Sex differences in cerebral blood flow among adolescents with bipolar disorder.

BACKGROUND: Abnormalities in cerebral blood flow (CBF) are common in bipolar disorder (BD). Despite known differences in CBF between healthy adolescent males and females, sex differences in CBF among adolescents with BD have never been studied. OBJECTIVE: To examine sex differences in CBF among adolescents with BD versus healthy controls (HC). METHODS: CBF images were acquired using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in 123 adolescents (72 BD: 30M, 42F; 51 HC: 22M, 29F) matched for age (13-20 years). Whole brain voxel-wise analysis was performed in a general linear model with sex and diagnosis as fixed factors, sex-diagnosis interaction effect, and age as a covariate. We tested for main effects of sex, diagnosis, and their interaction. Results were thresholded at cluster forming p = 0.0125, with posthoc Bonferroni correction (p = 0.05/4 groups). RESULTS: A main effect of diagnosis (BD > HC) was observed in the superior longitudinal fasciculus (SLF), underlying the left precentral gyrus (F =10.24 (3), p < 0.0001). A main effect of sex (F > M) on CBF was detected in the precuneus/posterior cingulate cortex (PCC), left frontal and occipital poles, left thalamus, left SLF, and right inferior longitudinal fasciculus (ILF). No regions demonstrated a significant sex-by-diagnosis interaction. Exploratory pairwise testing in regions with a main effect of sex revealed greater CBF in females with BD versus HC in the precuneus/PCC (F = 7.1 (3), p < 0.01). CONCLUSION: Greater CBF in female adolescents with BD versus HC in the precuneus/PCC may reflect the role of this region in the neurobiological sex differences of adolescent-onset BD. Larger studies targeting underlying mechanisms, such as mitochondrial dysfunction or oxidative stress, are warranted.

Differential association of endothelial function with brain structure in youth with versus without bipolar disorder.

BACKGROUND: Mood symptoms and disorders are associated with impaired endothelial function, a marker of early atherosclerosis. Given the increased vascular burden and neurostructural differences among individuals with mood disorders, we investigated the endothelial function and brain structure interface in relation to youth bipolar disorder (BD). METHODS: This cross-sectional case-controlled study included 115 youth, ages 13-20 years (n = 66 BD; n = 49 controls [CG]). Cortical thickness and volume for regions of interest (ROI; insular cortex, ventrolateral prefrontal cortex [vlPFC], temporal lobe) were acquired from FreeSurfer processed T1-weighted MRI images. Endothelial function was assessed using pulse amplitude tonometry, yielding a reactive hyperemia index (RHI). ROI and vertex-wise analyses controlling for age, sex, obesity, and intracranial volume investigated for RHI-neurostructural associations, and RHI-by-diagnosis interactions. RESULTS: In ROI analyses, higher RHI (i.e., better endothelial function) was associated with lower thickness in the insular cortex (ß = -0.19, pFDR = 0.03), vlPFC (ß = -0.30, pFDR = 0.003), and temporal lobe (ß = -0.22, pFDR = 0.01); and lower temporal lobe volume (ß = -0.16, pFDR = 0.01) in the overall sample. In vertex-wise analyses, higher RHI was associated with lower cortical thickness and volume in the insular cortex, prefrontal cortex (e.g., vlPFC), and temporal lobe. Additionally, higher RHI was associated with lower vlPFC and temporal lobe volume to a greater extent in youth with BD vs. CG. CONCLUSIONS: Better endothelial function was associated with lower regional brain thickness and volume, contrasting the hypothesized associations. Additionally, we found evidence that this pattern was exaggerated in youth with BD. Future studies examining the direction of the observed associations and underlying mechanisms are warranted.

A Systematic Review and Meta-Analysis of Lipid Signatures in Post-traumatic Stress Disorder.

Background: Research assessing lipid levels in individuals diagnosed with post-traumatic stress disorder (PTSD) has yielded mixed results. This study aimed to employ meta-analytic techniques to characterize the relationship between the levels of lipid profiles and PTSD. Methods: We performed meta-analyses of studies comparing profiles and levels of lipids between PTSD patients and healthy individuals by searching Embase, Ovid Medline, Scopus, PsycINFO, and Cochrane databases for the studies until March 2021. Meta-analyses were performed using random-effects models with the restricted maximum-likelihood estimator to synthesize the effect size assessed by standardized mean difference (SMD) across studies. Findings: A total of 8,657 abstracts were identified, and 17 studies were included. Levels of total cholesterol (TC) (SMD = 0.57 95% CI, 0.27-0.87, p = 0.003), low-density lipoprotein (LDL) (SMD = 0.48, 95% CI, 0.19-0.76, p = 0.004), and triglyceride (TG) (SMD = 0.46, 95% CI, 0.22-0.70, p = 0.001) were found to be higher, while levels of high-density lipoprotein (HDL) (SMD = -0.47, -0.88 to -0.07, p = 0.026) were found to be lower in PTSD patients compared to healthy controls. Subgroup analysis showed that TG levels were higher in PTSD patients who were on or off of psychotropic medications, both < 40 and ≥ 40 years of age, and having body mass index of < 30 and ≥ 30 compared to healthy controls. Interpretation: This work suggested dysregulation of lipids in PTSD that may serve as biomarker to predict the risk. The study will be useful for physicians considering lipid profiles in PTSD patients to reduce cardiovascular morbidity and mortality.

A systematic review and meta-analysis of lipid metabolomic signatures of Major Depressive Disorder.

The aim of this meta-analysis was to provide a comprehensive synthesis of the evidence examining biomarker signatures in MDD patients including lipids, lipid regulatory proteins (LRP), and polyunsaturated fatty acid (PUFA) as compared to healthy individuals. We performed meta-analyses and meta-regression of the studies comparing lipid, LRP, and PUFA levels between MDD patients and healthy individuals by searching Embase, Ovid Medline, Scopus, PsycINFO, PubMed, and Cochrane databases. Search was performed in these databases up to September 2019 and 29 studies were included. Levels of lipid parameter triglyceride (TG) (SMD 0.55, 95% CI 0.30-0.80, p < 0.0001) were higher while total cholesterol (TC) (SMD = -0.46, 95%CI -0.93 to -0.001, p = 0.04) and very low-density lipoprotein (VLDL) (SMD = -0.46, 95%CI -0.71 to -0.20, p = 0.02) were lower in MDD patients than controls. Subgroup analysis for age showed that the levels of high-density lipoprotein (HDL) were lower in ≥40-year age group (SMD = -0.38, 95%CI -0.70 to -0.06, p = 0.01) and levels of TC was lower in MDD patients in studies from Asian countries (SMD = -0.74, 95%CI -1.37 to -0.10, p = 0.02). TG levels were found to be high all subgroups in MDD patients than controls. A negative association between TC levels and use of lipid lowering medications and a positive association between smoking and LDL levels was found using meta-regression analysis. This study will be useful for physicians when considering the assessment of lipidand LRP profiles in MDD patients to reduce the cardiovascular morbidity and mortality.

Neurostructural phenotypes of CACNA1C rs1006737 in adolescents with bipolar disorder and healthy controls.

OBJECTIVE: Investigate the effects of CACNA1C rs1006737 on cortical and subcortical neurostructural phenotypes in Caucasian bipolar disorder (BD) and healthy control (HC) adolescents. METHODS: Seventy-one adolescents (14-20 years; 38BD, 33HC) underwent 3-Tesla Magnetic Resonance Imaging (MRI). Region of interest (ROI) and vertex-wise analyses examined cortical volume, surface area (SA), and thickness, as well as subcortical volume. ROIs included the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), putamen, and amygdala. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and total intracranial volume. RESULTS: Vertex-wise analysis found significant BD-by-rs1006737 interactions for prefrontal and occipital regions such that BD A-carriers were found to have greater SA relative to BD non-carriers, while HC A-carriers had reduced SA relative to HC non-carriers. ROI analysis found an interaction in the ACC such that BD A-carriers were found to have greater SA relative to BD non-carriers, while no significant difference was found in HCs. Main effects of rs1006737 were also found on ACC SA from ROI analysis, and occipital SA from vertex-wise analysis, such that A-carriers had larger SA relative to non-carriers in both of these regions. CONCLUSIONS: The current study identified neurostructural intermediate phenotypes relevant to the impact of CACNA1C rs1006737 on adolescent BD. Further investigation is warranted into the neurofunctional and neurocognitive relevance of rs1006737 associations with BD-specific elevations in regional SA.

Preliminary study of structural magnetic resonance imaging phenotypes related to genetic variation in Interleukin-1ß rs16944 in adolescents with Bipolar Disorder.

BACKGROUND: Bipolar disorder (BD), among the most heritable psychiatric conditions, is associated with increased pro-inflammatory blood markers and pro-inflammatory gene expression in post-mortem brain. We therefore examined the effects of pro-inflammatory single nucleotide polymorphism interleukin-1ß (IL-1ß) rs16944 on brain structure in adolescents with BD and healthy control (HC) adolescents. METHODS: T1-weighted 3-T magnetic resonance imaging data were acquired for 38 adolescents with BD and 32 HC adolescents (14-20 years). Using FreeSurfer, a priori regions of interest analyses, examining hippocampus, amygdala, dorsolateral prefrontal cortex (DLPFC), and caudal anterior cingulate cortex, were complemented by exploratory whole-brain vertex-wise analyses. General linear models assessed the association between IL-1ß rs16944 and the ROIs, controlling for sex, age, and intracranial volume. RESULTS: There was an IL-1ß rs16944 polymorphism-by-diagnosis interaction effect on the DLPFC; T-carriers with BD had greater surface area compared to non-carriers with BD. Whereas, HC T-carriers had smaller DLPFC volume compared to HC non-carriers. In vertex-wise analyses, similar interactions were evident in a pars triangularis surface area cluster and a lateral occipital cortex volume cluster. Whole-brain analyses also yielded a main effect of IL-1ß rs16944 polymorphism, whereby T-carriers had greater lateral occipital cortex surface area and volume. CONCLUSIONS: The IL-1ß rs16944 polymorphism is associated with neurostructural phenotypes in cognitive and visual regions that subserve functions, including facial recognition and response inhibition, which are known to be aberrant in BD. Future studies are warranted to evaluate whether the observed rs16944-related structural differences are relevant to neurocognitive function, functional neuroimaging phenotypes and IL-1ß protein levels.

Adherence to prescription guidelines for medical cannabis in disability claimants.

OBJECTIVE: To examine a case series of 70 disability claimants who were referred to a clinic for multidisciplinary medical evaluation for physician compliance with cannabis prescription guidelines for pre-existing cannabis prescriptions. DESIGN: Retrospective case series analysis. SETTING: A private clinic in New Brunswick specializing in multidisciplinary medical assessment for institutional third-party insurers. PARTICIPANTS: All referrals for independent review of cannabis prescriptions between May 2016 and February 2018 (N = 70). MAIN OUTCOME MEASURES: Compliance with the cannabis prescription guidelines. RESULTS: Treating physicians were found to have not adhered to the guidelines in 53 of 61 patients (86.9%) who were prescribed cannabis products for pain management and in 8 of 9 patients (88.9%) who were prescribed cannabis products for treatment of posttraumatic stress disorder. Clinical assessment and radiologic review failed to identify a neuropathic cause of pain in 70.5% of pain cases. Adequate trials of noncannabinoid medications had not been attempted for 72.1% of patients with pain nor for any of the patients with posttraumatic stress disorder. Contraindications to cannabis were identified in 65.7% of cases, including evidence suggesting a past or present cannabis use disorder or currently active substance use disorder in 34.3% of cases. The prescriptions were found to be consistent with prescription guidelines in just 12.9% of cases. CONCLUSION: Very few of the reviewed cannabis prescriptions were found to be consistent with cannabis prescription guidelines. Respectful attention to guidelines might avoid unwarranted overprescribing, limit the secondary increase in comorbidity, and facilitate future scientific study and evaluation of medical cannabis.

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study.

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Exaggerated Functional Impairment due to Malingered Neurocognitive Dysfunction Following Mild Traumatic Brain Injury.

OBJECTIVE: Functional impairment associated with Neurocognitive Disorder is often claimed in medico-legal settings after mild Traumatic Brain Injury (mTBI). This case-control study examined self-reported functional impairment and the plausibility of chronic disability claims following uncomplicated mTBI. METHOD: Independent Medical Evaluations included a battery of performance and symptom validity tests, along with self-reports of physical or emotional complaints and functional impairment. Slick and colleagues' (Slick, D. J., Sherman, E. M., & Iverson, G. L. (1999). Diagnostic criteria for malingered neurocognitive dysfunction: Proposed standards for clinical practice and research. The Clinical Neuropsychologist, 13, 545-561.) criteria ruled out probable malingering in 21 mTBI cases without psychiatric comorbidity and their self-reports were compared to those of seven non-malingering cases with a psychiatric comorbidity, 17 who were probable malingerers, and 31 orthopedic pain sufferers. Coherence Analysis of medical documentation corroborated assignment of mTBI cases to non-malingering versus probable malingering groups. RESULTS: Probable malingerers reported more postconcussion symptoms than non-malingerers (d = 0.79) but they did not differ significantly on tests of neurocognitive performance. Probable malingerers and orthopedic pain patients gave significantly higher ratings of functional impairment (d = 1.28 and 1.26) than non-malingerers. Orthopedic pain patients reported more disability due to pain than non-malingerers (d = 1.03), but pain catastrophizing was rated more highly by the probable malingerers (d = 1.21) as well as by the orthopedic pain patients (d = 0.98). The non-malingerers reported lower emotional distress than the other three groups, but only the probable malingerers reported elevated depression symptoms compared to the non-malingerers (d = 1.01). CONCLUSIONS: The combined evaluation of performance validity, function, and coherence analysis would appear to enhance the difficult clinical evaluation of postconcussion symptoms in the medical-legal setting.

Cortical Volume and Thickness Across Bipolar Disorder Subtypes in Adolescents: A Preliminary Study.

OBJECTIVES: Neuroimaging studies of adults with bipolar disorder (BD) have identified several BD subtype distinctions, including greater deficits in prefrontal gray matter volumes in BD-I (bipolar I disorder) compared to BD-II (bipolar II disorder). We sought to investigate BD subtype differences in brain structure among adolescents and young adults. METHODS: Forty-four youth with BD (14 BD-I, 16 BD-II, and 14 BD-not otherwise specified [NOS], mean age 17) underwent 3T-MRI and images were analyzed using FreeSurfer software. Cortical volume and thickness were analyzed for region of interest (ROI): ventrolateral prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate cortex (ACC), subgenual cingulate cortex, and amygdala, controlling for age, sex, and total intracranial volume. ROIs were selected as found to be implicated in BD in prior studies. A whole brain vertex-wise exploratory analysis was also performed. Uncorrected results are presented. RESULTS: There were group differences in ACC thickness (F = 3.88, p = 0.03, η2 = 0.173 uncorrected), which was reduced in BD-II in comparison to BD-I (p = 0.027 uncorrected) and BD-NOS (p = 0.019 uncorrected). These results did not survive correction for multiple comparisons and no other group differences were observed. The exploratory vertex-wise analysis found a similar pattern of lower cortical thickness in BD-II in the left and right superior frontal gyrus and left caudal middle frontal gyrus. CONCLUSIONS: This study found reduced cortical thickness for youth with BD-II, relative to BD-I, in regions associated with cognitive control. Further neurostructural differences between subtypes may emerge later during the course of illness.

Fronto-insular-parietal network engagement underlying arithmetic word problem solving.

Mathematical word problems are ubiquitous and standard for teaching and evaluating generalization of mathematical knowledge for real-world contexts. It is therefore concerning that the neural mechanisms of word problem solving are not well understood, as these insights represent strong potential for improving education and remediating deficits in this domain. Here, we investigate neural response to word problems via functional magnetic resonance imaging (fMRI). Healthy adults performed sentence judgment tasks on word problems that either contained one-step mathematical operations, or nonarithmetic judgments on parallel narratives without any numerical information. Behavioral results suggested that the composite efficiency measurement of combining accuracy and RT did not differ between the two problem types. Arithmetic sentence judgments elicited greater activation in the fronto-insular-parietal network including intraparietal sulcus (IPS), dorsolateral prefrontal cortex (PFC), and anterior insula (AI) than narrative sentence judgment. Narrative sentence judgments, conversely, resulted in greater activation predominantly in the left ventral PFC, angular gyrus and perisylvian cortex compared with reading arithmetic sentences. Moreover, task-dependent functional connectivity analyses showed the AI circuits were more strongly coupled with IPS during arithmetic sentence judgments than nonarithmetic sentences. Finally, activations in the IPS during arithmetic were highly correlated with out-of-scanner performance on a distinct set of problems with the same characteristics. These results show arithmetic word problem performance differences may rely more heavily on fronto-insular-parietal circuits for mathematical model building than narrative text comprehension of similar difficulty. More broadly, our study suggests that quantitative measurements of brain mechanisms can provide pivotal role for uncovering crucial arithmetic skills.

Attention-Related Brain Activation Is Altered in Older Adults With White Matter Hyperintensities Using Multi-Echo fMRI.

Cognitive decline is often undetectable in the early stages of accelerated vascular aging. Attentional processes are particularly affected in older adults with white matter hyperintensities (WMH), although specific neurovascular mechanisms have not been elucidated. We aimed to identify differences in attention-related neurofunctional activation and behavior between adults with and without WMH. Older adults with moderate to severe WMH (n = 18, mean age = 70 years), age-matched adults (n = 28, mean age = 72), and healthy younger adults (n = 19, mean age = 25) performed a modified flanker task during multi-echo blood oxygenation level dependent functional magnetic resonance imaging. Task-related activation was assessed using a weighted-echo approach. Healthy older adults had more widespread response and higher amplitude of activation compared to WMH adults in fronto-temporal and parietal cortices. Activation associated with processing speed was absent in the WMH group, suggesting attention-related activation deficits that may be a consequence of cerebral small vessel disease. WMH adults had greater executive contrast activation in the precuneous and posterior cingulate gyrus compared to HYA, despite no performance benefits, reinforcing the network dysfunction theory in WMH.

Magnetic resonance imaging of cerebrovascular reactivity in healthy adolescents.

BACKGROUND: Cerebrovascular reactivity (CVR), an important measure of cerebrovascular health in adults, has not been examined in healthy adolescents. Beyond the direct importance of understanding CVR in healthy youth, studies on this topic can yield insights regarding brain disease. We set out to evaluate 3 different CVR modelling approaches. NEW METHOD: Thirty-nine healthy adolescents (ages 13-19 years, 20 females) completed six blocks of 15-second breath-holds separated by 30-second blocks of free-breathing. CVR was measured using blood-oxygenation-level dependent functional magnetic resonance imaging at 3-Tesla; voxel-wise analyses were complemented by regional analyses in five major subdivisions of the brain. Hemodynamic response functions were modelled using: (1) an individualized delay term (double-gamma variate convolved with a boxcar function), (2) with a standard 9-second delay term, and (3) a sine-cosine regressor. RESULTS: Individual-delay yielded superior model fit or larger cluster volumes. Regional analysis found differences in CVR and time-to-peak CVR. Males had higher brain-wide CVR in comparison to females (p = 0.025, η2part = 0.345). BMI and blood pressure were not significantly associated with CVR (all p > 0.4). COMPARISON WITH EXISTING METHODS: This was the first study to compare these methods in youth. Regional differences were similar to adult studies. CONCLUSIONS: These findings lend support to future breath-hold CVR studies in youth, and highlight the merit of applying individualized-delay estimates. Regional variability and sex-related differences in CVR suggest that these variables should be considered in future studies, particularly those that examine disease states with predilection for specific brain regions or those diseases characterized by sex differences.

Greater body mass index is associated with reduced frontal cortical volumes among adolescents with bipolar disorder.

BACKGROUND: Higher body mass index (BMI) and obesity is common among youth with bipolar disorder (BD) and is associated with greater psychiatric illness severity, including suicidality. Obesity has been associated with frontal, temporal and subcortical volumetric reductions in adults with BD. We examined the neurostructural correlates of BMI in adolescents early in their course of BD. METHODS: We processed T1-weighted images of adolescents with BD and psychiatrically healthy controls using FreeSurfer to derive a priori region of interest (ROI) volumes/cortical thickness for the frontal lobe (FL), prefrontal cortex (PFC) and orbitofrontal cortex (OFC) as well as volumes for the amygdala and hippocampus. General linear models assessed the association between BMI and the ROIs, controlling for age, sex and intracranial volume. We also conducted exploratory within-BD group and whole brain vertex-wise analyses. RESULTS: We included 40 adolescents with BD and 48 controls in our analyses. In addition to a main effect of BMI on the ROIs, there were significant diagnosis × BMI interaction effects on FL volumes. In the BD group only, BMI was negatively associated with FL, OFC and PFC cortical thickness. Whole brain analysis of BMI-volume correlations revealed 2 significant interaction clusters: 1 in the medial OFC and 1 in the caudal anterior cingulate cortex, with BD showing a stronger negative correlation. LIMITATIONS: Reliance on BMI rather than a more nuanced measure of obesity may have influenced the findings. CONCLUSION: Our results suggest that elevated BMI among adolescents with BD is associated with frontal neurostructural differences that are not observed in controls. Prospective studies examining the direction of the observed associations and the effect of BMI optimization on brain structure in adolescents with BD are warranted.

Intrinsic insula network engagement underlying children's reading and arithmetic skills.

The neural substrates of children's reading and arithmetic skills have long been of great interest to cognitive neuroscientists. However, most previous studies have focused on the contrast between these skills as specific domains. Here, we investigate the potentially shared processes across these domains by focusing on how the neural circuits associated with cognitive control influence reading and arithmetic proficiency in 8-to-10-year-old children. Using a task-free resting state approach, we correlated the intrinsic functional connectivity of the right anterior insula (rAI) network with performance on assessments of Chinese character recognition, reading comprehension, subtraction, and multiplication performance. A common rAI network strengthened for reading and arithmetic skill, including the right middle temporal gyrus (MTG) and superior temporal gyrus (STG) in the lateral temporal cortex, as well as the inferior frontal gyrus (IFG). In addition, performance measures evidenced rAI network specializations. Single character recognition was uniquely associated with connectivity to the right superior parietal lobule (SPL). Reading comprehension only, rather than character recognition, was associated with connectivity to the right IFG, MTG and angular gyrus (AG). Furthermore, subtraction was associated with connectivity to premotor cortex whereas multiplication was associated with the supramarginal gyrus. Only reading comprehension and multiplication were associated with hyper connectivity within local rAI network. These results indicate that during a critical period for children's acquisition of reading and arithmetic, these skills are supported by both intra-network synchronization and inter-network connectivity of rAI circuits. Domain-general intrinsic insular connectivity at rest contained also, functional components that segregated into different sets of skill-related networks. The embedded components of cognitive control may be essential to understanding the interplay of multiple functional circuits necessary to more fully characterize cognitive skill acquisition.

Greater body mass index is associated with reduced frontal cortical volumes among adolescents with bipolar disorder.

BACKGROUND: Higher body mass index (BMI) and obesity is common among youth with bipolar disorder (BD) and is associated with greater psychiatric illness severity, including suicidality. Obesity has been associated with frontal, temporal and subcortical volumetric reductions in adults with BD. We examined the neurostructural correlates of BMI in adolescents early in their course of BD. METHODS: We processed T1-weighted images of adolescents with BD and psychiatrically healthy controls using FreeSurfer to derive a priori region of interest (ROI) volumes/cortical thickness for the frontal lobe (FL), prefrontal cortex (PFC) and orbitofrontal cortex (OFC) as well as volumes for the amygdala and hippocampus. General linear models assessed the association between BMI and the ROIs, controlling for age, sex and intracranial volume. We also conducted exploratory within-BD group and whole brain vertex-wise analyses. RESULTS: We included 40 adolescents with BD and 48 controls in our analyses. In addition to a main effect of BMI on the ROIs, there were significant diagnosis × BMI interaction effects on FL volumes. In the BD group only, BMI was negatively associated with FL, OFC and PFC cortical thickness. Whole brain analysis of BMI-volume correlations revealed 2 significant interaction clusters: 1 in the medial OFC and 1 in the caudal anterior cingulate cortex, with BD showing a stronger negative correlation. LIMITATIONS: Reliance on BMI rather than a more nuanced measure of obesity may have influenced the findings. CONCLUSION: Our results suggest that elevated BMI among adolescents with BD is associated with frontal neurostructural differences that are not observed in controls. Prospective studies examining the direction of the observed associations and the effect of BMI optimization on brain structure in adolescents with BD are warranted.

Heterogeneous and nonlinear development of human posterior parietal cortex function.

Human cognitive problem solving skills undergo complex experience-dependent changes from childhood to adulthood, yet most neurodevelopmental research has focused on linear changes with age. Here we challenge this limited view, and investigate spatially heterogeneous and nonlinear neurodevelopmental profiles between childhood, adolescence, and young adulthood, focusing on three cytoarchitectonically distinct posterior parietal cortex (PPC) regions implicated in numerical problem solving: intraparietal sulcus (IPS), angular gyrus (AG), and supramarginal gyrus (SMG). Adolescents demonstrated better behavioral performance relative to children, but their performance was equivalent to that of adults. However, all three groups differed significantly in their profile of activation and connectivity across the PPC subdivisions. Activation in bilateral ventral IPS subdivision IPS-hIP1, along with adjoining anterior AG subdivision, AG-PGa, and the posterior SMG subdivision, SMG-PFm, increased linearly with age, whereas the posterior AG subdivision, AG-PGp, was equally deactivated in all three groups. In contrast, the left anterior SMG subdivision, SMG-PF, showed an inverted U-shaped profile across age groups such that adolescents exhibited greater activation than both children and young adults. Critically, greater SMG-PF activation was correlated with task performance only in adolescents. Furthermore, adolescents showed greater task-related functional connectivity of the SMG-PF with ventro-temporal, anterior temporal and prefrontal cortices, relative to both children and adults. These results suggest that nonlinear up-regulation of SMG-PF and its interconnected functional circuits facilitate adult-level performance in adolescents. Our study provides novel insights into heterogeneous age-related maturation of the PPC underlying cognitive skill acquisition, and further demonstrates how anatomically precise analysis of both linear and nonlinear neurofunctional changes with age is necessary for more fully characterizing cognitive development.

Development of common neural representations for distinct numerical problems.

How the brain develops representations for abstract cognitive problems is a major unaddressed question in neuroscience. Here we tackle this fundamental question using arithmetic problem solving, a cognitive domain important for the development of mathematical reasoning. We first examined whether adults demonstrate common neural representations for addition and subtraction problems, two complementary arithmetic operations that manipulate the same quantities. We then examined how the common neural representations for the two problem types change with development. Whole-brain multivoxel representational similarity (MRS) analysis was conducted to examine common coding of addition and subtraction problems in children and adults. We found that adults exhibited significant levels of MRS between the two problem types, not only in the intraparietal sulcus (IPS) region of the posterior parietal cortex (PPC), but also in ventral temporal-occipital, anterior temporal and dorsolateral prefrontal cortices. Relative to adults, children showed significantly reduced levels of MRS in these same regions. In contrast, no brain areas showed significantly greater MRS between problem types in children. Our findings provide novel evidence that the emergence of arithmetic problem solving skills from childhood to adulthood is characterized by maturation of common neural representations between distinct numerical operations, and involve distributed brain regions important for representing and manipulating numerical quantity. More broadly, our findings demonstrate that representational analysis provides a powerful approach for uncovering fundamental mechanisms by which children develop proficiencies that are a hallmark of human cognition.

Fractionating the neural correlates of individual working memory components underlying arithmetic problem solving skills in children.

Baddeley and Hitch's multi-component working memory (WM) model has played an enduring and influential role in our understanding of cognitive abilities. Very little is known, however, about the neural basis of this multi-component WM model and the differential role each component plays in mediating arithmetic problem solving abilities in children. Here, we investigate the neural basis of the central executive (CE), phonological (PL) and visuo-spatial (VS) components of WM during a demanding mental arithmetic task in 7-9 year old children (N=74). The VS component was the strongest predictor of math ability in children and was associated with increased arithmetic complexity-related responses in left dorsolateral and right ventrolateral prefrontal cortices as well as bilateral intra-parietal sulcus and supramarginal gyrus in posterior parietal cortex. Critically, VS, CE and PL abilities were associated with largely distinct patterns of brain response. Overlap between VS and CE components was observed in left supramarginal gyrus and no overlap was observed between VS and PL components. Our findings point to a central role of visuo-spatial WM during arithmetic problem-solving in young grade-school children and highlight the usefulness of the multi-component Baddeley and Hitch WM model in fractionating the neural correlates of arithmetic problem solving during development.