Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

Headache Diary Mobile Application for Monitoring and Characterizing Posttraumatic Headaches.

OBJECTIVE: This study analyzed the data collected using a headache diary mobile application to characterize posttraumatic headaches (PTHs) in a sample of US veterans. Specifically, we measured patient engagement with the mobile application and compared our findings with previous literature regarding PTHs. SETTING: A Headache Center of Excellence (HCoE) in a Veterans Health Administration facility. PARTICIPANTS: Forty-nine veterans currently being treated for ongoing PTH-related complaints with English fluency, reliable access to the internet, and a mobile phone. DESIGN: Observational study of PTH characteristics using the mobile application over the course of 1 year. MEASURES: Main outcome measures were collected via a headache diary mobile application developed for patients to track headache-associated symptoms, headache location, triggers, type, intensity, and duration. Patients also completed a baseline Headache Impact Test (HIT-6) survey. RESULTS: In total, 1569 entries were completed during the first year of application deployment. On average, patients completed 2.5 entries per week and used the application for 70 days. They frequently reported associated PTH symptoms of photophobia (56.7%) and headaches triggered by emotional stress (35.1%). Network analyses revealed patterns of co-occurrence in triggers of headache pain, associated symptoms, and headache pain location. Headache pain severity and impact ratings from the headache diary demonstrated convergent validity with the established HIT-6 measure. CONCLUSIONS: Headache diary mobile applications are a promising tool for monitoring and characterizing PTHs in veterans. Present results mirror past studies of PTH characteristics. Mobile application headache diaries may be used in both clinical and research settings to monitor headache symptoms and communicate the functional impact of headaches in real time.

Sex differences in cortical thickness and diffusion properties in patients with traumatic brain injury: a pilot study.

OBJECTIVE: Cortical thickness and diffusion properties are important measures of gray and white matter integrity in those with traumatic brain injury (TBI). Many studies show that healthy adult females have greater cortical thickness than males across numerous brain sites. In this study, we explored this sex difference in patients with TBI. METHOD: Participants consisted of 32 patients with TBI and 21 neurologically healthy controls. All were scanned by magnetic resonance imaging (MRI). Differences in cortical thickness and diffusion properties were examined between groups (i.e., TBI/control, male/female). RESULTS: Patients with TBI had more cortical thinning (both hemispheres) compared to controls. They also showed decreased fractional anisotropy (FA) for several major white matter tracts. Healthy females had significantly greater cortical thickness compared to healthy males. However, this difference was smaller among the patients with TBI. We found no sex differences in diffusion properties. There were moderate correlations between cortical thickness, diffusion properties, and cognitive performance, as measured by the Trail Making Test B. CONCLUSION: These findings contribute to a growing discussion on sex differences in cortical thickness and diffusion properties. Sexual dimorphism could necessitate different clinical profiles, targets, and rehabilitation strategies in patients with TBI.

Use of Repetitive Transcranial Magnetic Stimulation in the Treatment of Neuropsychiatric and Neurocognitive Symptoms Associated With Concussion in Military Populations.

BACKGROUND: Since the year 2000, over 342 000 military service members have experienced a concussion, often associated with chronic neuropsychiatric and neurocognitive symptoms. Repetitive transcranial magnetic stimulation (rTMS) protocols have been developed for many of these symptoms in the general population. OBJECTIVE: To conduct a scoping review of the literature on rTMS for neuropsychological and neurocognitive symptoms following concussion. METHODS: PubMed and Google Scholar search engines identified 9 articles, written in English, corresponding to the search terms TBI or concussion; and TMS or rTMS; and depression, PTSD, or cognition. Studies that were not therapeutic trials or case reports, did not have neuropsychiatric or neurocognitive primary outcome measures, or described samples where 80% or more of the cohort did not have a TBI were excluded. RESULTS: There were no reports of seizures nor difference in the frequency or quality of other adverse events as compared with the broader rTMS literature, supporting the safety of rTMS in this population. Support for the efficacy of rTMS for the treatment of neuropsychiatric and neurocognitive symptoms, in this population, is limited. CONCLUSIONS: Large-scale, innovative, neuroscience-informed protocols are recommended to elucidate the potential utility of rTMS for the complex neuropsychiatric and neurocognitive symptoms associated with military concussions.

Sex differences in symptom presentation and functional outcomes: a pilot study in a matched sample of veterans with mild TBI.

Primary Objective: Research focused on mild traumatic brain injury in active military and veteran populations details the psychological, neurological and functional outcomes of mTBI, in a primarily male (~95%) cohort. This may misrepresent female symptoms and outcomes. Here we assess for genuine sex differences in symptom presentation and functional outcomes.Research Design: We used matched pairs to preclude potential sex bias in outcome data.Methods and Procedures: We matched 49 female/male pairs on; 1) mechanism of injury, 2) time from injury to assessment and 3) age at assessment. Statistics were t-tests, chi-square, correlations and post hoc linear regression.Main outcomes and results: Outcome assessment revealed four significant (p < .05) sex differences; Living situation, Marital status, Vocation and Branch of service. Only the Neurobehavioral Symptom Inventory (NSI) composite cognitive domain factor was significantly different between females (mean: 10.26) and males (mean: 7.58). Linear regression confirmed a significant effect of sex for the cognitive composite (p = .002).Conclusion: We conclude that sex has a moderate effect on mTBI post-concussive symptom presentation. The significant sex difference in the NSI cognitive domain characterizes sex-related symptomology profiles providers can focus on for better rehabilitation management. Replication in the larger cohort would improve generalizability.Abbreviation: TBI: Traumatic Brain Injuries; mTBI: mild Traumatic Brain Injuries; OIF: Operation Iraqi Freedom; OEF: Operation Enduring Freedom; VA: Veterans Affairs Health Care System; PSC: Polytrauma System of Care; PRC: Polytrauma Rehabilitation Center; PTRP: Polytrauma Transitional Rehabilitation Program; PNS: Polytrauma Network Site; PTSD: Post Traumatic Stress Disorder; DoD: Department of Defense; NSI: Neurobehavioral Symptom Inventory; LOC: loss of consciousness; AOC: alteration of consciousness; PTA: posttraumatic amnesia; CPRS: computerized patient record system; CTBIE: Comprehensive TBI Evaluation; OCD: obsessive compulsive disorder; ETOH: alcohol abuse.

The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial.

BACKGROUND: Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions. METHODS/DESIGN: In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action. DISCUSSION: The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field. TRIAL REGISTRATION: Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. PROTOCOL VERSION: This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

Traumatic brain injury among female veterans: a review of sex differences in military neurosurgery.

The impact of traumatic brain injury (TBI) has been demonstrated in various studies with respect to prevalence, morbidity, and mortality data. Many of the patients burdened with long-term sequelae of TBI are veterans. Although fewer in number, female veterans with TBI have been suggested to suffer from unique physical, mental, and social challenges. However, there remains a significant knowledge gap in the sex differences in TBI. Increased female representation in the military heralds an increased risk of TBI for female soldiers, and medical professionals must be prepared to address the unique health challenges in the face of changing demographics among the veteran TBI population. In this review, the authors aimed to present the current understanding of sex differences in TBI in the veteran population and suggest directions for future investigations.

Disentangling cognition and emotion in older adults: the role of cognitive control and mental health in emotional conflict adaptation.

OBJECTIVE: Recent research suggests cognition has a bidirectional relationship with emotional processing in older adults, yet the relationship is still poorly understood. We aimed to examine a potential relationship between late-life cognitive function, mental health symptoms, and emotional conflict adaptation. We hypothesized that worse cognitive control abilities would be associated with poorer emotional conflict adaptation. We further hypothesized that a higher severity of mental health symptoms would be associated with poorer emotional conflict adaptation. METHODS: Participants included 83 cognitively normal community-dwelling older adults who completed a targeted mental health and cognitive battery, and emotion and gender conflict-adaptation tasks. RESULTS: Consistent with our hypothesis, poorer performance on components of cognitive control, specifically attention and working memory, was associated with poorer emotional conflict adaptation. This association with attention and working memory was not observed in the non-affective-based gender conflict adaptation task. Mental health symptoms did not predict emotional conflict adaptation, nor did performance on other cognitive measures. CONCLUSION: Our findings suggest that emotion conflict adaptation is disrupted in older individuals who have poorer attention and working memory. Components of cognitive control may therefore be an important potential source of inter-individual differences in late-life emotion regulation and cognitive affective deficits. Copyright © 2016 John Wiley & Sons, Ltd.

Service needs and barriers to care five or more years after moderate to severe TBI among Veterans.

PRIMARY OBJECTIVE: The objective of this paper is to identify the most frequent service needs, factors associated with needs, and barriers to care among Veterans and service members five or more years after moderate to severe traumatic brain injury (TBI). RESEARCH DESIGN: Survey administered via telephone 5-16 years after injury (median eight years) and subsequent acute inpatient rehabilitation at a regional Veterans Affairs (VA) medical centre. METHODS AND PROCEDURES: Participants were 119 Veterans and military personnel, aged 23-70 (median 35), 90% male. Demographics, injury characteristics, service needs, whether needs were addressed, barriers to care, health and general functioning were assessed. MAIN OUTCOMES AND RESULTS: The most frequent needs were for help with memory, information about available services and managing stress. Obtaining information about services was the most consistently un-addressed need; managing stress was the most consistently addressed need. Cognitive and psychiatric symptoms and alienation from community were associated with needs going un-addressed. Participants treated after an expansion of TBI services at the study site reported fewer un-addressed needs. Not knowing where to get help was the most common barrier to care. CONCLUSION: Repeated outreach, assessment of needs and education about available services are needed throughout Veterans' lifespan after moderate to severe TBI.

Characteristics of the Structural Connectivity in Patients with Brain Injury and Chronic Health Symptoms: A Pilot Study.

Diffusion properties from diffusion tensor imaging (DTI) are exquisitely sensitive to white matter abnormalities incurred during traumatic brain injury (TBI), especially for those patients with chronic post-TBI symptoms such as headaches, dizziness, fatigue, etc. The evaluation of structural and functional connectivity using DTI has become a promising method for identifying subtle alterations in brain connectivity associated with TBI that are otherwise not visible with conventional imaging. This study assessed whether TBI patients with (n = 17) or without (n = 16) chronic symptoms (TBIcs/TBIncs) exhibit any changes in structural connectivity (SC) and mean fractional anisotropy (mFA) of intra- and inter-hemispheric connections when compared to a control group (CG) (n = 13). Reductions in SC and mFA were observed for TBIcs compared to CG, but not for TBIncs. More connections were found to have mFA reductions than SC reductions. On the whole, SC is dominated by ipsilateral connections for all the groups after the comparison of contralateral and ipsilateral connections. More contra-ipsi reductions of mFA were found for TBIcs than TBIncs compared to CG. These findings suggest that TBI patients with chronic symptoms not only demonstrate decreased global and regional mFA but also reduced structural network connectivity.

The absence of formal work experience may affect the rate of cognitive decline in older adult women: findings from the health and retirement study.

Objective: This study investigated the relationship between years of employment and cognitive health among older non-Latinx Black, Latinx, and non-Latinx White women. We hypothesized that women who had never been formally employed (i.e., zero years of formal work experience) would exhibit a pronounced cognitive decline. Methods: Our study included 5,664 older adult women from the Health and Retirement Study (2010-2016) aged 65-101 (M = 75.41). Out of 5,664 participants, 850 identified as non-Latinx Black, 475 identified as Latinx, and 4,339 identified as non-Latinx White. Furthermore, 5,292 women indicated having a professional employment history of at least one year, whereas 372 women reported no formal work experience. The Telephone Interview for Cognitive Status-27 (TICS-27) was used to assess cognitive performance. Linear mixed effects models were conducted to assess whether employment history was associated with the rate of cognitive decline. Results: In all three racial and ethnic groups, lower age, higher education, greater number of years worked, fewer chronic conditions, and greater household income were associated with better cognitive performance at baseline (p < .05). Additionally, women who had not worked in any formal capacity had a lower baseline cognitive performance (p < .001) and a more extreme decline in cognitive performance over time (p = .04). Conclusion: In conclusion, we found that women without any formal work experience performed lower at baseline and experienced a steeper cognitive decline over time. These findings underscore the need to further explore the complex interrelationships between employment duration and cognitive trajectories, especially among older women and those from different racial and ethnic backgrounds.

Military environmental exposures and risk of breast cancer in active-duty personnel and veterans: a scoping review.

Background: The effects of military environmental exposures (MEE) such as volatile organic compounds (VOCs), endocrine-disrupting chemicals (EDCs), tactile herbicides, airborne hazards and open burn pits (AHOBP), and depleted uranium on health are salient concerns for service members and Veterans. However, little work has been done to investigate the relationship between MEE and risk of breast cancer. Data sources and methods: We conducted a scoping review on MEE, military deployment/service, and risk of breast cancer among active-duty service members and Veterans. PRISMA was used. PubMed, Embase, and citations of included articles were searched, resulting in 4,364 articles to screen: 28 articles were included. Results: Most papers on military deployment and military service found a lower/equivalent risk of breast cancer when comparing rates to those without deployment or civilians. Exposure to VOCs due to military occupation or contaminated groundwater was associated with a slightly higher risk of breast cancer. Exposure to Agent Orange was not associated with an increased risk of breast cancer. Evidence regarding EDCs was limited. No paper directly measured exposure to AHOBP or depleted uranium, but deployments with known exposures to AHOBP or depleted uranium were associated with an equivalent/lower risk of breast cancer. Conclusions: Women are the fastest growing population within the military, and breast cancer poses a unique risk to women Veterans who were affected by MEE during their service. Unfortunately, the literature on MEE and breast cancer is mixed and limited, in part due to the Healthy Soldier Paradox and poor classification of exposure(s).

ENIGMA's simple seven: Recommendations to enhance the reproducibility of resting-state fMRI in traumatic brain injury.

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field.

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Fixel-based analysis of the diffusion properties of the patients with brain injury and chronic health symptoms.

The diffusion properties from diffusion tensor imaging (DTI) are sensitive to white matter (WM) abnormalities and could serve as indicators of diffuse axonal damages incurred during a traumatic brain injury (TBI). Analyses of diffusion metrics in the regions of interest (ROIs) were used to compare the differences in the 18 major fiber tracts in 46 participants, between TBI participants with (n = 17) or without (n = 16) chronic symptoms (CS) and a control group (CG, n = 13). In addition to the widely used diffusion metrics, such as fractional anisotropy (FA), mean (MD), axial (AD) and radial (RD) diffusivities, apparent fiber density (AFD), complexity (CX) and fixel number (FN) derived from Mrtrix3 software package were used to characterize WM tracts and compare between participant groups in the ROIs defined by the fixel numbers. Significant differences were found in FA, AFD, MD, RD and CX in ROIs with different FNs in the corpus callosum forceps minor, left and right inferior longitudinal fasciculus, and left and right uncinate fasciculus for both TBI groups compared to controls. Diffusion properties in ROIs with different FNs can serve as detailed biomarkers of WM abnormalities, especially for individuals with chronic TBI related symptoms.

The Emerging Role of Virtual Reality as an Adjunct to Procedural Sedation and Anesthesia: A Narrative Review.

Over the past 20 years, there has been a significant reduction in the incidence of adverse events associated with sedation outside of the operating room. Non-pharmacologic techniques are increasingly being used as peri-operative adjuncts to facilitate and promote anxiolysis, analgesia and sedation, and to reduce adverse events. This narrative review will briefly explore the emerging role of immersive reality in the peri-procedural care of surgical patients. Immersive virtual reality (VR) is intended to distract patients with the illusion of "being present" inside the computer-generated world, drawing attention away from their anxiety, pain, and discomfort. VR has been described for a variety of procedures that include colonoscopies, venipuncture, dental procedures, and burn wound care. As VR technology develops and the production costs decrease, the role and application of VR in clinical practice will expand. It is important for medical professionals to understand that VR is now available for prime-time use and to be aware of the growing body in the literature that supports VR.

Pilot expertise and hippocampal size: associations with longitudinal flight simulator performance.

BACKGROUND: Previous research suggests that the size of the hippocampus can vary in response to intensive training (e.g., during the acquisition of expert knowledge). However, the role of the hippocampus in maintenance of skilled performance is not well understood. The Stanford/Veterans Affairs Aviation MRI Study offers a unique opportunity to observe the interaction of brain structure and multiple levels of expertise on longitudinal flight simulator performance. METHODS: The current study examined the relationship between hippocampal volume and three levels of aviation expertise, defined by pilot proficiency ratings issued by the U.S. Federal Aviation Administration (11). At 3 annual time points, 60 pilots who varied in their level of aviation expertise (ages ranging from 45 to 69 yr) were tested. RESULTS: At baseline, higher expertise was associated with better flight simulator performance, but not with hippocampal volume. Longitudinally, there was an Expertise x Hippocampal volume interaction, in the direction that a larger hippocampus was associated with better performance at higher levels of expertise. DISCUSSION: These results are consistent with the notion that expertise in a cognitively demanding domain involves the interplay of acquired knowledge ('mental schemas') and basic hippocampal-dependent processes.

Transdiagnostic role of glutamate and white matter damage in neuropsychiatric disorders: A Systematic Review.

Neuropsychiatric disorders including generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have been considered distinct categories of diseases despite their overlapping characteristics and symptomatology. We aimed to provide an in-depth review elucidating the role of glutamate/Glx and white matter (WM) abnormalities in these disorders from a transdiagnostic perspective. The PubMed online database was searched for studies published between 2010 and 2021. After careful screening, 401 studies were included. The findings point to decreased levels of glutamate in the Anterior Cingulate Cortex in both SZ and BD, whereas Glx is elevated in the Hippocampus in SZ and MDD. With regard to WM abnormalities, the Corpus Callosum and superior Longitudinal Fascicle were the most consistently identified brain regions showing decreased fractional anisotropy (FA) across all the reviewed disorders, except GAD. Additionally, the Uncinate Fasciculus displayed decreased FA in all disorders, except OCD. Decreased FA was also found in the inferior Longitudinal Fasciculus, inferior Fronto-Occipital Fasciculus, Thalamic Radiation, and Corona Radiata in SZ, BD, and MDD. Decreased FA in the Fornix and Corticospinal Tract were found in BD and SZ patients. The Cingulum and Anterior Limb of Internal Capsule exhibited decreased FA in MDD and SZ patients. The results suggest a gradual increase in severity from GAD to SZ defined by the number of brain regions with WM abnormality which may be partially caused by abnormal glutamate levels. WM damage could thus be considered a potential marker of some of the main neuropsychiatric disorders.

Electrophysiological and behavioral effects of unilateral and bilateral rTMS; A randomized clinical trial on rumination and depression.

BACKGROUND: Rumination is significantly frequent in major depressive disorder (MDD). However, not a lot of studies have investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on rumination. METHODS: 61 participants with a minimum Hamilton Depression Rating Scale (HAM-D) score of 20 were randomly assigned to sham, bilateral stimulation (BS) or unilateral stimulation (US) groups. EEG, The Ruminative Response Scale (RRS), and HAM-D were administered before and after the 20 sessions of rTMS. Phase locked values (PLV) were calculated as a measure of connectivity. RESULTS: There was a significant decrease in HAM-D scores in both BS and US. In responders, BS and US differed significantly in RRS total scores, with greater reduction in BS. PLV significantly changed in the default mode network (DMN) in delta, theta, alpha, and beta in BS, in responders of which PLV decreased in the DMN in beta and gamma. Positive correlations between PLV and brooding in delta and theta, and negative correlations between PLV and reflection were found in theta, alpha, and beta. In US, connectivity in the DMN increased in beta, and PLV increased in theta and beta, and decreased in alpha and beta in its responders. Positive correlations between PLV and brooding in the delta and theta, as well as negative correlations between PLV and reflection in theta were observed in the DMN. CONCLUSION: US and BS resulted in different modulations in the DMN, however, both could alleviate both rumination and depression. Reductions in the beta and alpha frequency bands in the DMN can be considered as potential EEG-based markers of response to bilateral and unilateral rTMS, respectively.