PURPOSE: To report long-term ophthalmic findings in Wolfram syndrome, including rates of visual decline, macular thinning, retinal nerve fiber layer (RNFL) thinning, and outer plexiform layer (OPL) lamination. DESIGN: Single-center, cohort study. METHODS: A total of 38 participants were studied, who underwent a complete ophthalmic examination as well as optical coherence tomography imaging of the macula and nerve on an annual basis. Linear mixed-effects models for longitudinal data were used to examine both fixed and random effects related to visual acuity and optic nerve quadrants of RNFL and macula thickness. RESULTS: Participants completed a mean of 6.44 years of follow-up (range 2-10 years). Visual acuity declined over time in all participants, with a mean slope of 0.059 logMAR/y (95% CI = 0.07-0.05 logMAR/y), although nearly 25% of participants experienced more rapid visual decline. RNFL thickness decreased in superior, inferior, and nasal quadrants (ß = -0.5 µm/y, -0.98 µm/y, -0.28 µm/y, respectively). OPL lamination was noted in 3 study participants, 2 of whom had autosomal dominant mutations. CONCLUSIONS: Our study describes the longest and largest natural history study of visual acuity decline and retinal morphometry in Wolfram syndrome to date. Results suggest that there are slower and faster progressing subgroups and that OPL lamination is present in some individuals with this disease.

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome.

Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8-13.9) pg/mL] relative to controls [5.6 (4.5-7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome.