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To characterize seasonal variation of three allergens (dust mite, cat, and cockroach) and total culturable fungi and to explore whether residential characteristics were associated with the concentrations of these agents, floor dust was collected from 47 inner-city homes in Minneapolis, Minnesota, over a 1-year period. A longitudinal analysis of allergen and fungal concentrations was carried out using mixed-effect models. Overall, relative humidity was a better predictor of allergen concentrations over time than indoor temperature. Seasonal variation of cat and cockroach allergens was negligible compared with the variability associated with residential characteristics such as race/ethnicity, family income, and the presence of cats. Fungal concentrations showed significant seasonal variation that outweighed the variability associated with residential characteristics. Less than 30% of the dust mite allergen and cockroach allergens concentrations were above limits of detection. Observed cockroach allergen concentrations were higher in Spanish- and Somali-speaking households than in English-speaking households, while English-speaking households had significantly higher cat allergen concentrations compared with the other language groups. The ratios of within-home to between-home variance for total culturable fungi, dust mite, cockroach, and cat allergen concentrations were 2.54, 1.91, 0.55, and 0.24, respectively. This ratio is used to predict the number of repeated measurements of each allergen required to robustly estimate long-term exposure estimates such that exposure misclassification bias is kept within acceptable limits. It is not clear whether repeated measurements of dust mite and cockroach allergens are required for long-term average exposure because of the large fraction of nondetects. It is concluded that a single measurement of cat allergen is a reasonable surrogate for long-term average exposure, since repeated measurements over time were highly correlated. Total culturable fungi will require greater than nine repeated measurements for robust assessment of long-term exposures because of low correlations in fungal measures over time. [ABSTRACT FROM AUTHOR]

Objective: To examine the long-term association of metabolic syndrome with mortality among those at high risk for cardiovascular disease (CVD).Research Design and Methods: A total of 10,950 Multiple Risk Factor Intervention Trial (MRFIT) survivors were followed for mortality an additional median 18.4 years (1980-1999). Proportional hazards models examined multivariate-adjusted risks associated with Adult Treatment Panel III-defined metabolic syndrome conditions, with BMI substituted for waist circumference.Results: At MRFIT annual visit 6, 4,588 (41.9%) men, mean age (+/-SD) 53.0 +/- 5.9 years, had metabolic syndrome and 6,362 did not. Comparing men with metabolic syndrome to men without, adjusted hazard ratios (HRs) were 1.21 (95% CI 1.13-1.29), 1.49 (1.35-1.64), and 1.51 (1.34-1.70) for 18-year total, CVD, and coronary heart disease mortality, respectively. Among men with metabolic syndrome, elevated glucose (1.54 [1.34-1.78]) and low HDL cholesterol (1.45 [1.17-1.54]) were most predictive of CVD mortality, followed by elevated BMI (1.34 [1.17-1.54]), elevated blood pressure (1.25 [0.98-1.58]), and elevated triglycerides (1.06 [0.86-1.30]). In contrast, for men without metabolic syndrome, the HR for low HDL cholesterol was 1.02 (0.86-1.22). Among metabolic syndrome men with no nonfatal CVD event, smokers with elevated LDL cholesterol showed higher CVD mortality (1.79 [1.22-2.63]) compared with nonsmokers without elevated LDL cholesterol; this additional risk was even greater for metabolic syndrome men with a nonfatal CVD event (2.11 [1.32-3.38]).Conclusions: Metabolic syndrome is associated with an increased risk of mortality. Among those with metabolic syndrome, risk is further increased by having more metabolic syndrome conditions, by cigarette smoking, and by elevated LDL cholesterol. Primary prevention of each metabolic syndrome condition should be emphasized, and presence of each condition should be treated in accordance with current guidelines. [ABSTRACT FROM AUTHOR]

Besides being responsible for olfaction and air intake, the nose contains abundant vasculature and autonomic nervous system innervations, and it is a cerebrospinal fluid clearance site. Therefore, the nose is an attractive target for functional MRI (fMRI). Yet, nose fMRI has not been possible so far due to signal losses originating from nasal air-tissue interfaces. Here, we demonstrated feasibility of nose fMRI by using novel ultrashort/zero echo time (TE) MRI. Results obtained in the resting-state from 13 healthy participants at 7T and in 5 awake mice at 9.4T revealed a highly reproducible resting-state nose functional network that likely reflects autonomic nervous system activity. Another network observed in humans involves the nose, major brain vessels and CSF spaces, presenting a temporal dynamic that correlates with heart rate and breathing rate. These resting-state nose functional signals should help elucidate peripheral and central nervous system integrations., (© 2024. The Author(s).)

Engagement in nonsuicidal self-injury (NSSI) often begins in adolescence, and commonly occurs when a person is emotionally dysregulated. Parental emotion socialization (ES) plays a key role in shaping children's emotional expression, experience, and regulation. Longitudinal work is needed to understand how links between parental ES and adolescent clinical outcomes unfold over time. In this longitudinal study (N = 118; all assigned female at birth with a range of NSSI - from none to severe; age 12-17 years, Mage = 14.98 at the first assessment), for the Time 1 (T1) and Time 2 (T2) annual assessments; adolescents reported NSSI and adolescents and parents reported depressive symptoms. Parents (primarily mothers) reported on their supportive and unsupportive ES responses to youth expressions of sadness, anger, and happiness. We examined (1) concurrent relationships across time points, (2) longitudinal models (T1 to T2 change in parental ES and its associated T1 to T2 changes in adolescent clinical outcomes), and (3) prediction models (T1 parental ES predicting changes in adolescent clinical outcomes). Concurrent associations between parental supportive ES responses to sadness and anger were inversely related to adolescent's depressive symptoms and NSSI episodes. Longitudinal analyses showed that increases in unsupportive responses to sadness correspond with increases in depressive symptoms from T1 to T2. The findings underscore the importance of examining how parents respond to their children's emotions. Next steps are to investigate potential mechanisms of risk and consider interventions that enhance adaptive responses of parents to adolescents embroiled in negative emotional states., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Quantitative maps of rotating frame relaxation (RFR) time constants are sensitive and useful magnetic resonance imaging tools with which to evaluate tissue integrity in vivo. However, to date, only moderate image resolutions of 1.6 x 1.6 x 3.6 mm 3 have been used for whole-brain coverage RFR mapping in humans at 3 T. For more precise morphometrical examinations, higher spatial resolutions are desirable. Towards achieving the long-term goal of increasing the spatial resolution of RFR mapping without increasing scan times, we explore the use of the recently introduced Transform domain NOise Reduction with DIstribution Corrected principal component analysis (T-NORDIC) algorithm for thermal noise reduction. RFR acquisitions at 3 T were obtained from eight healthy participants (seven males and one female) aged 52 ± 20 years, including adiabatic T1ρ, T2ρ, and nonadiabatic Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n = 4 (RAFF4) with both 1.6 x 1.6 x 3.6 mm 3 and 1.25 x 1.25 x 2 mm 3 image resolutions. We compared RFR values and their confidence intervals (CIs) obtained from fitting the denoised versus nondenoised images, at both voxel and regional levels separately for each resolution and RFR metric. The comparison of metrics obtained from denoised versus nondenoised images was performed with a two-sample paired t-test and statistical significance was set at p less than 0.05 after Bonferroni correction for multiple comparisons. The use of T-NORDIC on the RFR images prior to the fitting procedure decreases the uncertainty of parameter estimation (lower CIs) at both spatial resolutions. The effect was particularly prominent at high-spatial resolution for RAFF4. Moreover, T-NORDIC did not degrade map quality, and it had minimal impact on the RFR values. Denoising RFR images with T-NORDIC improves parameter estimation while preserving the image quality and accuracy of all RFR maps, ultimately enabling high-resolution RFR mapping in scan times that are suitable for clinical settings., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD., Objective/hypothesis: This pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD., Methods: 15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R)., Results: 14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response., Limitations: Main limitations include a small sample size and open-label design., Conclusions: These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To better communicate and improve post-visit outcomes, a remote patient monitoring (RPM) program was implemented for patients discharged from emergency departments (ED) across 10 hospitals. The solution was offered to patients at the time of ED discharge and staffed by a group of care coordinators to respond to questions/urgent needs. Of 107,477 consecutive patients offered RPM, 28,425 patients (26.4%) engaged with the program. Activated patients with RPM were less likely to return to the ED within 90 days of their index visit [19.8% compared to 23.6%, p<.001]. While activation rates were modest, we observed fewer return visits to the ED in patients using RPM, with a 16.2% lower hazard of returning in the next year. Future research is needed to understand methods to improve RPM activation, any causal effects of RPM activation on return ED visits, and external validation of these findings.

Introduction: Subcutaneous macroencapsulation devices circumvent disadvantages of intraportal islet therapy. However, a curative dose of islets within reasonably sized devices requires dense cell packing. We measured internal PO2 of implanted devices, mathematically modeled oxygen availability within devices and tested the predictions with implanted devices containing densely packed human islets., Methods: Partial pressure of oxygen (PO2) within implanted empty devices was measured by noninvasive 19 F-MRS. A mathematical model was constructed, predicting internal PO2, viability and functionality of densely packed islets as a function of external PO2. Finally, viability was measured by oxygen consumption rate (OCR) in day 7 explants loaded at various islet densities., Results: In empty devices, PO2 was 12 mmHg or lower, despite successful external vascularization. Devices loaded with human islets implanted for 7 days, then explanted and assessed by OCR confirmed trends proffered by the model but viability was substantially lower than predicted. Co-localization of insulin and caspase-3 immunostaining suggested that apoptosis contributed to loss of beta cells., Discussion: Measured PO2 within empty devices declined during the first few days post-transplant then modestly increased with neovascularization around the device. Viability of islets is inversely related to islet density within devices., Competing Interests: KP is the co-founder and CEO of Procyon Technologies, LLC, a startup company focused on the development of oxygenated cell encapsulation devices. BW, who was a graduate student at the time of this study, is now employed by Sylvatica Biotech Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author MG declared that he was an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Einstein, Steyn, Weegman, Suszynski, Sambanis, O'Brien, Avgoustiniatos, Firpo, Graham, Janecek, Eberly, Garwood, Putnam and Papas.)

Objective: To determine sex differences in the neurochemical concentrations measured by in vivo proton magnetic resonance spectroscopy ( 1 H MRS) of healthy mice on a genetic background commonly used for neurodegenerative disease models., Methods: 1 H MRS data collected from wild type mice with C57BL/6 or related genetic backgrounds in seven prior studies were used in this retrospective analysis. To be included, data had to be collected at 9.4 tesla magnetic field using advanced 1 H MRS protocols, with isoflurane anesthesia and similar animal handling protocols, and a similar number of datasets from male and female mice had to be available for the brain regions analyzed. Overall, 155 spectra from female mice and 166 spectra from male mice (321 in total), collected from six brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, and striatum) at various ages were included., Results: Concentrations of taurine, total creatine (creatine + phosphocreatine), ascorbate, glucose and glutamate were consistently higher in male vs. female mice in most brain regions. Striatum was an exception with similar total creatine in male and female mice. The sex difference pattern in the hypothalamus was notably different from other regions. Interaction between sex and age was significant for total creatine and taurine in the cerebellum and hippocampus., Conclusion: Sex differences in regional neurochemical levels are small but significant and age-dependent, with consistent male-female differences across most brain regions. The neuroendocrine region hypothalamus displays a different pattern of sex differences in neurochemical levels. Differences in energy metabolism and cellular density may underlie the differences, with higher metabolic rates in females and higher osmoregulatory and antioxidant capacity in males., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Tkáč, Xie, Shah, Larson, Dubinsky, Gomez-Pastor, McLoughlin, Orr, Eberly and Öz.)

Objective: Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS)., Methods: Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2-way analysis of variance mixed-effects sex-adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior., Results: MR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease., Interpretation: SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658-671., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The goals of this study were to measure the apparent transverse relaxation time constant, T 2 , of scyllo-inositol (sIns) in young and older healthy adults' brains and to investigate the effect of alcohol usage on sIns in young and older healthy adults' brains, using proton magnetic resonance spectroscopy (MRS) at 3 T. Twenty-nine young adults (age 21 ± 1 years) and 24 older adults (age 74 ± 3 years) participated in this study. MRS data were acquired from two brain regions (the occipital cortex and posterior cingulate cortex) at 3 T. The T 2 of sIns was measured using a localization by adiabatic selective refocusing (LASER) sequence at various echo times, while the sIns concentrations were measured using a short-echo-time stimulated echo acquisition mode (STEAM) sequence. A trend towards lower T 2 relaxation values of sIns in older adults was observed, although these were not significant. sIns concentration was higher with age in both brain regions and was significantly higher in the young when considering alcohol consumption of more than two drinks per week. This study shows that differences in sIns can be found in two distinct regions of the brain across two age groups, potentially reflecting normal aging. In addition, it is important to take into account alcohol consumption when reporting the sIns level in the brain., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Friedreich ataxia is a progressive neurodegenerative disorder characterized by cerebellar and spinal atrophy. However, studies to elucidate the longitudinal progression of the pathology in the brain are somewhat inconsistent and limited, especially for early-stage Friedreich ataxia. Using a multimodal neuroimaging protocol, combined with advanced analysis methods, we sought to identify macrostructural and microstructural alterations in the brain of patients with early-stage Friedreich ataxia to better understand its distribution patterns and progression. We enrolled 28 patients with Friedreich ataxia and 20 age- and gender-matched controls. Longitudinal clinical and imaging data were collected in the patients at baseline, 12, 24 and 36 months. Macrostructural differences were observed in patients with Friedreich ataxia, compared to controls, including lower volume of the cerebellar white matter (but not cerebellar grey matter), superior cerebellar peduncle, thalamus and brainstem structures, and higher volume of the fourth ventricle. Diffusion tensor imaging and fixel-based analysis metrics also showed microstructural differences in several brain regions, especially in the cerebellum and corticospinal tract. Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar grey and white matter volumes, and microstructure of the superior cerebellar peduncle, posterior limb of the internal capsule and superior corona radiata. In addition, linear regressions showed significant associations between many of those imaging metrics and clinical scales. This study provides evidence of early-stage macrostructural and microstructural alterations and of progression over time in the brain in Friedreich ataxia. Moreover, it allows to non-invasively map such brain alterations over a longer period (3 years) than any previous study, and identifies several brain regions with significant involvement in the disease progression besides the cerebellum. We show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials., Competing Interests: C.L. and P.G.H. received research grants from Minoryx Therapeutics. All other authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Recent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord., Methods: We acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section., Results: We demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics., Conclusions: Our findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials., (© 2023. The Author(s).)

Modern data often take the form of a multiway array. However, most classification methods are designed for vectors, i.e., 1-way arrays. Distance weighted discrimination (DWD) is a popular high-dimensional classification method that has been extended to the multiway context, with dramatic improvements in performance when data have multiway structure. However, the previous implementation of multiway DWD was restricted to classification of matrices, and did not account for sparsity. In this paper, we develop a general framework for multiway classification which is applicable to any number of dimensions and any degree of sparsity. We conducted extensive simulation studies, showing that our model is robust to the degree of sparsity and improves classification accuracy when the data have multiway structure. For our motivating application, magnetic resonance spectroscopy (MRS) was used to measure the abundance of several metabolites across multiple neurological regions and across multiple time points in a mouse model of Friedreich's ataxia, yielding a four-way data array. Our method reveals a robust and interpretable multi-region metabolomic signal that discriminates the groups of interest. We also successfully apply our method to gene expression time course data for multiple sclerosis treatment. An R implementation is available in the package MultiwayClassification at http://github.com/lockEF/MultiwayClassification., Competing Interests: Competing Interests The authors report there are no competing interests to declare.

Striatal medium spiny neurons are highly susceptible in Huntington's disease (HD), resulting in progressive synaptic perturbations that lead to neuronal dysfunction and death. Non-invasive imaging techniques, such as proton magnetic resonance spectroscopy ( 1 H-MRS), are used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the association between brain neurochemical alterations and synaptic dysregulation remains unknown, limiting our ability to monitor potential treatments that may affect synapse function. We conducted in vivo longitudinal 1 H-MRS in the striatum followed by ex vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD, thalamo-striatal (T-S), and cortico-striatal (C-S) pathways, to assess the relationship between neurochemical alterations and changes in synapse density. We used the zQ175 (Tg/0) HD mouse model as well as zQ175 mice lacking one allele of CK2α'(zQ175 (Tg/0) :CK2α' (+/-) ), a kinase previously shown to regulate synapse function in HD. Longitudinal analyses of excitatory synapse density showed early and sustained reduction in T-S synapses in zQ175 mice, preceding C-S synapse depletion, which was rescued in zQ175:CK2α' (+/-) . Changes in T-S and C-S synapses were accompanied by progressive alterations in numerous neurochemicals between WT and HD mice. Linear regression analyses showed C-S synapse number positively correlated with 1 H-MRS-measured levels of GABA, while T-S synapse number positively correlated with levels of phosphoethanolamine and negatively correlated with total creatine levels. These associations suggest that these neurochemical concentrations measured by 1 H-MRS may facilitate monitoring circuit-specific synaptic dysfunction in the zQ175 mouse model and in other HD pre-clinical studies., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: With the development of continuous glucose monitoring systems (CGMS), detailed glycemic data are now available for analysis. Yet analysis of this data-rich information can be formidable. The power of CGMS-derived data lies in its characterization of glycemic variability. In contrast, many standard glycemic measures like hemoglobin A1c (HbA1c) and self-monitored blood glucose inadequately describe glycemic variability and run the risk of bias toward overreporting hyperglycemia. Methods that adjust for this bias are often overlooked in clinical research due to difficulty of computation and lack of accessible analysis tools., Methods: In response, we have developed a new R package rGV, which calculates a suite of 16 glycemic variability metrics when provided a single individual's CGM data. rGV is versatile and robust; it is capable of handling data of many formats from many sensor types. We also created a companion R Shiny web app that provides these glycemic variability analysis tools without prior knowledge of R coding. We analyzed the statistical reliability of all the glycemic variability metrics included in rGV and illustrate the clinical utility of rGV by analyzing CGM data from three studies., Results: In subjects without diabetes, greater glycemic variability was associated with higher HbA1c values. In patients with type 2 diabetes mellitus (T2DM), we found that high glucose is the primary driver of glycemic variability. In patients with type 1 diabetes (T1DM), we found that naltrexone use may potentially reduce glycemic variability., Conclusions: We present a new R package and accompanying web app to facilitate quick and easy computation of a suite of glycemic variability metrics.

High-impact temporomandibular disorder (TMD) pain may involve brain mechanisms related to maladaptive central pain modulation. We investigated brain responses to stimulation of trigeminal sites not typically associated with TMD pain by applying noxious dentoalveolar pressure to high- and low-impact TMD pain cases and pain-free controls during functional magnetic resonance imaging (fMRI). Fifty female participants were recruited and assigned to one of three groups based on the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and Graded Chronic Pain Scale: controls (n = 17), low-impact (n = 17) and high-impact TMD (n = 16). Multimodal whole-brain MRI was acquired following the Human Connectome Project Lifespan protocol, including stimulus-evoked fMRI scans during which painful dentoalveolar pressure was applied to the buccal gingiva of participants. Group analyses were performed using non-parametric permutation tests for parcellated cortical and subcortical neuroimaging data. There were no significant between-group differences for brain activations/deactivations evoked by the noxious dentoalveolar pressure. For individual group mean activations/deactivations, a gradient in the number of parcels surviving thresholding was found according to the TMD pain grade, with the highest number seen in the high-impact group. Among the brain regions activated in chronic TMD pain groups were those previously implicated in sensory-discriminative and motivational-affective pain processing. These results suggest that dentoalveolar pressure pain evokes abnormal brain responses to sensory processing of noxious stimuli in high-impact TMD pain participants, which supports the presence of maladaptive brain plasticity in chronic TMD pain., Competing Interests: The authors have declared that no competing interests exist.

Friedreich ataxia is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. MRI and magnetic resonance spectroscopy are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in Friedreich ataxia using MRI and diffusion MRI. However, to our knowledge no longitudinal MRI, diffusion MRI or MRS results have been reported in the spinal cord. Here, we investigated early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in Friedreich ataxia, using a multimodal magnetic resonance protocol comprising morphometric (anatomical MRI), microstructural (diffusion MRI), and neurochemical ( 1 H-MRS) assessments.We enrolled 28 early-stage individuals with Friedreich ataxia and 20 age- and gender-matched controls (cross-sectional study). Disease duration at baseline was 5.5 ± 4.0 years and Friedreich Ataxia Rating Scale total neurological score at baseline was 42.7 ± 13.6. Twenty-one Friedreich ataxia participants returned for 1-year follow-up, and 19 of those for 2-year follow-up (cohort study). Each visit consisted in clinical assessments and magnetic resonance scans. Controls were scanned at baseline only. At baseline, individuals with Friedreich ataxia had significantly lower spinal cord cross-sectional area (-31%, P = 8 × 10 -17 ), higher eccentricity (+10%, P = 5 × 10 -7 ), lower total N-acetyl-aspartate (tNAA) (-36%, P = 6 × 10 -9 ) and higher myo-inositol (mIns) (+37%, P = 2 × 10 -6 ) corresponding to a lower ratio tNAA/mIns (-52%, P = 2 × 10 -13 ), lower fractional anisotropy (-24%, P = 10 -9 ), as well as higher radial diffusivity (+56%, P = 2 × 10 -9 ), mean diffusivity (+35%, P = 10 -8 ) and axial diffusivity (+17%, P = 4 × 10 -5 ) relative to controls. Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline ( P = 4 × 10 -4 ), the ratio tNAA/mIns decreased by 5.8% per year ( P = 0.03), and fractional anisotropy showed a trend to decrease (-3.2% per year, P = 0.08). Spinal cord cross-sectional area correlated strongly with clinical measures, with the strongest correlation coefficients found between cross-sectional area and Scale for the Assessment and Rating of Ataxia (R = -0.55, P = 7 × 10 -6 ) and between cross-sectional area and Friedreich ataxia Rating Scale total neurological score (R = -0.60, P = 4 × 10 -7 ). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns. We report here the first quantitative longitudinal magnetic resonance results in the spinal cord in Friedreich ataxia. The largest longitudinal effect size was found for spinal cord cross-sectional area, followed by tNAA/mIns and fractional anisotropy. Our results provide direct evidence that abnormalities in the spinal cord result not solely from hypoplasia, but also from neurodegeneration, and show that disease progression can be monitored non-invasively in the spinal cord., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: The point prevalence of epilepsy is high in nursing homes (NH), but the incidence of epilepsy after admission is unknown. This study was done to determine the incidence of epilepsy/seizure (epi/sz) comorbid with other conditions in older adult NH residents., Design: Retrospective evaluation of Minimum Data Set records to identify new onset epi/sz in NH residents., Setting and Participants: Five cross-sectional cohorts of all residents in any Medicare/Medicaid certified NH in the United States on July 15 of each year 2003-2007., Measures: Epi/sz was identified by International Classification of Diseases, Ninth Revision codes (345.xx or 780.39) or check box on the Minimum Data Set. Those with no such code on admission and with 1 to 3 plus years of follow-up (n = 3,609,422) were followed through 2007 or end of stay., Results: Overall incidence of epi/sz was 16.42/1000 patient years (PY). Incidence was highest in the first year after admission and declined thereafter. There were more women (n = 2,523,951) than men (n = 1,089,631), but men had a higher incidence (21.17/1000PY) compared with women (14.81/1000PY). Although the 65‒74 years of age cohort included fewer residents (n = 594,722) compared with the age 85 years + cohort (n = 1,520,167), the younger residents had the highest incidence (28.53/1000 PY) compared with the oldest, 10.22/1000 PY for the age 85+ years cohort. The highest incidences were among those with brain tumor (122.55/1000PY), followed by head injury (45.66/1000PY). Overall, 714,340 had a diagnosis of stroke, and incidence was 27.52/1000PY. Those with none of selected risk factors had an overall incidence of 12.45/1000PY., Conclusions and Implications: The incidence of epi/sz in older individuals after admission to a NH is high. There is a need to develop practice approaches to best manage this large cohort. There does not appear to be a uniform approach to managing new onset epilepsy in NHs at this time. Studies to develop evidence for practice guidelines are needed., (Copyright © 2022 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Neuroimaging pipelines have long been known to generate mildly differing results depending on various factors, including software version. While considered generally acceptable and within the margin of reasonable error, little is known about their effect in common research scenarios such as inter-group comparisons between healthy controls and various pathological conditions. The aim of the presented study was to explore the differences in the inferences and statistical significances in a model situation comparing volumetric parameters between healthy controls and type 1 diabetes patients using various FreeSurfer versions., Methods: T1- and T2-weighted structural scans of healthy controls and type 1 diabetes patients were processed with FreeSurfer 5.3, FreeSurfer 5.3 HCP, FreeSurfer 6.0 and FreeSurfer 7.1, followed by inter-group statistical comparison using outputs of individual FreeSurfer versions., Results: Worryingly, FreeSurfer 5.3 detected both cortical and subcortical volume differences out of the preselected regions of interest, but newer versions such as FreeSurfer 5.3 HCP and FreeSurfer 6.0 reported only subcortical differences of lower magnitude and FreeSurfer 7.1 failed to find any statistically significant inter-group differences., Conclusion: Since group averages of individual FreeSurfer versions closely matched, in keeping with previous literature, the main origin of this disparity seemed to lie in substantially higher within-group variability in the model pathological condition. Ergo, until validation in common research scenarios as case-control comparison studies is included into the development process of new software suites, confirmatory analyses utilising a similar software based on analogous, but not fully equivalent principles, might be considered as supplement to careful quality control., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Temporomandibular disorders (TMD) patients can present clinically significant jaw pain fluctuations which can be debilitating and lead to poor global health. The Graded Chronic Pain Scale evaluates pain-related disability and its dichotomous grading (high/low impact pain) can determine patient care pathways and in general high-impact pain patients have worse treatment outcomes. Individuals with low-impact TMD pain are thought to have better psychosocial functioning, more favorable disease course, and better ability to control pain, while individuals with high-impact pain can present with higher levels of physical and psychological symptoms. Thereby, there is reason to believe that individuals with low- and high-impact TMD pain could experience different pain trajectories over time. Our primary objective was to determine if short-term jaw pain fluctuations serve as a clinical marker for the impact status of TMD pain. To this end, we estimated the association between high/low impact pain status and jaw pain fluctuations over three visits (≤ 21-day-period) in 30 TMD cases. Secondarily, we measured the association between jaw pain intensity and pressure pain thresholds (PPT) over the face and hand, the latter measurements compared to matched pain-free controls (n = 17). Jaw pain fluctuations were more frequent among high-impact pain cases (n = 15) than low-impact pain cases (n = 15) (OR 5.5; 95% CI 1.2, 26.4; p value = 0.033). Jaw pain ratings were not associated with PPT ratings (p value > 0.220), suggesting different mechanisms for clinical versus experimental pain. Results from this proof-of-concept study suggest that targeted treatments to reduce short-term pain fluctuations in high-impact TMD pain is a potential strategy to achieve improved patient perception of clinical pain management outcomes., (© 2022. The Author(s).)

In mammalian species with prolonged maternal investment in which high-ranking males gain disproportionate numbers of mating opportunities, males that quickly ascend the hierarchy may benefit from eliminating the dependent offspring of their competitors. In savanna baboons, high-ranking females are the most profitable targets of infanticide or feticide, because their offspring have higher survival rates and their daughters reach sexual maturity at a younger age. However, such patterns may be obscured by environmental stressors that are known to exacerbate fetal losses, especially in lower-ranking females. Using 30 years of data on wild olive baboons (Papio anubis) in Gombe National Park, Tanzania, we found evidence that rapidly-rising immigrant males induced miscarriages in high-ranking females outside of drought conditions. However, miscarriage rates were largely reversed during prolonged periods of low rainfall, suggesting that low-ranking females are particularly vulnerable to low food availability and social instability. Infanticide did not emerge as a recurrent male strategy in this population, likely because of the protective behavior of resident males towards vulnerable juveniles.

Introduction: Many commonly prescribed drugs cause cognitive deficits. We investigated whether parameters of the resting-state electroencephalogram (rsEEG) are related to the severity of cognitive impairments associated with administration of the antiseizure drug topiramate (TPM) and the benzodiazepine lorazepam (LZP)., Methods: We conducted a double-blind, randomized, placebo-controlled crossover study. After a baseline visit, subjects completed three sessions at which they received either a single dose of TPM, LZP, or placebo. Four-hours after drug administration and at baseline, subjects completed a working memory (WM) task after their rsEEG was recorded. After quantifying drug-related behavioral (WM accuracy (ACC)/reaction time (RT)) and electrophysiological (alpha, theta, beta (1,2), gamma power) change for each subject, we constructed drug-specific mixed effects models of change for each WM and EEG measure. Regression models were constructed to characterize the relationship between baseline rsEEG measures and drug-related performance changes., Results: Linear mixed effects models showed theta power increases in response to TPM administration. The results of the regression models revealed a number of robust relationships between baseline rsEEG parameters and TPM-related, but not LZP-related, WM impairment., Conclusions: We showed for the first time that parameters of the rsEEG are associated with the severity of TPM-related WM deficits; this suggests that rsEEG measures may have novel clinical applications in the future., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The prevalence of non-suicidal self-injury (NSSI) is high in adolescents and young adults. However, there is a paucity of evidence-based treatments to address this clinical problem. An open-label, pilot study in the target population showed that treatment with oral N-acetylcysteine (NAC), a widely available dietary supplement, was associated with reduction in NSSI frequency. In preparation for a biologically informed design of an efficacy trial, a critical preliminary step is to clarify NAC's biological signatures, or measures of the mechanisms underlying its clinical effects. Toward that end, we propose a 2-stage project to investigate NAC's biological signatures (changes in glutathione (GSH) and/or glutamate (Glu)) in women with NSSI. The first stage; a double-blind randomized placebo-controlled study will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term (4 weeks) NAC treatment in 36 women aged 16-24 years with NSSI. Go/No-go criteria to determine if the study will progress to the second stage include pre-specified changes in brain and blood measures of GSH. Changes in the brain GSH are measured through magnetic resonance spectroscopy (MRS). The dose for the stage 2 will be selected based on the biological changes and the tolerability observed in the stage 1. The stage 2 will seek to replicate the biological signature findings in an 8-week trial in a new patient cohort, and examine the relationships among biological signatures, NAC pharmacokinetics and clinical response. This 2-stage project is unique as it unifies clinical psychiatric measurements, quantitative MRS and pharmacological approaches in the first placebo-controlled clinical trial of NAC in young women with NSSI., Trial Registration: The stage 1 trial protocol has been registered on https://clinicaltrials.gov/ with ClinicalTrials.gov ID "NCT04005053" (Registered on 02 July 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04005053)., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.

Even though well known in type 2 diabetes, the existence of brain changes in type 1 diabetes (T1D) and both their neuroanatomical and clinical features are less well characterized. To fill the void in the current understanding of this disease, we sought to determine the possible neural correlate in long-duration T1D at several levels, including macrostructural, microstructural cerebral damage, and blood flow alterations. In this cross-sectional study, we compared a cohort of 61 patients with T1D with an average disease duration of 21 years with 54 well-matched control subjects without diabetes in a multimodal MRI protocol providing macrostructural metrics (cortical thickness and structural volumes), microstructural measures (T1-weighted/T2-weighted [T1w/T2w] ratio as a marker of myelin content, inflammation, and edema), and cerebral blood flow. Patients with T1D had higher T1w/T2w ratios in the right parahippocampal gyrus, the executive part of both putamina, both thalami, and the cerebellum. These alterations were reflected in lower putaminal and thalamic volume bilaterally. No cerebral blood flow differences between groups were found in any of these structures, suggesting nonvascular etiologies of these changes. Our findings implicate a marked nonvascular disruption in T1D of several essential neural nodes engaged in both cognitive and motor processing., (© 2020 by the American Diabetes Association.)

Normal brain aging is associated with changes occurring at all levels. This study investigates age-related differences in the brain intracellular microenvironment by comparing the apparent diffusion coefficients (ADC) and apparent transverse relaxation time constants (T 2 ) of 5 neurochemicals (i.e., total N-acetyl-aspartate, total creatine, total choline, glutamate, and myo-inositol) between young and older adults. Thirty-two young healthy adults (18-22 years) and 26 older healthy adults (70-83 years) were recruited. Three brain regions were studied at 3 T: prefrontal, posterior cingulate and occipital cortices. ADC and T 2 were measured using stimulated echo acquisition mode and localization by adiabatic selective refocusing sequences, respectively. This study shows that the diffusivities of several neurochemicals are higher in older than in younger adults. In contrast, shorter apparent T 2 values for several metabolites were measured in older adults. Age-related difference in ADC and apparent T 2 of metabolites seem to be region-specific. Furthermore, this study shows that it is feasible to observe age-related differences in the cellular microenvironment of neurochemicals in the normal aging brain., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The neurobiology of adolescent depression remains poorly understood. Initial studies suggested impaired white matter microstructure in adults and adolescents, but findings have not been consistent. Challenges in this literature have included small samples, medication confounds and inconsistent correction for type I error. This study addressed these issues in a new examination of fractional anisotropy (FA) in adolescents with major depressive disorder (MDD) using diffusion tensor imaging. We examined FA in 81 adolescents aged 12-19 (44 MDD [all unmedicated], 37 controls). We conducted logistic regression analyses to examine the odds of MDD versus control based on FA within standard white matter tracts that were delineated by probabilistic tractography. We also examined relationships between FA and disease severity (overall depression and dimensions of illness). Finally, we conducted a voxel-wise group comparison of FA. All analyses covaried for age, sex and socioeconomic status, and applied rigorous corrections for multiple testing. Logistic regression did not reveal significant associations between diagnosis and FA within white matter tracts defined by probabilistic tractography. Dimensional analyses revealed that greater lassitude was associated with higher FA in right cingulum bundle and bilateral corticospinal tracts, but with lower FA in right anterior thalamic radiation. Voxel-wise group comparisons of FA did not reveal significant group differences. The current findings do not support low FA as a neurobiological marker of adolescent depression. Dimensional results suggest that FA relates to lassitude but not overall depression. Given the clinical and neurobiological heterogeneity of depression, future work utilizing dimensional approaches may help elucidate the role of white matter microstructure in adolescent depression neurobiology.

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease that causes progressive degeneration of motor neurons in the brain and the spinal cord. Corticospinal tract degeneration is a defining feature of ALS. However, there have been very few longitudinal, controlled studies assessing diffusion MRI (dMRI) metrics in different fiber tracts along the spinal cord in general or the corticospinal tract in particular. Here we demonstrate that a tract-specific analysis, with segmentation of ascending and descending tracts in the spinal cord white matter, substantially increases the sensitivity of dMRI to disease-related changes in ALS. Our work also identifies the tracts and spinal levels affected in ALS, supporting electrophysiologic and pathologic evidence of involvement of sensory pathways in ALS. We note changes in diffusion metrics and cord cross-sectional area, with enhanced sensitivity to disease effects through a multimodal analysis, and with strong correlations between these metrics and spinal components of ALSFRS-R.

Development of imaging biomarkers for rare neurodegenerative diseases such as spinocerebellar ataxia (SCA) is important to non-invasively track progression of disease pathology and monitor response to interventions. Diffusion MRI (dMRI) has been shown to identify cross-sectional degeneration of white matter (WM) microstructure and connectivity between healthy controls and patients with SCAs, using various analysis methods. In this paper, we present dMRI data in SCAs type 1, 2, 3, and 6 and matched controls, including longitudinal acquisitions at 12-24-month intervals in a subset of the cohort, with up to 5 visits. The SCA1 cohort also contained 3 premanifest patients at baseline, with 2 showing ataxia symptoms at the time of the follow-up scans. We focused on two aspects: first, multimodal evaluation of the dMRI data in a cross-sectional approach, and second, longitudinal trends in dMRI data in SCAs. Three different pipelines were used to perform cross-sectional analyses in WM: region of interest (ROI), tract-based spatial statistics (TBSS), and fixel-based analysis (FBA). We further analyzed longitudinal changes in dMRI metrics throughout the brain using ROI-based analysis. Both ROI and TBSS analyses identified higher mean (MD), axial (AD), and radial (RD) diffusivity and lower fractional anisotropy (FA) in the cerebellum for all SCAs compared to controls, as well as some cerebral alterations in SCA1, 2, and 3. FBA showed lower fiber density (FD) and fiber crossing (FC) regions similar to those identified by ROI and TBSS analyses. FBA also highlighted corticospinal tract (CST) abnormalities, which was not detected by the other two pipelines. Longitudinal ROI-based analysis showed significant increase in AD in the middle cerebellar peduncle (MCP) for patients with SCA1, suggesting that the MCP may be a good candidate region to monitor disease progression. The patient who remained symptom-free throughout the study displayed no microstructural abnormalities. On the other hand, the two patients who were at the premanifest stage at baseline, and showed ataxia symptoms in their follow-up visits, displayed AD values in the MCP that were already in the range of symptomatic patients with SCA1 at their baseline visit, demonstrating that microstructural abnormalities are detectable prior to the onset of ataxia., (Copyright © 2020 Park, Joers, Guo, Hutter, Bushara, Adanyeguh, Eberly, Öz and Lenglet.)

Non-suicidal self-injury (NSSI) is a serious clinical problem that is common in adolescents. Novel, biologically-informed approaches for treating NSSI in adolescents are needed to prevent negative outcomes such as chronic NSSI and future suicide attempts. N-acetylcysteine (NAC) has been used successfully to address other conditions that involve repetitive maladaptive behaviors and may have utility in addressing NSSI. This study explored neural circuit changes following an open-label, 8-week trial of NAC in female adolescents with NSSI. We measured whole-brain resting-state functional connectivity (RSFC) of the amygdala and the nucleus accumbens before and after treatment using resting-state functional neuroimaging. Usable neuroimaging data from both pre- and post-treatment were available for 18 participants. Reduction in NSSI frequency was associated with a decrease in left amygdala RSFC with right supplementary motor area (SMA), but with an increase in right amygdala RSFC with right inferior frontal cortex. For nucleus accumbens, a reduction in NSSI frequency was associated with a decrease in connectivity between right nucleus accumbens and left superior medial frontal cortex. We also report change in similar circuits accompanying clinical improvement in depression and global psychopathology measures. These preliminary findings suggest amygdala and nucleus accumbens-based circuits as potential treatment targets, and set the stage for future research designed to confirm these neural targets using randomized, placebo-controlled designs to confirm clinical efficacy and mechanisms of effect., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical profile. Upregulation of hippocampal glucose transport as a result of recurrent exposure to hypoglycemia may preserve cognitive function during future hypoglycemia in subjects with T1D and impaired awareness of hypoglycemia (IAH). The effect of T1D on hippocampal neurochemical profile and glucose transport is unknown., Objective: To test the hypothesis that hippocampal neurochemical composition is altered in T1D and glucose transport is upregulated in T1D with IAH., Design and Participants: Hippocampal neurochemical profile was measured with single-voxel magnetic resonance spectroscopy at 3T during euglycemia in 18 healthy controls (HC), 10 T1D with IAH, and 12 T1D with normal awareness to hypoglycemia (NAH). Additionally, 12 HC, 8 T1D-IAH, and 6 T1D-NAH were scanned during hyperglycemia to assess hippocampal glucose transport with metabolic modeling., Setting: University medical center., Main Outcome Measures: Concentrations of hippocampal neurochemicals measured during euglycemia and ratios of maximal transport rate to cerebral metabolic rate of glucose (Tmax/CMRGlc), derived from magnetic resonance spectroscopy-measured hippocampal glucose as a function of plasma glucose., Results: Comparison of hippocampal neurochemical profile revealed no group differences (HC, T1D, T1D-IAH, and T1D-NAH). The ratio Tmax/CMRGlc was not significantly different between the groups, T1D-IAH (1.58 ± 0.09) and HC (1.65 ± 0.07, P = 0.54), between T1D-NAH (1.50 ± 0.09) and HC (P = 0.19), and between T1D-IAH and T1D-NAH (P = 0.53)., Conclusions: Subjects with T1D with sufficient exposure to recurrent hypoglycemia to create IAH did not have alteration of Tmax/CMRglc or neurochemical profile compared with participants with T1D-NAH or HC., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Even though MRI visualization of white matter lesions is pivotal for the diagnosis and management of multiple sclerosis (MS), the issue of detecting diffuse brain tissue damage beyond the apparent T2-hyperintense lesions continues to spark considerable interest. Motivated by the notion that rotating frame MRI methods are sensitive to slow motional regimes critical for tissue characterization, here we utilized novel imaging protocols of rotating frame MRI on a clinical 3 Tesla platform, including adiabatic longitudinal, T1ρ, and transverse, T2ρ, relaxation methods, and Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank 4 (RAFF4), in 10 relapsing-remitting multiple sclerosis patients and 10 sex- and age-matched healthy controls. T1ρ, T2ρ and RAFF4 relaxograms extracted from the whole white matter exhibited a significant shift towards longer relaxation time constants in MS patients as compared to controls. T1ρ and RAFF4 detected alterations even when considering only regions of normally appearing white matter (NAWM), while other MRI metrics such as T1w/T2w ratio and diffusion tensor imaging measures failed to find group differences. In addition, RAFF4, T2ρ and, to a lesser extent, T1ρ showed differences in subcortical grey matter structures, mainly hippocampus, whereas no functional changes in this region were detected in resting-state functional MRI metrics. We conclude that rotating frame MRI techniques are exceptionally sensitive methods for the detection of subtle abnormalities not only in NAWM, but also in deep grey matter in MS, where they surpass even highly sensitive measures of functional changes, which are often suggested to precede detectable structural alterations. Such abnormalities are consistent with a wide spectrum of different, but interconnected pathological features of MS, including the loss of neuronal cells and their axons, decreased levels of myelin even in NAWM, and altered iron content., Competing Interests: Declaration of Competing Interest There are no potential conflicts of interests regarding this paper and no financial or personal relationships that might bias this work., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The introduction of intracranial air (ICA) during deep brain stimulation (DBS) surgery is thought to have a negative influence on targeting and clinical outcomes., Objective: To investigate ICA volumes following surgery and other patient-specific factors as potential variables influencing translocation of the DBS electrode and proximal lead bowing., Methods: High-resolution postoperative computed tomography scans (≤1.0 mm resolution in all directions) within 24 h following DBS surgery and 4-6 weeks of follow-up were acquired. A total of 50 DBS leads in 33 patients were available for analysis. DBS leads included Abbott/St. Jude Medical InfinityTM, Boston Scientific VerciseTM, and Medtronic 3389TM., Results: Both ICA volume and anatomical target were significantly associated with measures of DBS electrode translocation. ICA volume and DBS lead model were found to be significant predictors of proximal lead bowing. Measures of proximal lead bowing and translocation along the electrode trajectory for the Medtronic 3389TM DBS lead were significantly larger than measures for the Abbott/St. Jude Medical InfinityTM and Boston Scientific VerciseTM DBS leads., Conclusion: The association between ICA volume and translocation of the DBS electrode is small in magnitude and not clinically relevant for DBS cases within a normal range of postoperative subdural air volumes. Differences in proximal lead bowing observed between DBS leads may reflect hardware engineering subtleties in the construction of DBS lead models., (© 2020 S. Karger AG, Basel.)

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method commonly used in the disciplines of neuroscience, neurology, and neuropsychiatry to examine or modulate brain function. Low frequency rTMS (e.g., 1 Hz) is associated with a net suppression of cortical excitability, whereas higher frequencies (e.g., 5 Hz) purportedly increase excitability. Magnetic resonance spectroscopy (MRS) and resting-state functional MRI (rsfMRI) allow investigation of neurochemistry and functional connectivity, respectively, and can assess the influence of rTMS in these domains. This pilot study investigated the effects of rTMS on the primary motor cortex using pre and post MRS and rsfMRI assessments at 7 T. Seven right-handed males (age 27 ± 7 y.o.) underwent single-voxel MRS and rsfMRI before and about 30-min after rTMS was administered outside the scanner for 20-min over the primary motor cortex of the left (dominant) hemisphere. All participants received 1-Hz rTMS; one participant additionally received 5-Hz rTMS in a separate session. Concentrations of 17 neurochemicals were quantified in left and right motor cortices. Connectivity metrics included fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) of both motor cortices, strength of related brain networks, and inter-hemispheric connectivity. The group-analysis revealed few trends (i.e., uncorrected for multiple comparisons), including a mean increase in the concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) after the inhibitory rTMS protocol as compared to baseline in the stimulated (left) motor cortex (+8%, p = 0.043), along with a slight increase of total creatine (+2%, p = 0.018), and decrease of aspartate (-18%, p = 0.016). Additionally, GABA tended to decrease in the contralateral hemisphere (-6%, p = 0.033). No other changes of metabolite concentrations were found. Whereas functional connectivity outcomes did not exhibit trends of significant changes induced by rTMS, the percent changes of few connectivity metrics in both hemispheres were negatively correlated with GABA changes in the contralateral hemisphere. While studies in larger cohorts are needed to confirm these preliminary findings, our results indicate the safety and feasibility of detecting changes in key metabolites associated with neurotransmission after a single 1-Hz rTMS session, establishing the construct for future exploration of the neurochemical, and connectivity mechanisms of cortical responses to neuromodulation., (Copyright © 2019 Gröhn, Gillick, Tkáč, Bednařík, Mascali, Deelchand, Michaeli, Meekins, Leffler-McCabe, MacKinnon, Eberly and Mangia.)

Background and Aims: In some clinical studies men and women have been found to differ in their ability to quit smoking, perhaps as a result of progesterone. The primary aim of this study was to provide a preliminary test of whether progesterone (PRO), compared with placebo (PBO), was more effective for smoking cessation in men and women., Design: Pilot double-blind, placebo-controlled randomized clinical trial., Setting: Minneapolis/St Paul metro area, Minnesota, USA., Participants: A total of 216 participants were randomized, including 113 men (18-60 years; PRO = 56, PBO = 57) and 103 women (18-50 years, pre-menopausal with self-reported regular menstrual cycles; PRO = 51, PBO = 52)., Intervention: Participants were randomized (1 : 1 within sex group) to either PRO (200 mg twice daily) or PBO. Participants were assigned a quit date approximately 7 days after starting medication (luteal phase for women) and were followed for 12 weeks to assess relapse., Measurements: The primary outcome was self-reported 7-day point prevalence abstinence (PPA) at week 4. Secondary outcomes included 7-day PPA at weeks 8 and 12, prolonged abstinence, continuous abstinence, urine cotinine < 50 ng/ml, expired carbon monoxide ≤ 5 parts per million (p.p.m.) and days to relapse., Findings: There was a significant difference in 7-day PPA at week 4 among women [PRO: 18 (35.3%) versus PBO: 9 (17.3%), odds ratio (OR) = 2.61, 95% confidence interval (CI) = 1.04, 6.54, P = 0.041], but not among men [PRO: 13 (23.2%) versus PBO: 12 (21.1%), 1.13 (0.47, 2.76), P = 0.782]. There was some evidence that PRO delayed relapse in women (days to relapse; PRO: 20.5 ± 29.6 versus PBO: 14.3 ± 26.8, P = 0.03) but not in men (PRO: 13.4 ± 25.9 versus PBO: 13.3 ± 23.8, P = 0.69)., Conclusions: Oral micronized progesterone may aid smoking cessation in women., (© 2019 Society for the Study of Addiction.)

Background: Spinocerebellar ataxia type 1 (SCA1) causes progressive degeneration of the cerebellum and brainstem. Volumetric magnetic resonance imaging (MRI) was shown to be more sensitive to disease progression than the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia (SARA), in longitudinal studies, and magnetic resonance spectroscopy (MRS) was shown to detect neurochemical abnormalities with high sensitivity cross-sectionally in SCA1., Objectives: The objectives of this study were to compare the sensitivities to change of volumetric MRI, MRS, and SARA in a 3-year longitudinal study in SCA1., Methods: A total of 16 early-to-moderate stage patients with SCA1 (SARA 0-14) and 21 matched healthy participants were scanned up to 3 times with 1.5-year intervals. Ataxia severity was assessed with SARA. T 1 -weighted images and magnetic resonance spectra from the cerebellar vermis, cerebellar white matter, and pons were acquired at 3T., Results: The pontine total N -acetylaspartate-to- myo -inositol ratio was the most sensitive MRS measure to change (-3.9 ± 4.6%/yr in SCA1 vs. -0.3 ± 3.5%/yr in controls; P  < 0.02), and the pontine volume was the most sensitive MRI measure to change (-2.6 ± 1.2%/yr in SCA1 vs. -0.1 ± 1.2 in controls; P  < 0.02). Effect size (mean percent change/standard deviation of percent change) of pontine volume was highest (-2.13) followed by pontine N -acetylaspartate-to- myo -inositol ratio (-0.84) and SARA (+0.60). The pontine N -acetylaspartate-to- myo -inositol ratio was abnormal for 1 premanifest patient at all visits and predicted study withdrawal as a result of disease progression in 3 patients., Conclusion: Both MRI and MRS were more sensitive to disease progression than SARA in SCA1. Pontine volume was most sensitive to change, whereas MRS may have more sensitivity at the premanifest stage and predictive value for disease progression.

Mild traumatic brain injury (mTBI) is a significant cause of disability, especially when symptoms become chronic. This chronicity is often linked to oculomotor dysfunction (OMD). To our knowledge, this is the first prospective study to localize aberrations in brain function between mTBI cohorts, by comparing patients with mTBI with OMD with an mTBI control group without OMD, using task and resting-state functional magnetic resonance imaging (fMRI). Ten subjects with mTBI who had OMD (OMD group) were compared with nine subjects with mTBI who had no findings of OMD (control group). These groups were determined by a developmental optometrist using objective testing for OMD. The (convergence) task fMRI data demonstrated significantly decreased brain activity, measured as decreases in the blood oxygen level dependent (BOLD) signal, in the OMD group compared with the control group in three brain regions: the left posterior lingual gyrus, the bilateral anterior lingual gyrus and cuneus, and the parahippocampal gyrus. When doing a seed-based resting state fMRI analysis in the lingual/parahippocampal region, a large cluster covering the left middle frontal gyrus and the dorsolateral pre-frontal cortex (Brodmann areas 9 and 10), with decreased functional correlation in the OMD group, was identified. Together these observations provide evidence for neural networks of interactions involving the control of eye movement for visual processing, reading comprehension, spatial localization and navigation, and spatial working memory that appear to be decreased in mTBI patients with OMD compared with mTBI patients without OMD. The clinical symptomatology associated with post-traumatic OMD correlates well with these MRI findings.

Objective: To determine whether proton magnetic resonance spectroscopy ( 1 H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline., Methods: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1 H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1 H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression., Results: Motor cortex total N -acetylaspartate to myo -inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups., Conclusion: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1 H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R., Competing Interests: Competing interests: IC, DKD, LEE, MM, GM and GG report no disclosures. DW consults for Acceleron Pharma and receives research support from the ALS Association, Acceleron Pharma, Pharnext and FLEX Pharma. GO received research support from Takeda Pharmaceuticals and NeuroVia., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies that focused on treating major depressive disorder with conventional deep brain stimulation (DBS) paradigms produced inconsistent results. In this proof-of-concept preclinical study in rats ( n = 8), we used novel paradigms of orientation selective DBS for stimulating the complex circuitry crossing the infralimbic cortex, an area considered analogous to human subgenual cingulate cortex. Using functional MRI at 9.4 T, we monitored whole brain responses to varying the electrical field orientation of DBS within the infralimbic cortex. Substantial alterations of functional MRI responses in the amygdala, a major node connected to the infralimbic cortex implicated in the pathophysiology of depression, were observed. As expected, the activation cluster near the electrode was insensitive to the changes of the stimulation orientation. Hence, our findings substantiate the ability of orientation selective stimulation (OSS) to recruit neuronal pathways of distinct orientations relative to the position of the electrode, even in complex circuits such as those involved in major depressive disorder. We conclude that OSS is a promising approach for stimulating brain areas that inherently require individualisation of the treatment approach.

Introduction: Despite extensive efforts to develop effective smoking cessation interventions, 70-85% of American cigarette smokers who quit relapse within one year. Exercise has shown promise as an intervention; however, many results have been equivocal. This study explored how exercise is associated with smoking-related symptomatology, smoking behavior and impulsivity in male and female smokers., Methods: Participants were recruited throughout the United States using the on-line crowdsourcing platform, Amazon's Mechanical Turk. They completed a survey with self-report measures assessing exercise, smoking-related symptomatology, smoking behavior and impulsivity. Differences between men and women were tested using t- and chi-square tests. Regression analyses tested for associations between exercise and smoking-related symptomatology, smoking behavior and impulsivity., Results: Participants (N = 604) were, on average, 32 (SD = 6.2) years old, mostly Caucasian, with at least some college education and approximately half were women. Women exercised slightly less than men and had more negative affect, craving, physical symptoms and withdrawal. Women smoked more cigarettes per day, had greater nicotine dependency and more years of smoking. Positive affect was positively associated with exercise for both men and women; however, this association was significantly stronger in women. Negative affect and withdrawal were inversely associated with exercise for women only. Impulsivity was inversely associated with exercise for both men and women., Conclusion: Exercise was significantly associated with several smoking-related symptomatology, smoking behavior and impulsivity variables for both men and women, suggesting that exercise may be a useful intervention for smoking cessation. Future prospective research should determine how exercise directly impacts smoking cessation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose/background: Topiramate (TPM) and lorazepam (LZP) are two examples of frequently prescribed medications that are associated with a high incidence of cognitive impairment; however, the factors that underlie interindividual differences in side effect profiles have not been fully characterized. Our objective was to determine whether working memory capacity (WMC), the amount of information that can be stored and manipulated in memory over short time intervals, is one such factor., Methods/procedures: Twenty-nine healthy volunteers completed a double-blind, randomized, placebo-controlled crossover study during which they received placebo (PBO), TPM, and LZP in random order. Four hours after drug administration, a blood draw was taken to establish drug concentrations, and subjects performed a verbal working memory task while the accuracy and reaction time of their responses were recorded. Working memory capacity was calculated based on accuracy rates during the PBO session, and the role of WMC in moderating the severity of drug-related cognitive impairment was assessed by examining drug-related performance changes from PBO as a function of WMC., Findings/results: Both TPM and LZP had a negative impact on task performance, although only TPM-related deficits were modulated by WMC; high WMC was associated with more severe impairments and heightened sensitivity to increasing TPM concentrations., Implications/conclusions: We have identified a potential clinical risk factor, high WMC, which is associated with drug-related adverse cognitive events. These data provide objective evidence in support of clinical observations that high-functioning patients are more likely to experience severe cognitive impairments.

Introduction: Our objective was to examine the association between perseverations produced on the semantic verbal fluency (SVF) task in asymptomatic individuals and the future diagnosis of cognitive impairment (CI)., Method: Participants were individuals participating in the Mayo Clinic Study of Aging (N = 1269, M age  = 79.3 years, SD = 5.1; 51% men). All were cognitively normal at baseline and were followed in 15-month intervals for up to 6 visits. Each neurocognitive assessment included SVF tasks ("animals," "fruits," and "vegetables"). Cox modeling was used to test for associations between perseverations and time to CI diagnosis., Results: Perseverations on the "animals" SVF task were associated with incident CI (hazard ratio = 1.35; 95% confidence interval, CI [1.10, 1.66]). No significant association was found with perseverations on the "fruits" or "vegetables" SVF tasks. Mixed-effects modeling in cognitively normal participants revealed that the number of perseverations at baseline is significantly associated with decline in memory and visuospatial cognitive domains but is not associated with decline in attention., Conclusions: Assessing perseverations together with standard SVF scores on the "animals" SVF task can help in early identification of asymptomatic individuals at an increased risk for CI. Perseverations are not associated with attention, but rather visual and verbal working memory mechanisms. In longitudinal settings aimed at early detection of signs of CI in presymptomatic individuals, SVF testing with scoring that includes counting of perseverations may potentially serve as a practical alternative to the more cumbersome memory tests.