Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were −0.75 points on the HDRS-21 at 2 hours (P = 0.73), −1.41 points at 24 hours (P = 0.52), −4.35 points at week 1 (P = 0.05), and −5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were −0.87 points at 2 hours (P = 0.69), −1.93 points at 24 hours (P = 0.37), −2.44 points at week 1 (P = 0.25), and −7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Objective The Montreal Cognitive Assessment (MoCA) is a brief screening measure commonly used to determine cognitive status among older adults. Despite the popularity of the MoCA, there has been little research into how performance on the MoCA changes over time in healthy older adults. Methods The present study examined a sample of older adults (n = 53) recruited for a longitudinal study of healthy aging. Change in total MoCA score at three time-points (baseline, 12 months, and 48 months) and scores from the Repeatable Battery for the Assessment of Neuropsychological Status at five time-points (RBANS; baseline 12 months, 24 months, 36 months, 48 months) were assessed using repeated measures analyses. Results Total MoCA score significantly increased across time, particularly between the first and second administrations. Scores did not significantly differ between the second (12 month) and third (48 month) administrations. When grouped by baseline performance, individuals who scored low at baseline significantly improved performance at 12 month testing, but had little change between 12 month and 48 month testing. Conversely, individuals who scored high at baseline did not significantly change between baseline and 12 month testing, but improved between 12 month and 48 month testing. RBANS scores did not significantly change over time. Conclusions These results suggest that the MoCA may be susceptible to practice effects, particularly between the first and second administrations. These practice effects should be taken into consideration when repeatedly employing the MoCA to screen for cognitive status in healthy older adults.

Obesity, commonly measured with body mass index (BMI), is associated with numerous deleterious health conditions including alterations in brain integrity related to advanced age. Prior research has suggested that white matter integrity observed using diffusion tensor imaging (DTI) is altered in relation to high BMI, but the integrity of specific white matter tracts remains poorly understood. Additionally, no studies have examined white matter tract integrity in conjunction with neuropsychological evaluation associated with BMI among older adults. The present study examined white matter tract integrity using DTI and cognitive performance associated with BMI in 62 healthy older adults (20 males, 42 females) aged 51 to 81. Results revealed that elevated BMI was associated with lower fractional anisotropy (FA) in the uncinate fasciculus, though there was no evidence of an age by BMI interaction relating to FA in this tract. No relationships were observed between BMI and other white matter tracts or cognition after controlling for demographic variables. Findings suggest that elevated BMI is associated with lower structural integrity in a brain region connecting frontal and temporal lobes and this alteration precedes cognitive dysfunction. Future studies should examine biological mechanisms that mediate the relationships between BMI and white matter tract integrity, as well as the evolution of these abnormalities utilizing longitudinal designs.

Aging is associated with microstructural changes in brain tissue that can be visualized using diffusion tensor imaging (DTI). While previous studies have established age-related changes in white matter (WM) diffusion using DTI, the impact of age on gray matter (GM) diffusion remains unclear. The present study utilized DTI metrics of mean diffusivity (MD) to identify age differences in GM/WM micro-structure in a sample of healthy older adults (N=60). A secondary aim was to determine the functional significance of whole-brain GM/WM MD on global cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Participants were divided into three age brackets (ages 50–59, 60–69, and 70+) to examine differences in MD and cognition by decade. MD was examined bilaterally in the frontal, temporal, parietal, and occipital lobes for the primary analyses and an aggregate measure of whole-brain MD was used to test relationships with cognition. Significantly higher MD was observed in bilateral GM of the temporal and parietal lobes, and in right hemisphere WM of the frontal and temporal lobes of older individuals. The most robust differences in MD were between the 50–59 and 70+ age groups. Higher whole-brain GM MD was associated with poorer RBANS performance in the 60–69 age group. Results suggest that aging has a significant and differential impact on GM/WM diffusion in healthy older adults, which may explain a modest degree of cognitive variability at specific time points during older adulthood.

Military service members frequently sustain traumatic brain injuries (TBI) while on active duty, a majority of which are related to explosive blasts and are mild in severity. Studies evaluating the cortical gray matter in persons with injuries of this nature remain scarce. The purpose of this study was to assess cortical thickness in a sample of military veterans with chronic blast-related TBI. Thirty-eight veterans with mild TBI and 17 veterans with moderate TBI were compared with 58 demographically matched healthy civilians. All veterans with TBI sustained injuries related to a blast and were between 5 and 120 months post-injury (M = 62.08). Measures of post-traumatic stress disorder (PTSD) and depression were administered, along with a battery of neuropsychological tests to assess cognition. The Freesurfer software package was used to calculate cortical thickness of the participants. Results demonstrated significant clusters of cortical thinning in the right hemispheric insula and inferior portions of the temporal and frontal lobe in both mild and moderate TBI participants. The TBI sample from this study demonstrated a high incidence of comorbid PTSD and depression symptoms, which is consistent with the previous literature. Cortical thickness values correlated with measures of PTSD, depression, and post-concussive symptoms. This study provides evidence of cortical thinning in the context of chronic blast-related mild and moderate TBI in military veterans who have comorbid psychiatric symptoms. Our findings provide important insight into the natural progression of long-term cortical change in this population and may have implications for future clinical evaluation and treatment.

Increased body mass index (BMI) has been linked to various detrimental health outcomes, including cognitive dysfunction. Recent work investigating associations between obesity and the brain has revealed decreased white matter microstructural integrity in individuals with elevated BMI, independent of age or comorbid health conditions. However, the relationship between high BMI and white matter fiber bundle length (FBL), which represents a novel metric of microstructural brain integrity, remains unknown. The present study utilized quantitative tractography based on diffusion tensor imaging (DTI) to investigate the relationship between BMI and FBL in 72 otherwise healthy older adults (24 males, 48 females). All participants were between 51 and 85 years of age (M = 63.26, SD = 8.76). Results revealed that elevated BMI was associated with shorter FBL in the temporal lobe, independent of age (p < .01). In addition, increased age was associated with shorter frontal, temporal, and whole brain FBL (all p values < .01). These findings indicate that, while increased age is an important factor associated with reduced FBL, high BMI is uniquely associated with reduced FBL in the temporal lobe. These data offer evidence for additive adverse effects of high BMI on the brain, especially in areas already vulnerable to aging processes and age-related neurodegenerative diseases. Further research is necessary to determine the physiological mechanisms associated with the shortening of FBL in individuals with high BMI.

Technological advances over recent decades now allow for in vivo observation of human brain tissue through the use of neuroimaging methods. While this field originated with techniques capable of capturing macrostructural details of brain anatomy, modern methods such as diffusion tensor imaging (DTI) that are now regularly implemented in research protocols have the ability to characterize brain microstructure. DTI has been used to reveal subtle micro-anatomical abnormalities in the prodromal phase ofº various diseases and also to delineate “normal” age-related changes in brain tissue across the lifespan. Nevertheless, imaging artifact in DTI remains a significant limitation for identifying true neural signatures of disease and brain-behavior relationships. Cerebrospinal fluid (CSF) contamination of brain voxels is a main source of error on DTI scans that causes partial volume effects and reduces the accuracy of tissue characterization. Several methods have been proposed to correct for CSF artifact though many of these methods introduce new limitations that may preclude certain applications. The purpose of this review is to discuss the complexity of signal acquisition as it relates to CSF artifact on DTI scans and review methods of CSF suppression in DTI. We will then discuss a technique that has been recently shown to effectively suppress the CSF signal in DTI data, resulting in fewer errors and improved measurement of brain tissue. This approach and related techniques have the potential to significantly improve our understanding of “normal” brain aging and neuropsychiatric and neurodegenerative diseases. Considerations for next-level applications are discussed.

Objective: To investigate the relationship between older age and mean cerebral white matter fiber bundle lengths (FBLs) in specific white matter tracts in the brain using quantified diffusion MRI.Methods: Sixty-three healthy adults older than 50 years underwent diffusion tensor imaging.Tractography tracings of cerebral white matter fiber bundles were derived from the diffusion tensor imaging data.Results: Results revealed significantly shorter FBLs in the anterior thalamic radiation for every 1-year increase over the age of 50 years. Conclusions:We investigated the effects of age on FBL in specific white matter tracts in the brains of healthy older individuals utilizing quantified diffusion MRI. The results revealed a significant inverse relationship between age and FBL. Longitudinal studies of FBL across a lifespan are needed to examine the specific changes to the integrity of white matter. Diffusion tensor imaging (DTI) is a noninvasive imaging technique frequently used to visualize age-related changes in white matter integrity. DTI measures water movement within a voxel and captures abnormalities in the underlying microstructural anatomy that change the direction and speed of diffusion in specific brain regions.1 Age effects demonstrated with DTI are regionally diverse and typically show an anterior-to-posterior pattern of age-related decline.2-4 In quantifying age-related decline, most DTI studies have examined white matter integrity in focal brain regions, utilizing region of interest (ROI) and voxel-based morphometry approaches.Quantitative tractography based on DTI (qtDTI) combines traditional tractography methods 4 with scalar metrics to detect region-specific microstructural changes in white matter fiber bundles.5 Specifically, the approach computes fiber bundle length (FBL) using fractional anisotropy (FA) to produce tract lines representing coherent bundles of nerve fibers. FBL constructed utilizing qtDTI provides additional detail about the direction and curvature of white matter pathways coursing throughout the brain. 6 This method is sensitive to white matter changes within entire tracts and thus may be more beneficial than methods that involve placing ROIs on 2-dimensional scalar DTI parameter maps. 6 In the present study, we utilized qtDTI tractography methods to examine the impact of aging on the white matter integrity in the brains among healthy older adults. All selected tracts have been previously associated with various factors related to age. We hypothesized that advanced age would negatively affect the microstructural integrity of white matter, resulting in shorter mean FBL in white matter tracts.