Intracortical Myelin in Youths at Risk for Depression.

Background: Major depressive disorder (MDD) is a leading cause of disability. To understand why depression develops, it is important to distinguish between early neural markers of vulnerability that precede the onset of MDD and features that develop during depression. Recent neuroimaging findings suggest that reduced global and regional intracortical myelination (ICM), especially in the lateral prefrontal cortex, may be associated with depression, but it is unknown whether it is a precursor or a consequence of MDD. The study of offspring of affected parents offers the opportunity to distinguish between precursors and consequences by examining individuals who carry high risk at a time when they have not experienced depression. Methods: We acquired 129 T1-weighted and T2-weighted scans from 56 (25 female) unaffected offspring of parents with depression and 114 scans from 63 (34 female) unaffected offspring of parents without a history of depression (ages 9 to 16 years). To assess scan quality, we calculated test-retest reliability. We used the scan ratios to calculate myelin maps for 68 cortical regions. We analyzed data using mixed-effects modeling. Results: ICM did not differ between high and low familial risk youths in global (B = 0.06, SE = 0.03, p = .06) or regional (B = 0.05, SE = 0.03, p = .08) analyses. Our pediatric sample had high ICM reliability (intraclass correlation coefficient = 0.79; 95% CI, 0.55-0.88). Conclusions: Based on our results, reduced ICM does not appear to be a precursor of MDD. Future studies should examine ICM in familial high-risk youths across a broad developmental period.

Vascular Disease Is Associated With Differences in Brain Structure and Lower Cognitive Functioning in Inflammatory Bowel Disease: A Cross-Sectional Study.

BACKGROUND: Vascular disease and cognitive impairment have been increasingly documented in inflammatory bowel disease (IBD), and both have been individually correlated with changes in brain structure. This study aimed to determine if both macro- and microstructural brain changes are prevalent in IBD and whether alterations in brain structure mediate the relationship between vascular disease and cognitive functioning. METHODS: Eighty-four IBD participants underwent multimodal magnetic resonance imaging. Volumetric and mean diffusivity measures of the thalamus, hippocampus, normal-appearing white matter, and white matter lesions were converted to age- and sex-adjusted z scores. Vascular comorbidity was assessed using a modified Framingham Risk Score and cognition was assessed using a battery of neuropsychological tests. Test scores were standardized using local regression-based norms. We generated summary statistics for the magnetic resonance imaging metrics and cognitive tests, and these were examined using canonical correlation analysis and linear regression modeling. RESULTS: Greater vascular comorbidity was negatively correlated with thalamic, normal-appearing white matter, and white matter lesion volumes. Higher Framingham Risk Score were also correlated with lower processing speed, learning and memory, and verbal fluency. Increased vascular comorbidity was predictive of poorer cognitive functioning, and this effect was almost entirely mediated (94.76%) by differences in brain structure. CONCLUSIONS: Vascular comorbidity is associated with deleterious effects on brain structure and lower cognitive functioning in IBD. These findings suggest that proper identification and treatment of vascular disease is essential to the overall management of IBD, and that certain brain areas may serve as critical targets for predicting the response to therapeutic interventions.

Vascular disease is associated with decreased cognitive performance in persons with inflammatory bowel disease, and this is mainly driven by changes in the brain, including both gray matter and white matter regions.

Effects of Vascular Comorbidity on Cognition in Multiple Sclerosis Are Partially Mediated by Changes in Brain Structure.

Objective: Vascular comorbidities are associated with reduced cognitive performance and with changes in brain structure in people with multiple sclerosis (MS). Understanding causal pathways is necessary to support the design of interventions to mitigate the impacts of comorbidities, and to monitor their effectiveness. We assessed the inter-relationships among vascular comorbidity, cognition and brain structure in people with MS. Methods: Adults with neurologist-confirmed MS reported comorbidities, and underwent assessment of their blood pressure, HbA1c, and cognitive functioning (i.e., Symbol Digit Modalities Test, California Verbal Learning Test, Brief Visuospatial Memory Test-Revised, and verbal fluency). Test scores were converted to age-, sex-, and education-adjusted z-scores. Whole brain magnetic resonance imaging (MRI) was completed, from which measures of thalamic and hippocampal volumes, and mean diffusivity of gray matter and normal-appearing white matter were converted to age and sex-adjusted z-scores. Canonical correlation analysis was used to identify linear combinations of cognitive measures (cognitive variate) and MRI measures (MRI variate) that accounted for the most correlation between the cognitive and MRI measures. Regression analyses were used to test whether MRI measures mediated the relationships between the number of vascular comorbidities and cognition measures. Results: Of 105 participants, most were women (84.8%) with a mean (SD) age of 51.8 (12.8) years and age of symptom onset of 29.4 (10.5) years. Vascular comorbidity was common, with 35.2% of participants reporting one, 15.2% reporting two, and 8.6% reporting three or more. Canonical correlation analysis of the cognitive and MRI variables identified one pair of variates (Pillai's trace = 0.45, p = 0.0035). The biggest contributors to the cognitive variate were the SDMT and CVLT-II, and to the MRI variate were gray matter MD and thalamic volume. The correlation between cognitive and MRI variates was 0.50; these variates were used in regression analyses. On regression analysis, vascular comorbidity was associated with the MRI variate, and with the cognitive variate. After adjusting for the MRI variate, vascular comorbidity was not associated with the cognitive variate. Conclusion: Vascular comorbidity is associated with lower cognitive function in people with MS and this association is partially mediated via changes in brain macrostructure and microstructure.

The comorbidity and cognition in multiple sclerosis (CCOMS) neuroimaging protocol: Study rationale, MRI acquisition, and minimal image processing pipelines.

The Comorbidity and Cognition in Multiple Sclerosis (CCOMS) study represents a coordinated effort by a team of clinicians, neuropsychologists, and neuroimaging experts to investigate the neural basis of cognitive changes and their association with comorbidities among persons with multiple sclerosis (MS). The objectives are to determine the relationships among psychiatric (e.g., depression or anxiety) and vascular (e.g., diabetes, hypertension, etc.) comorbidities, cognitive performance, and MRI measures of brain structure and function, including changes over time. Because neuroimaging forms the basis for several investigations of specific neural correlates that will be reported in future publications, the goal of the current manuscript is to briefly review the CCOMS study design and baseline characteristics for participants enrolled in the three study cohorts (MS, psychiatric control, and healthy control), and provide a detailed description of the MRI hardware, neuroimaging acquisition parameters, and image processing pipelines for the volumetric, microstructural, functional, and perfusion MRI data.

The Developmental Brain Age Is Associated With Adversity, Depression, and Functional Outcomes Among Adolescents.

BACKGROUND: Most psychiatric disorders emerge in the second decade of life. In the present study, we examined whether environmental adversity, developmental antecedents, major depressive disorder, and functional impairment correlate with deviation from normative brain development in adolescence. METHODS: We trained a brain age prediction model using 189 structural magnetic resonance imaging brain features in 1299 typically developing adolescents (age range 9-19 years, mean = 13.5, SD = 3.04), validated the model in a holdout set of 322 adolescents (mean = 13.5, SD = 3.07), and used it to predict age in an independent risk-enriched cohort of 150 adolescents (mean = 13.6, SD = 2.82). We tested associations between the brain age gap and adversity, early antecedents, depression, and functional impairment. RESULTS: We accurately predicted chronological age in typically developing adolescents (mean absolute error = 1.53 years). The model generalized to the validation set (mean absolute error = 1.55 years, 1.98 bias adjusted) and to the independent at-risk sample (mean absolute error = 1.49 years, 1.86 bias adjusted). The brain age estimate was reliable in repeated scans (intraclass correlation = 0.94). Experience of environmental adversity (ß = 0.18; 95% CI, 0.04 to 0.31; p = .02), diagnosis of major depressive disorder (ß = 0.61; 95% CI, 0.23 to 0.99; p = .01), and functional impairment (ß = 0.16; 95% CI, 0.05 to 0.27; p = .01) were associated with a positive brain age gap. CONCLUSIONS: Risk factors, diagnosis, and impact of mental illness are associated with an older-appearing brain during development.

Higher Framingham Risk Scores are associated with greater loss of brain volume over time in multiple sclerosis.

BACKGROUND: Few studies have evaluated the association between comorbidities associated with increased vascular risk and brain volume changes in multiple sclerosis (MS). To date, findings have not been consistent with respect to which comorbidities are associated with lower brain volumes or whether comorbidities associated with increased vascular risk are associated with greater brain volume loss over time. OBJECTIVES: We aimed to evaluate the association between the Framingham Risk Score (FRS) which evaluates vascular risk and normalized whole brain volume in MS. METHODS: We included 98 participants with MS who underwent two brain MRIs two years apart, from which whole brain volumes were calculated. Each participant reported their comorbidities and medications taken. Blood pressure, height and weight were recorded and we calculated the FRS. We tested the association between the FRS at baseline and brain volume at the second time point using quantile regression adjusting for baseline normalized brain volume, age, gender and use of disease-modifying therapy. RESULTS: As the FRS increased, brain volume was lower, both at enrollment (ß= -0.24; 95%CI: -0.42, -0.04) and at follow-up (-0.27; 95%CI: -0.45, -0.08). After further adjustment for age, gender, and use of disease modifying therapy, higher FRS remained associated with lower brain volume at follow-up at the 90th percentile of brain volume (ß= -2.22; 95%CI: -3.40, -1.04) but not at the 10th or 50th percentiles. CONCLUSION: Higher FRS were associated with lower brain volumes in persons with MS at baseline, and with brain volume loss over time. This effect was most pronounced for persons with higher brain volumes at baseline, which suggests that prevention, detection and effective management of comorbidities associated with vascular risk in people with MS is particularly important early in the disease course.

Neural and Behavioral Outcomes Differ Following Equivalent Bouts of Motor Imagery or Physical Practice.

Despite its reported effectiveness for the acquisition of motor skills, we know little about how motor imagery (MI)-based brain activation and performance evolves when MI (the imagined performance of a motor task) is used to learn a complex motor skill compared to physical practice (PP). The current study examined changes in MI-related brain activity and performance driven by an equivalent bout of MI- or PP-based training. Participants engaged in 5 days of either MI or PP of a dart-throwing task. Brain activity (via fMRI) and performance-related outcomes were obtained using a pre/post/retention design. Relative to PP, MI-based training did not drive robust changes in brain activation and was inferior for realizing improvements in performance: Greater activation in regions critical to refining the motor program was observed in the PP versus MI group posttraining, and relative to those driven via PP, MI led only to marginal improvements in performance. Findings indicate that the modality of practice (i.e., MI vs. PP) used to learn a complex motor skill manifests as differences in both resultant patterns of brain activity and performance. Ultimately, by directly comparing brain activity and behavioral outcomes after equivalent training through MI versus PP, this work provides unique knowledge regarding the neural mechanisms underlying learning through MI.

Reliability of multimodal MRI brain measures in youth at risk for mental illness.

INTRODUCTION: A new generation of large-scale studies is using neuroimaging to investigate adolescent brain development across health and disease. However, imaging artifacts such as head motion remain a challenge and may be exacerbated in pediatric clinical samples. In this study, we assessed the scan-rescan reliability of multimodal MRI in a sample of youth enriched for risk of mental illness. METHODS: We obtained repeated MRI scans, an average of 2.7 ± 1.4 weeks apart, from 50 youth (mean age 14.7 years, SD = 4.4). Half of the sample (52%) had a diagnosis of an anxiety disorder; 22% had attention-deficit/hyperactivity disorder (ADHD). We quantified reliability with the test-retest intraclass correlation coefficient (ICC). RESULTS: Gray matter measurements were highly reliable with mean ICCs as follows: cortical volume (ICC = 0.90), cortical surface area (ICC = 0.89), cortical thickness (ICC = 0.82), and local gyrification index (ICC = 0.85). White matter volume reliability was excellent (ICC = 0.98). Diffusion tensor imaging (DTI) components were also highly reliable. Fractional anisotropy was most consistently measured (ICC = 0.88), followed by radial diffusivity (ICC = 0.84), mean diffusivity (ICC = 0.81), and axial diffusivity (ICC = 0.78). We also observed regional variability in reconstruction, with some brain structures less reliably reconstructed than others. CONCLUSIONS: Overall, we showed that developmental MRI measures are highly reliable, even in youth at risk for mental illness and those already affected by anxiety and neurodevelopmental disorders. Yet, caution is warranted if patterns of results cluster within regions of lower reliability.

Spatial normalization of multiple sclerosis brain MRI data depends on analysis method and software package.

BACKGROUND: Spatially normalizing brain MRI data to a template is commonly performed to facilitate comparisons between individuals or groups. However, the presence of multiple sclerosis (MS) lesions and other MS-related brain pathologies may compromise the performance of automated spatial normalization procedures. We therefore aimed to systematically compare five commonly used spatial normalization methods for brain MRI - including linear (affine), and nonlinear MRIStudio (LDDMM), FSL (FNIRT), ANTs (SyN), and SPM (CAT12) algorithms - to evaluate their performance in the presence of MS-related pathologies. METHODS: 3 Tesla MRI images (T1-weighted and T2-FLAIR) were obtained for 20 participants with MS from an ongoing cohort study (used to assess a real dataset) and 1 healthy control participant (used to create a simulated lesion dataset). Both raw and lesion-filled versions of each participant's T1-weighted brain images were warped to the Montreal Neurological Institute (MNI) template using all five normalization approaches for the real dataset, and the same procedure was then repeated using the simulated lesion dataset (i.e., total of 400 spatial normalizations). As an additional quality-assurance check, the resulting deformations were also applied to the corresponding lesion masks to evaluate how each processing pipeline handled focal white matter lesions. For each normalization approach, inter-subject variability (across normalized T1-weighted images) was quantified using both mutual information (MI) and coefficient of variation (COV), and the corresponding normalized lesion volumes were evaluated using paired-sample t-tests. RESULTS: All four nonlinear warping methods outperformed conventional linear normalization, with SPM (CAT12) yielding the highest MI values, lowest COV values, and proportionately-scaled lesion volumes. Although lesion-filling improved spatial normalization accuracy for each of the methods tested, these effects were small compared to differences between normalization algorithms. CONCLUSIONS: SPM (CAT12) warping, ideally combined with lesion-filling, is recommended for use in future MS brain imaging studies requiring spatial normalization.

Psychotic symptoms are associated with lower cortical folding in youth at risk for mental illness

Background: Cortical folding is essential for healthy brain development. Previous studies have found regional reductions in cortical folding in adult patients with psychotic illness. It is unknown whether these neuroanatomical markers are present in youth with subclinical psychotic symptoms. Methods: We collected MRIs and examined the local gyrification index in a sample of 110 youth (mean age ± standard deviation 14.0 ± 3.7 yr; range 9­25 yr) with a family history of severe mental illness: 48 with psychotic symptoms and 62 without. Images were processed using the Human Connectome Pipeline and FreeSurfer. We tested for group differences in local gyrification index using mixed-effects generalized linear models controlling for age, sex and familial clustering. Sensitivity analysis further controlled for intracranial volume, IQ, and stimulant and cannabis use. Results: Youth with psychotic symptoms displayed an overall trend toward lower cortical folding across all brain regions. After adjusting for multiple comparisons and confounders, regional reductions were localized to the frontal and occipital lobes. Specifically, the medial (B = ­0.42, pFDR = 0.04) and lateral (B = ­0.39, pFDR = 0.04) orbitofrontal cortices as well as the cuneus (B = ­0.47, pFDR = 0.03) and the pericalcarine (B = ­0.45, pFDR = 0.03) and lingual (B = ­0.38, pFDR = 0.04) gyri. Limitations: Inference about developmental trajectories was limited by the cross-sectional data. Conclusion: Psychotic symptoms in youth are associated with cortical folding deficits, even in the absence of psychotic illness. The current study helps clarify the neurodevelopmental basis of psychosis at an early stage, before medication, drug use and other confounds have had a persistent effect on the brain.

The impacts of actual and perceived nicotine administration on insula functional connectivity with the anterior cingulate cortex and nucleus accumbens.

BACKGROUND: Changes in resting state functional connectivity between the insula and dorsal anterior cingulate cortex as well as between the insula and nucleus accumbens have been linked to nicotine withdrawal and/or administration. However, because many of nicotine's effects in humans appear to depend, at least in part, on the belief that nicotine has been administered, the relative contribution of nicotine's pharmacological actions to such effects requires clarification. AIMS: The purpose of this study was to examine the impacts of perceived and actual nicotine administration on neural responses. METHODS: Twenty-six smokers were randomly assigned to receive either a nicotine inhaler (4 mg deliverable) or a nicotine-free inhaler across two sessions. Inhaler content instructions (told nicotine vs told nicotine-free) differed across sessions. Resting state functional connectivity between sub-regions of the insula and the dorsal anterior cingulate cortex and nucleus accumbens was measured using magnetic resonance imaging before and after inhaler administration. RESULTS: Both actual and perceived nicotine administration independently altered resting state functional connectivity between the anterior insula and the dorsal anterior cingulate cortex, with actual administration being associated with decreased resting state functional connectivity, and perceived administration with increased resting state functional connectivity. Actual nicotine administration also contralaterally reduced resting state functional connectivity between the anterior insula and nucleus accumbens, while reductions in resting state functional connectivity between the mid-insula and right nucleus accumbens were observed when nicotine was administered unexpectedly. Changes in resting state functional connectivity associated with actual or perceived nicotine administration were unrelated to changes in subjective withdrawal and craving. Changes in withdrawal and craving were however independently associated with resting state functional connectivity between the nucleus accumbens and insula. CONCLUSIONS: Our findings highlight the importance of considering non-pharmacological factors when examining drug mechanisms of action.

Brain age in bipolar disorders: Effects of lithium treatment.

OBJECTIVE: Bipolar disorders increase the risk of dementia and show biological and brain alterations, which resemble accelerated aging. Lithium may counter some of these processes and lower the risk of dementia. However, until now no study has specifically investigated the effects of Li on brain age. METHODS: We acquired structural magnetic resonance imaging scans from 84 participants with bipolar disorders (41 with and 43 without Li treatment) and 45 controls. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants, and calculated BrainAGE by subtracting chronological from the estimated brain age. RESULTS: BrainAGE was significantly greater in non-Li relative to Li or control participants, F(2, 125) = 10.22, p < 0.001, with no differences between the Li treated and control groups. The estimated brain age was significantly higher than the chronological age in the non-Li (4.28 ± 6.33 years, matched t(42) = 4.43, p < 0.001), but not the Li-treated group (0.48 ± 7.60 years, not significant). Even Li-treated participants with partial prophylactic treatment response showed lower BrainAGE than the non-Li group, F(1, 64) = 4.80, p = 0.03. CONCLUSIONS: Bipolar disorders were associated with greater, whereas Li treatment with lower discrepancy between brain and chronological age. These findings support the neuroprotective effects of Li, which were sufficiently pronounced to affect a complex, multivariate measure of brain structure. The association between Li treatment and BrainAGE was independent of long-term thymoprophylactic response and thus may generalize beyond bipolar disorders, to neurodegenerative disorders.

Neural coding of movement direction in the healthy human brain.

Neurophysiological studies in monkeys show that activity of neurons in primary cortex (M1), pre-motor cortex (PMC), and cerebellum varies systematically with the direction of reaching movements. These neurons exhibit preferred direction tuning, where the level of neural activity is highest when movements are made in the preferred direction (PD), and gets progressively lower as movements are made at increasing degrees of offset from the PD. Using a functional magnetic resonance imaging adaptation (fMRI-A) paradigm, we show that PD coding does exist in regions of the human motor system that are homologous to those observed in non-human primates. Consistent with predictions of the PD model, we show adaptation (i.e., a lower level) of the blood oxygen level dependent (BOLD) time-course signal in M1, PMC, SMA, and cerebellum when consecutive wrist movements were made in the same direction (0° offset) relative to movements offset by 90° or 180°. The BOLD signal in dorsolateral prefrontal cortex adapted equally in all movement offset conditions, mitigating against the possibility that the present results are the consequence of differential task complexity or attention to action in each movement offset condition.