Microstructural white matter abnormalities in Lesch-Nyhan disease.

Lesch-Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch-Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch-Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch-Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch-Nyhan disease (n = 5), Lesch-Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch-Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch-Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch-Nyhan disease.

Interventions for multidimensional aspects of breast cancer-related fatigue: a meta-analytic review.

PURPOSE: This meta-analysis sought to determine whether exercise, psychological, or alternative forms of interventions differentially improve cognitive, physical, and general dimensions of cancer-related fatigue (CRF) in women with a history of breast cancer. METHODS: Databases (PubMed, PsychINFO, EMBASE, and Cochrane Library) were systematically reviewed from inception through March 2019, with data extracted from randomized controlled trials of fatigue interventions using multidimensional CRF outcome measures. Two authors independently assessed methodological quality using the Cochrane Collaboration's risk of bias tool. Analyses were performed with Comprehensive Meta-Analysis (v.3). RESULTS: A total of 471 studies were assessed, of which 11 studies with 12 sets of data involving 1067 patients were included. Across intervention types, small to moderate improvements were observed for cognitive (g = - 0.38), physical (g = - 0.46), and general (g = - 0.45) CRF (p values < 0.01). Exercise produced moderate benefit for cognitive (g = - 0.44), physical (g = - 0.48), and general (g = - 0.49) CRF (p values < 0.01) whereas psychotherapy and disparate forms of alterative interventions were not effective (p values > 0.45). However, a large effect size was observed for a single trial of acupressure across all three CRF dimensions (p < 0.05). CONCLUSIONS: Exercise improved both cognitive and physical aspects of CRF. Further studies should determine the most effective forms, duration, intensity, and methods of supporting exercise in breast cancer patients. Further investigation of acupressure as an intervention for CRF should also be considered.

A prospective evaluation of whole brain volume loss and neurocognitive decline following hippocampal-sparing prophylactic cranial irradiation for limited-stage small-cell lung cancer.

INTRODUCTION: This study evaluated an association between whole brain volume loss and neurocognitive decline following prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC). METHODS: This was a secondary analysis of a prospective clinical trial that accrued patients at a single institution from 2013 to 2016. Patients with limited-stage SCLC treated with standard chemo-radiation received PCI 25 Gy/10 fractions, with mean hippocampal dose limited to < 8 Gy. Whole brain volumes were measured using MR imaging obtained before and at 6, 12, 18, and 24 months after PCI. Verbal memory was measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) before and at 6 and 12 months after PCI. Univariate and multivariate linear regression evaluated associations between changes in whole brain volume and verbal memory. RESULTS: Twenty-two patients enrolled. The median whole brain volume before PCI was 1301 mL. Subsequent reduction in whole brain volume was greatest at 18 months after PCI (median change - 23 mL, range - 142 to 20, p = 0.03). At 6 months after PCI, reduction in volume was independently associated with decline in verbal memory, measured by two components of the HVLT-R (Delayed Recall: 0.06/mL volume change, p = 0.046; Percent Retained: 0.66/mL volume change, p = 0.030), when controlling for education and global cognitive function at baseline. CONCLUSION: This is the first study to correlate reduction in whole brain volume and decline in neurocognitive function following whole brain radiation therapy (WBRT). This suggests that loss of brain volume after WBRT may be clinically significant and subsequently impact cognition and quality of life.

The link between childhood adversity and late-life mental health: evidence for the influence of early-life experiences or illusory correlations?

Adverse childhood experiences (ACEs) reflect stressful or traumatic early life events such as abuse, neglect, and significant household challenges. These experiences are increasingly appreciated as factors that exert influence on physical and mental functioning throughout the lifespan. Numerous studies have demonstrated dose-response relationships between the number of ACEs reported and negative health outcomes in adulthood (Anda et al., 2006). At the same time, evidence points to the role of ACEs in the development of heightened biological reactivity to stress that may serve to increase vulnerability to the development of mental and substance use disorders (e.g., Heim et al., 2010). Furthermore, the existence of sex differences in both stress reactivity and the prevalence of various forms of psychopathology in adulthood (Doom et al., 2013) raises the question of whether men and women are differentially vulnerable to the health risks posed by ACEs. Much of the work concerning ACEs has focused on outcomes as they present in middle adulthood, which may not generalize to later life, as there may be cohort effects in the prevalence of (or likelihood of reporting) ACEs. Studies finding that the newly old report greater numbers of ACEs than their more senior counterparts imply that rates of ACEs are increasing over time and may be contributing to the development of mental and substance abuse disorders (MSUDs) in the growing population of aging adults, and make a case for better understanding these associations in later life.

Reproducibility of tDCS Results in a Randomized Trial: Failure to Replicate Findings of tDCS-Induced Enhancement of Verbal Fluency.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been shown to enhance verbal productivity, but the finding and extent of enhancement vary across studies. Few attempts to replicate positive tDCS findings have been reported, suggesting the possibility of publication bias. OBJECTIVE: We aimed to replicate the tDCS methodology and findings of Cattaneo, Pisoni, and Papagno (2011, Neuroscience 183:64-70) in a new population sample. We hypothesized that our study of anodal tDCS would improve verbal fluency production similarly to the original study. METHODS: In our single-blind, sham-controlled crossover experiment, 14 healthy young adults were randomly assigned to receive 2 mA of anodal and sham stimulation to the Broca area in counterbalanced order before completing verbal fluency tasks. RESULTS: Participants tolerated the stimulation well. Despite closely mirroring the original study methods, we saw no main effect of stimulation condition: F1,13=0.002, P=0.97, letter fluency sham mean (standard deviation)=16.8 (2.3), letter fluency anodal=17.5 (3.8), category fluency sham=25.3 (5.4), or category fluency anodal=24.7 (5.2), η≤0.01. CONCLUSIONS: While tDCS may enhance cerebral functions in general, the lack of consistency between studies suggests either that this tDCS protocol does not affect verbal fluency or, at minimum, that tDCS may be more sensitive to experimental conditions than has been thought. Our findings also highlight the need for replication studies in brain stimulation research. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier NCT01602263).

Hippocampal volume reduction correlates with apathy in traumatic brain injury, but not schizophrenia.

Apathy commonly accompanies both traumatic brain injury (TBI) and deficit syndrome schizophrenia (DSZ), despite unclear neurological bases. The authors examined differences in cortical thickness and subcortical/cerebellar regional volumes between adult TBI survivors, patients with DSZ, and healthy-control subjects by use of 3-D magnetic resonance imaging (MRI), and correlated imaging findings with clinical ratings of apathy and selected cognitive test scores. Imaging findings revealed specific areas of volume reduction in TBI survivors and areas of cortical thinning among patients with DSZ. The severity of apathy symptoms was similar across patient groups; however, severity of apathy was only correlated with imaging findings in TBI survivors.

Characterizing Symptoms and Identifying Biomarkers of Long COVID in People With and Without HIV: Protocol for a Remotely Conducted Prospective Observational Cohort Study.

BACKGROUND: Living with HIV is a risk factor for severe acute COVID-19, but it is unknown whether it is a risk factor for long COVID. OBJECTIVE: This study aims to characterize symptoms, sequelae, and cognition formally and prospectively 12 months following SARS-CoV-2 infection in people living with HIV compared with people without HIV. People with no history of SARS-CoV-2 infection, both with and without HIV, are enrolled as controls. The study also aims to identify blood-based biomarkers or patterns of immune dysregulation associated with long COVID. METHODS: This prospective observational cohort study enrolled participants into 1 of the following 4 study arms: people living with HIV who had SARS-CoV-2 infection for the first time <4 weeks before enrollment (HIV+COVID+ arm), people without HIV who had SARS-CoV-2 infection for the first time within 4 weeks of enrollment (HIV-COVID+ arm), people living with HIV who believed they never had SARS-CoV-2 infection (HIV+COVID- arm), and people without HIV who believed they never had SARS-CoV-2 infection (HIV-COVID- arm). At enrollment, participants in the COVID+ arms recalled their symptoms, mental health status, and quality of life in the month before having SARS-CoV-2 infection via a comprehensive survey administered by telephone or on the web. All participants completed the same comprehensive survey 1, 2, 4, 6, and 12 months after post-acute COVID-19 symptom onset or diagnosis, if asymptomatic, (COVID+ arms) or after enrollment (COVID- arms) on the web or by telephone. In total, 11 cognitive assessments were administered by telephone at 1 and 4 months after symptom onset (COVID+ arms) or after enrollment (COVID- arms). A mobile phlebotomist met the participants at a location of their choice for height and weight measurements, orthostatic vital signs, and a blood draw. Participants in the COVID+ arms donated blood 1 and 4 months after COVID-19, and participants in the COVID- arms donated blood once or none. Blood was then shipped overnight to the receiving study laboratory, processed, and stored. RESULTS: This project was funded in early 2021, and recruitment began in June 2021. Data analyses will be completed by summer 2023. As of February 2023, a total of 387 participants were enrolled in this study, with 345 participants having completed enrollment or baseline surveys together with at least one other completed study event. The 345 participants includes 76 (22%) HIV+COVID+, 121 (35.1%) HIV-COVID+, 78 (22.6%) HIV+COVID-, and 70 (20.3%) HIV-COVID- participants. CONCLUSIONS: This study will provide longitudinal data to characterize COVID-19 recovery over 12 months in people living with and without HIV. Additionally, this study will determine whether biomarkers or patterns of immune dsyregulation associate with decreased cognitive function or symptoms of long COVID. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47079.

Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas.

Background: Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. Methods: A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1-21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Results: Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Conclusions: Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

PASC in Solid Organ Transplant Recipients With Self-reported SARS-CoV-2 Infection.

BACKGROUND: Postacute sequelae of SARS-CoV-2 infection (PASC) is an increasingly recognized phenomenon and manifested by long-lasting cognitive, mental, and physical symptoms beyond the acute infection period. We aimed to estimate the frequency of PASC symptoms in solid organ transplant (SOT) recipients and compared their frequency between those with SARS-CoV-2 infection requiring hospitalization and those who did not require hospitalization. METHODS: A survey consisting of 7 standardized questionnaires was administered to 111 SOT recipients with history of SARS-CoV-2 infection diagnosed >4 wk before survey administration. RESULTS: Median (interquartile range) time from SARS-CoV-2 diagnosis was 167 d (138-221). Hospitalization for SARS-CoV-2 infection was reported in 33 (30%) participants. Symptoms after the COVID episode were perceived as following: significant trauma (53%), cognitive decline (50%), fatigue (41%), depression (36%), breathing problems (35%), anxiety (23%), dysgeusia (22%), dysosmia (21%), and pain (19%). Hospitalized patients had poorer median scores in cognition (Quick Dementia Rating System survey score: 2.0 versus 0.5, P = 0.02), quality of life (Health-related Quality of Life survey: 2.0 versus 1.0, P = 0.015), physical health (Global physical health scale: 10.0 versus 11.0, P = 0.005), respiratory status (Breathlessness, Cough and Sputum Scale: 1.0 versus 0.0, P = 0.035), and pain (Pain score: 3 versus 0 out of 10, P = 0.003). Among patients with infection >6 mo prior, some symptoms were still present as following: abnormal breathing (42%), cough (40%), dysosmia (29%), and dysgeusia (34%). CONCLUSIONS: SOT recipients reported a high frequency of PASC symptoms. Multidisciplinary approach is needed to care for these patients beyond the acute phase.

International study of the Complex Stress Reaction Syndrome: Implications for transdiagnostic clinical practice.

BACKGROUND: The debate regarding diagnostic classification systems in psychiatry (categorial vs dimensional systems) has essential implications for the diagnosis, prevention and treatment of stress reactions. We previously found a unique pattern of stress reaction in a study executed during the coronavirus disease 2019 pandemic using large representative samples in two countries, and termed it the Complex Stress Reaction Syndrome (CSRS). AIM: To investigate CSRS, Type A (psychiatric symptoms, spanning anxiety, depression, stress symptoms, and post-traumatic stress disorder (PTSD)), with or without long-coronavirus disease (COVID) residuals (CSRS, Type B, neuropsychiatric symptoms spanning cognitive deficits and fatigue, excluding systemic symptoms). Our two-tailed hypothesis was that CSRS is a condition related to an unrecognized type of stress reaction in daily life in the general population (Type A) or that it is related to the severe acute respiratory syndrome coronavirus 2 infection and its long-COVID residuals (Type B). METHODS: 977 individuals in four continents (North America, Europe, Australia and the Middle East) completed the online study questionnaire in six languages using the Qualtrics platform. The study was managed by six teams in six countries that promoted the study on social media. The questionnaire assessed anxiety, depression, stress symptoms and PTSD (CSRS, Type A), cognitive deficits and fatigue (CSRS, Type B). The data were analyzed using Proportion Analyses, Multivariate Analysis of Co-Variance (MANCOVA), linear regression analyses and validated clinical cutoff points. RESULTS: The results of the Proportion Analyses showed that the prevalence of 4 symptoms spanning anxiety, depression, stress symptoms, and PTSD was significantly higher than the most prevalent combinations of fewer symptoms across 4 continents, age groups, and gender. This supports the transdiagnostic argument embedded in the CSRS (Type A). The same pattern of results was found in infected/recovered individuals. The prevalence of the 4 psychiatric symptoms combination was significantly greater than that of 5 and 6 symptoms, when adding cognitive deficits and fatigue, respectively. MANCOVA showed a significant three-way interaction (age × gender × continent). Further analyses showed that the sources of this three-way interaction were threefold relating to two sub-populations at-risk: (1) Individuals that self-identified as non-binary gender scored significantly higher on all 4 psychiatric symptoms of the CSRS, Type A at young age groups (< 50 years old) in North America compared to (self-identified) women and men located in the 4 continents studied, and to other ages across the adult life span; and (2) This pattern of results (CSRS, Type A) was found also in women at young ages (< 40 years old) in North America who scored higher compared to men and women in other continents and other ages. Linear regression analyses confirmed the MANCOVA results. CONCLUSION: These results show a combined mental health risk factor related to stress reactivity, suggesting that the CSRS is sensitive to populations at risk and may be applied to future identification of other vulnerable sub-populations. It also supports the transdiagnostic approach for more accurate prevention and treatment. Time will tell if such transdiagnostic syndromes will be part of the discussions on the next revisions of the traditional classification systems or whether the crisis in psychiatry further evolves.

Hierarchical organization of cortical morphology of decision-making when deconstructing Iowa Gambling Task performance in healthy adults.

The Iowa Gambling Task (IGT) is a measure of decision-making, in which alternative metrics have greater construct validity than conventional metrics. No large scale study has examined the neural correlates in healthy adults. We administered the IGT and structural MRI to 124 healthy participants. We analyzed the conventional IGT metric of advantageous minus disadvantageous choices (i.e., decks C + D minus decks A + B), and three alternative metrics based on choices from decks D and A alone, and all selections from each deck. Using regression and voxel-based morphometry, we examined regional gray matter volumes as predictors of IGT performance. No neural correlates of the conventional metric emerged, and the neural correlates of individual deck selections were disparate from one another. Alternative metrics showed expected neural correlates of decision-making in prefrontal cortex, insula, thalamus, and other regions. IGT alternative metrics have neural correlates consistent with decision-making theory as those difference scores reduce heterogeneity in cognitive processes. The CD-AB metric construct failure may reflect an artificial amalgamation of processes. The D-A metric appears to more successfully combine multiple levels of representation (dorsolateral prefrontal cortex, sub-cortical, cerebellar).

Semantic clustering of category fluency in schizophrenia examined with singular value decomposition.

Decreased productivity on verbal fluency tasks by persons with schizophrenia has been attributed to semantic system abnormalities. Semantic structure is often assessed using multidimensional scaling (MDS) to detect normal and aberrant semantic clustering. However, MDS has limitations that may be particularly problematic for such assessments. Here, we introduce a different clustering technique, singular value decomposition (SVD), to elucidate abnormalities of the semantic system in schizophrenia. We compared 102 treated outpatients with schizophrenia to 109 healthy adults on two category-cued word fluency tasks. Patients with schizophrenia showed semantic clustering patterns that differ markedly from those of healthy adults. However, SVD revealed more detailed and critical semantic system abnormalities than previously appreciated using MDS. Patients with schizophrenia showed less coherent semantic clustering of both low- and high-frequency category exemplars than healthy adults. These results suggest the intriguing possibility that impaired automatic activation of semantic information is a key deficit in schizophrenia.

Crossword Puzzles for Brain Training in Mild Cognitive Impairment.

Given the increasing prevalence and public health impact of dementia, it is imperative that we identify prevention strategies. One approach, broadly termed brain training, can be defined as guided drill-and-practice mental exercises targeting cognitive domains. We have evidence suggesting that brain training may prevent dementia in cognitively intact adults, including the well-validated protective effect of education early in life and the results of the ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) trial,1 which showed not only a long-term cognitive benefit of training in processing speed, but also a possible decrease in dementia incidence and transfer of cognitive benefits to performance in everyday functioning (as measured by performance on instrumental activities of daily living).

Cognitive Dysfunction, Psychiatric Distress, and Functional Decline After COVID-19.

BACKGROUND: There is a limited understanding of the cognitive and psychiatric sequelae of COVID-19 during the post-acute phase, particularly among racially and ethnically diverse patients. OBJECTIVE: We sought to prospectively characterize cognition, mental health symptoms, and functioning approximately four months after an initial diagnosis of COVID-19 in a racially and ethnically diverse group of patients. METHODS: Approximately four months after COVID-19 diagnosis, patients in the Johns Hopkins Post-Acute COVID-19 Team Pulmonary Clinic underwent a clinical telephone-based assessment of cognition, depression, anxiety, trauma, and function. RESULTS: Most Johns Hopkins Post-Acute COVID-19 Team patients assessed were women (59%) and members of racial/ethnic minority groups (65%). Of 82 patients, 67% demonstrated ≥1 abnormally low cognitive score. Patients requiring intensive care unit (ICU) stays displayed greater breadth and severity of impairment than those requiring less intensive treatment. Processing speed (35%), verbal fluency (26%-32%), learning (27%), and memory (27%) were most commonly impaired. Among all patients, 35% had moderate symptoms of depression (23%), anxiety (15%), or functional decline (15%); 25% of ICU patients reported trauma-related distress. Neuropsychiatric symptoms and functional decline did not differ by post-ICU versus non-ICU status and were unrelated to global cognitive composite scores. CONCLUSIONS: At approximately 4 months after acute illness, cognitive dysfunction, emotional distress, and functional decline were common among a diverse clinical sample of COVID-19 survivors varying in acute illness severity. Patients requiring ICU stays demonstrated greater breadth and severity of cognitive impairment than those requiring less intensive treatment. Findings help extend our understanding of the nature, severity, and potential duration of neuropsychiatric morbidity after COVID-19 and point to the need for longitudinal assessment of cognitive and mental health outcomes among COVID-19 survivors of different demographic backgrounds and illness characteristics.

Depressive Symptoms at Kidney Transplant Evaluation and Access to the Kidney Transplant Waitlist.

Introduction: Depressive symptoms, even without a clinical diagnosis of depression, are common in kidney failure patients and may be a barrier to completing the complex process of kidney transplant (KT) evaluation. We assessed depressive symptom burden and association between depressive symptoms and access to KT waitlist by age. Methods: In a prospective cohort of 3728 KT patients (aged 18-88 years), the Center for Epidemiologic Studies-Depression (CES-D) scale was used to measure depressive symptoms at evaluation. Depressive symptom severity was defined as follows: none: 0; minimal: 1 to 15; mild: 16 to 20; moderate: 21 to 25; severe: 26 to 60. Hazard ratios (HRs) of active listing within 1 year after evaluation were estimated using Cox proportional hazards models, adjusted for clinical and social factors. Results: At evaluation, 85.8% of the patients reported at least minimal depressive symptoms; the proportion was lower among older patients: 18 to 29 years = 92.0%; 30 to 39 years = 88.3%; 40 to 49 years = 87.2%; 50 to 59 years = 87.0%; 60 to 69 years = 83.4%; and ≥70 years = 82.0%. Chance of active listing decreased with more severe depressive symptoms (log-rank, P < 0.001). After adjustment, every 5-point higher CES-D score (more depressive symptoms) was associated with a 13% lower chance of listing (HR = 0.87, 95% CI: 0.85-0.90); the strongest association was found among patients aged ≥70 years (adjusted HR [aHR] = 0.73, 95% CI: 0.62-0.86). Furthermore, minimal (HR = 0.69, 95% CI: 0.60-0.79), mild (HR = 0.57, 95% CI: 0.44-0.72), moderate (HR = 0.53, 95% CI: 0.39-0.71), and severe (HR = 0.44, 95% CI: 0.34-0.57) depressive symptoms were all associated with a lower chance of listing. Conclusion: Older candidates were less likely to report depressive symptoms at KT evaluation. Regardless of age, candidates who did report depressive symptoms, and even minimal symptoms, had a lower chance of listing. Transplant centers should routinely screen patients for depressive symptoms and refer the affected patients to mental health services to improve access to KT.

Transcranial direct current stimulation (tDCS) in a realistic head model.

Distributions of current produced by transcranial direct current stimulation (tDCS) in humans were predicted by a finite-element model representing several individual and collective refinements over prior efforts. A model of the entire human head and brain was made using a finely meshed (1.1x1.1x1.4mm(3) voxel) tissue dataset derived from the MRI data set of a normal human brain. The conductivities of ten tissues were simulated (bone, scalp, blood, CSF, muscle, white matter, gray matter, sclera, fat, and cartilage). We then modeled the effect of placing a "stimulating" electrode with a saline-like conductivity over F3, and a similar "reference" electrode over a right supraorbital (RS) location, as well as the complements of these locations, to compare expectations derived from the simulation with experimental data also using these locations in terms of the presence or absence of subjective and objective effects. The sensitivity of the results to changes in conductivity values were examined by varying white matter conductivity over a factor of ten. Our simulations established that high current densities were found directly under the stimulating and reference electrodes, but values of the same order of magnitude occurred in other structures, and many areas of the brain that might be behaviorally active were also subjected to what may be substantial amounts of current. The modeling also suggests that more targeted stimulations might be achieved by different electrode topologies.

A morphometric analysis of neuroanatomic abnormalities in traumatic brain injury.

Cognitive and structural brain abnormalities are common following traumatic brain injury (TBI). The authors compared cognition and brain structure in 14 TBI survivors and 28 matched healthy comparison subjects. TBI survivors showed reduced cerebral volume, due mainly to white matter changes, and poorer attention, psychomotor speed, and memory. Severity of white matter abnormality correlated with worse performance on several cognitive measures that distinguished between groups. Using voxel-based morphometry, regions of reduced white matter concentration were found throughout the cerebrum along with more localized gray matter reductions. Findings suggest that diffuse rather than focal aspects of TBI contribute most to cognitive outcome.

A Prospective Cohort Study of Neural Progenitor Cell-Sparing Radiation Therapy Plus Temozolomide for Newly Diagnosed Patients With Glioblastoma.

BACKGROUND: In treating glioblastoma, irradiation of the neural progenitor cell (NPC) niches is controversial. Lower hippocampal doses may limit neurocognitive toxicity, but higher doses to the subventricular zones (SVZ) may improve survival. OBJECTIVE: To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with glioblastoma. METHODS: Patients with glioblastoma received resection followed by standard chemoradiation. Radiation dose to the NPC niches, including the bilateral hippocampi and SVZ, was minimized without compromising tumor coverage. The primary outcome was tumor progression in the spared NPC niches. Follow-up magnetic resonance imaging was obtained bimonthly. Neurocognitive testing was performed before treatment and at 6- and 12-mo follow-up. Cox regression evaluated predictors of overall and progression-free survival. Linear regression evaluated predictors of neurocognitive decline. RESULTS: A total of 30 patients enrolled prospectively. The median age was 58 yr. Median mean doses to the hippocampi and SVZ were 49.1 and 41.8 gray (Gy) ipsilaterally, and 16.5 and 19.9 Gy contralaterally. Median times to death and tumor progression were 16.0 and 7.6 mo, and were not significantly different compared to a matched historical control. No patients experienced tumor progression in the spared NPC-containing regions. Overall survival was associated with neurocognitive function (P ≤ .03) but not dose to the NPC niches. Higher doses to the hippocampi and SVZ predicted greater decline in verbal memory (P ≤ .01). CONCLUSION: In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes. Further studies are needed to confirm these results.

Cerebral ischemia mediates the effect of serum uric acid on cognitive function.

BACKGROUND AND PURPOSE: High normal concentrations of serum uric acid (UA) are associated with mild cognitive dysfunction and increased cerebral ischemia as indexed by white matter hyperintensity volumes. We hypothesized that individual differences in white matter hyperintensities mediate the association between UA and mild cognitive dysfunction. METHODS: One hundred eighty community-dwelling adults aged 20 to 96 years completed neuropsychological testing, laboratory blood studies, and a brain MRI scan. RESULTS: Serum UA was associated (P<0.05) with greater white matter hyperintensities and poorer working memory, processing speed, fluency, and verbal memory. Associations remained after controlling for age, sex, race, education, hypertension, diabetes, alcohol abuse, smoking, and body mass. Adding a term for white matter hyperintensity attenuated these associations such that UA no longer predicted cognitive performance. CONCLUSIONS: Severity of cerebral ischemia might mediate the association between UA and cognitive dysfunction. Even mild elevations in UA appear to contribute to structural and functional brain changes.