Brain age predicts disability accumulation in multiple sclerosis

OBJECTIVE: Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of brain age analysis on disability in MS using a large, real-world dataset. METHODS: Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (\u3e13,000 imaging sessions from \u3e6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models. RESULTS: MS was associated with advanced predicted brain age cross-sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability. INTERPRETATION: Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation

Functional imaging of cognition in an old-old population: A case for portable functional near-infrared spectroscopy

In this study, functional near-infrared spectroscopy (fNIRS) was used to record brain activa- tion during cognitive testing in older individuals (88±6yo; N = 19) living in residential care communities. This population, which is often associated with loss of personal independence due to physical or cognitive decline associated with aging, is also often under-represented in neuroscience research because of a limited means to participate in studies which often take place in large urban or university centers. In this study, we demonstrate the feasibility and initial results using a portable 8-source by 4-detector fNIRS system to measure brain activity from participants within residential care community centers. Using fNIRS, brain sig- nals were recorded during a series of computerized cognitive tests, including a Symbol Digit Coding test (SDC), Stroop Test (ST), and Shifting Attention Test (SAT). The SDC and SAT elicited greater activity in the left middle frontal region of interest. Three components of the ST produced increases in the right middle frontal and superior frontal, and left superior frontal regions. An association between advanced age and increased activation in the right middle frontal region was observed during the incongruent ST. Although none of the partici- pants had clinical dementia based on the short portable mental status questionnaire, the group performance was slightly below age-normed values on these cognitive tests. These results demonstrate the capability for obtaining functional neuroimaging measures in resi- dential settings, which ultimately may aid in prognosis and care related to dementia in older adults

Reproducibility and Bias in Healthy Brain Segmentation: Comparison of Two Popular Neuroimaging Platforms

We evaluated and compared the performance of two popular neuroimaging processing platforms: Statistical Parametric Mapping (SPM) and FMRIB Software Library (FSL). We focused on comparing brain segmentations using Kirby21, a magnetic resonance imaging (MRI) replication study with 21 subjects and two scans per subject conducted only a few hours apart. We tested within- and between-platform segmentation reliability both at the whole brain and in 10 regions of interest (ROIs). For a range of fixed probability thresholds we found no differences between-scans within-platform, but large differences between-platforms. We have also found very large differences between- and within-platforms when probability thresholds were changed. A randomized blinded reader study indicated that: (1) SPM and FSL performed well in terms of gray matter segmentation; (2) SPM and FSL performed poorly in terms of white matter segmentation; and (3) FSL slightly outperformed SPM in terms of CSF segmentation. We also found that tissue class probability thresholds can have profound effects on segmentation results. We conclude that the reproducibility of neuroimaging studies depends on the neuroimaging software-processing platform and tissue probability thresholds. Our results suggest that probability thresholds may not be comparable across platforms and consistency of results may be improved by estimating a probability threshold correspondence function between SPM and FSL

Low-dose augmentation with buprenorphine increases emotional reactivity but not reward activity in treatment resistant mid- and late-life depression

Buprenorphine is currently being studied for treatment-resistant depression because of its rapid effect, relative safety, and unique pharmacodynamics. To understand the neural impact of buprenorphine in depression, we examined acute limbic and reward circuit changes during an intervention with low-dose buprenorphine augmentation pharmacotherapy. Mid and late-life adults with major depression (N = 31) who did not completely respond to an adequate trial of venlafaxine were randomized to augmentation with low-dose buprenorphine or matching placebo. We investigated early neural changes using functional magnetic resonance imaging (fMRI) from pre-randomization to 3 weeks using both an emotional reactivity task and a gambling task. We tested if: 1) there were significant neural changes acutely per intervention group, and 2) if acute neural changes were associated with depressive symptom change over 8 weeks using both the total score and the dysphoria subscale of the Montgomery Asberg Depression Rating Scale. Participants in both the buprenorphine and placebo groups showed similar changes in depressive symptoms. Neither the emotional reactivity nor gambling task resulted in significant neural activation changes from pre-randomization to 3-weeks. In both groups, increases in rostral anterior cingulate (rACC) and ventromedial prefrontal cortex (vmPFC) activation during the emotional reactivity task were associated with overall symptom improvement. In the buprenorphine but not the placebo group, increased activation in left anterior insula (aINS) and bilateral middle frontal gyrus (MFG) was associated with improvement on the dysphoria subscale. Activation changes in the reward task were not associated with buprenorphine. This is the first study to show an association between acute neural changes during emotion reactivity and changes in depression severity with buprenorphine treatment. Keywords: Treatment-resistant depression, Geriatric, Buprenorphine, Placebo, fMRI, Clinical tria

Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study

International audienceNitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group x time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant