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.

Structural neuroimaging phenotypes of a novel multi-gene risk score in youth bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD. METHODS: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions. RESULTS: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; ß=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC. LIMITATIONS: Cross-sectional design, modest sample size. CONCLUSIONS: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.

Elevated lipids are associated with reduced regional brain structure in youth with bipolar disorder.

OBJECTIVE: Abnormal blood lipid levels are common in bipolar disorder (BD) and correlate with mood symptoms and neurocognition. However, studies have not examined the lipid-brain structure association in BD or youth. METHODS: This study examined low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides, and total cholesterol (TC) levels in relation to brain structure utilizing T1-weighted images, among participants ages 13-20 with BD (n = 55) and healthy controls (HC; n = 47). General linear models investigated group differences in the association of lipids with anterior cingulate cortex (ACC), hippocampus, and inferior parietal lobe structure, controlling for age, sex, body mass index, and intracranial volume. For significant associations, post hoc within-group analyses were undertaken. Exploratory vertex-wise analyses further investigated group differences in the lipid-brain structure association. RESULTS: There were significant group differences in the association of LDL-C (ß = -0.29 p = 0.001), and TC (ß = -0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (ß = -0.25 p = 0.01) and area (ß = -0.26 p = 0.004). Elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC. Post hoc analyses revealed that elevated LDL-C (ß = -0.27 p = 0.007) and reduced HDL-C (ß = 0.24 p = 0.01) were associated with smaller hippocampal volume in the BD group. Exclusion of BD second-generation antipsychotic users did not alter these results. Vertex-wise analyses further showed that elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC, across the cortex. CONCLUSION: Elevated lipids are associated with smaller brain structure in BD. Research evaluating lipid-brain structure associations prospectively and whether lipid optimization has salutary effects on brain structure is necessary.

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.

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.

Sex differences in brain structure among adolescents with bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is twice as prevalent amongst female as amongst male adolescents. Thus far, little is known regarding the neurostructural substrates underlying this disparity. We therefore examined sex differences in neurostructural magnetic resonane imaging (MRI) phenotypes amongst adolescents with BD. METHODS: T1-weighted structural MRI was acquired from 44 BD (25 female [F] and 19 male [M]) and 58 (28 F and 30 M) healthy control (HC) adolescents (13-21 years old). Whole-brain and region-of-interest (ROI) analyses examined structural volume and cortical thickness using FreeSurfer. ROIs included the ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), amygdala and hippocampus. General linear models evaluated sex-by-diagnosis interactions, controlling for age and intracranial volume. RESULTS: Whole-brain analysis revealed sex-by-diagnosis interactions in the left supramarginal gyrus (SMG) (P = .02, η2  = 0.02) and right inferior parietal lobule (IPL) volumes (P = .04, η2  = 0.01). Sex differences in HCs were found in the SMG (M > F) and IPL (F > M). In BD, sex differences were reversed and of smaller magnitude in the SMG (M < F) and of greater magnitude in the IPL (F > M), driven by trends towards smaller SMG and IPL in BD vs HC male participants (P = .05 and .14). Whole-brain analyses for cortical thickness, and ROI analyses for volume and cortical thickness, were not significant. CONCLUSIONS: Normative sex differences may be disrupted in adolescent BD in the SMG and IPL, heteromodal association network hubs responsible for higher order integration of cognitive and emotional processing. Unexpectedly, these findings may inform our understanding of aberrant brain structure in adolescent BD male patients, rather than female patients. Future work should focus on replication, as well as the impact of puberty status and sex hormones on measures of brain structure and function.

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.

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.

Increased cerebral blood flow among adolescents with bipolar disorder at rest is reduced following acute aerobic exercise.

OBJECTIVE: Cerebral blood flow (CBF) is altered in mood disorders but has not been examined among adolescents with bipolar disorder (BD). Similarly, little is known about the acute neurophysiologic effects of aerobic exercise in BD. We therefore compared CBF between adolescents with and without BD at rest and acutely following a single exercise session. METHODS: Thirty-one adolescents with BD and 20 age and sex-matched controls participated in this study. CBF magnetic resonance images (MRI) were acquired using arterial spin labeling at a baseline as well as 15 and 45min after a single 20-min session of recumbent cycling. Voxel-based CBF analyses compared groups at baseline and after exercise. Clinical, body mass index (BMI) and exercise-induced feelings inventory (EFI) data were examined for their influence on CBF findings. RESULTS: Baseline CBF was increased in medial frontal and middle cingulate regions in BD compared to controls. Analysis of the acute CBF changes revealed pronounced exercise-related decreases in CBF in BD. Exercise-related feelings of exhaustion were associated with CBF changes in frontal but not parietal regions. DISCUSSION: A single bout of moderate-intensity aerobic exercise reduced regional CBF to a greater extent in BD compared to controls; these time dependent CBF responses were associated with exercise-induced feelings of exhaustion.