Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence.

BACKGROUND: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms. METHODS: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria. RESULTS: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic-ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%). CONCLUSIONS: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

A review on investigation of the basic contrast mechanism underlying multidimensional diffusion MRI in assessment of neurological disorders.

INTRODUCTION: Multidimensional diffusion MRI (MDD MRI) is a novel diffusion technique that uses advanced gradient waveforms for microstructural tissue characterization to provide information about average rate, anisotropy and orientation of the diffusion and to disentangle the signal fraction from specific cell types i.e., elongated cells, isotropic cells and free water. AIM: To review the diagnostic potential of MDD MRI in the clinical setting for microstructural tissue characterization in patients with neurological disorders to aid in patient care and treatment. METHOD: A scoping review on the clinical applications of MDD MRI was conducted from original articles published in PubMed and Scopus from 2015 to 2021 using the keywords "Multidimensional diffusion MRI" OR "diffusion tensor distribution" OR "Tensor-Valued Diffusion" OR "b-tensor encoding" OR "microscopic diffusion anisotropy" OR "microscopic anisotropy" OR "microscopic fractional anisotropy" OR "double diffusion encoding" OR "triple diffusion encoding" OR "double pulsed field gradients" OR "double wave vector" OR "correlation tensor imaging" AND "brain" OR "axons". RESULTS: Initially 145 articles were screened and after applying inclusion and exclusion criteria, nine articles were included in the final analysis. In most of these studies, microscopic diffusion anisotropy within the lesion showed deviation from the normal-appearing tissue. CONCLUSION: Multidimensional diffusion MRI can provide better quantification and visualization of tissue microstructure than conventional diffusion MRI and can be used in the clinical setting for diagnosis of neurological disorders.

Temporal trends and yield of clinical diagnostic genetic testing in adult neurology.

While genetics evaluation is increasingly utilized in adult neurology patients, its usage and efficacy are not well characterized. Here, we report our experience with 1461 consecutive patients evaluated in an adult neurogenetics clinic at a large academic medical center between January 2015 and March 2020. Of the 1461 patients evaluated, 1215 patients were referred for the purposes of identifying a genetic diagnosis for an undiagnosed condition, 90.5% of whom underwent genetic testing. The modalities of genetic testing utilized varied across referral diagnostic categories, including a range of utilization of whole exome sequencing (WES) as an initial test in 13.9% of neuromuscular patients to 52.9% in white matter disorder patients. The usage of WES increased over time, from 7.7% of initial testing in 2015 to a peak of 27.3% in 2019. Overall, genetic testing yielded a causal genetic diagnosis in 30.7% of patients. This yield was higher in certain referring diagnosis categories, such as neuromuscular (39.0%) and epilepsy (29.8%). Our study demonstrates that evaluation at an adult neurogenetics referral center can yield diagnoses in a substantial fraction of patients. Additional research will be needed to determine optimal genetic testing strategies and cost effectiveness of adult neurogenetics evaluation.

Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids.

In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson's disease, and Alzheimer's disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.

THE ASSESSMENT OF COMORBID PATHOLOGY IN CLEAN-UP WORKERS OF THE ACCIDENT CONSEQUENCES AT THE CHORNOBYL NPP HAVING CARDIOVASCULAR DISEASES. / OTsINKA KOMORBIDNOÏ PATOLOGIÏ V UChASNYKIV LIKVIDATsIÏ NASLIDKIV AVARIÏ NA ChORNOBYL'S'KII AES Z ZAKhVORIuVANNIaMY SERTsEVO-SUDYNNOÏ SYSTEMY.

OBJECTIVE: Analysis of comorbid pathology based on the use of methods for its quantitative assessment in personswho were exposed to radiation because of the Chornobyl accident. MATERIALS AND METHODS: Comorbid pathology was studied in 608 men, including 420 clean-up workers (CW) of theaccident consequences at the Chornobyl NPP (main group) and 188 non-irradiated persons (control group - CG). Allpatients had cardiovascular diseases as their main pathology and were examined in the cardiology department ofthe NRCRM hospital during 2011-2019. The groups did not differ by age, either at the beginning of the accident orat the time of their last examination. Patients of both groups before the accident were practically healthy peopleand were not registered at the dispensary. The Cumulative Illness Rating Scale (CIRS) was used to quantify comorbid pathology. RESULTS: Comorbid pathology was detected in 418 CW (99.5 %) and 183 patients of CG (99.3 %). The total score inCW (10.3 ± 2.9) units significantly (р = 0.000) exceeded the same index in non-irradiated patients (8.8 ± 3.0) units,as well as the mean number of CIRS categories, whose level severity was 1 point (3.3 ± 1.7 vs. 2.6 ± 1.5, р = 0.000),2 points (1.8 ± 1.0 vs. 1.6 ± 1.0, p = 0.032) and 3-4 points (1.2 ± 0.8 vs. 1.0 ± 0.9, р = 0.062). In contrast, the meanvalue of the categories with zero score, i.e. without diseases, was more common in CG (7.8 ± 1.8 vs. 8.8 ± 1.7,р = 0.000). The most common pathology in CW and CG were heart (98.3 % vs. 94.7 %, р < 0.05) and vascular diseases(92.9 % vs. 87.8 %, р > 0.05), followed by diseases of nervous system (79.0 % vs. 57.4 %, р <0.001), musculoskeletal system and skin (69.8 % vs. 56.9 %, р < 0.01), endocrine (56.0 % vs. 49,5 %, р > 0.05) and the respiratory system (53.8 % vs. 53.7 %, р > 0.05) and liver (51.2 % vs. 36.2 %, р < 0.001), which were detected more than in halfpatients of the main group. Diseases of the kidneys (3.3 % vs. 4.8 %, р > 0.05) and lower gastrointestinal tract(3.3 % vs. 0.5 %, р < 0.01) were quite rare. The incidence of the other four CIRS categories was 18.6-34 %. The totalscore in subgroups with different ages varied in descending order of mean values as follows: CW > 65 years (10.5 ± 2.9)units, CW < 65 years (9.9 ± 2.8) units, CG > 65 years (9.5 ± 2.8) units and CG < 65 years (7.8 ± 2.9) units with significant differences both between age subgroups in each of the groups and between CW and CG older subgroups. CONCLUSIONS: Quantitative assessment of comorbidity by CIRS showed that in persons irradiated during their emergency work due to the Chornobyl accident, the incidence of combined pathology of such organ systems as cardiovascular, nervous, endocrine, hematopoietic, urogenital, musculoskeletal, gastrointestinal, liver and kidneys wassignificantly higher than in non-irradiated patients. In irradiated patients, the course of comorbid pathology wasmore severe for each system and in general, reflecting higher values of the total CIRS score. Both among CW andnon-irradiated controls, higher values of the total comorbidity score were observed in patients 65 years and older,compared with younger individuals. In both age subgroups of CW the total score was higher than in patients of thecontrol group.

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults.

BACKGROUND: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood. OBJECTIVE: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults. METHODS: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. RESULTS: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-ß plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups. CONCLUSION: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

Hospitalization, Alzheimer's Disease and Related Neuropathologies, and Cognitive Decline.

OBJECTIVE: To test the hypothesis that Alzheimer's disease and related neuropathologies contribute to the association between hospitalization and cognitive decline in old age. METHODS: As part of a longitudinal clinical-pathologic cohort study, 526 older persons (mean age at death = 90.9 years, 71% female) without dementia at baseline completed annual cognitive testing and were autopsied at death. Hospitalization information was obtained from linked Medicare claims records. Neuropathologic examination assessed ß-amyloid burden, tau tangle density, neocortical Lewy bodies, hippocampal sclerosis, chronic gross and microscopic cerebral infarcts, and transactive response DNA binding protein 43 kDa. RESULTS: Over a mean of 5.1 years, a total of 1,383 hospitalizations occurred, and the mean annual rate of hospitalization was 0.5 (standard deviation = 0.6, median = 0.4). Higher rate of hospitalization was not directly related to higher burden for any of the neuropathologic markers. Higher rate of hospitalization was associated with more rapid cognitive decline (estimate = -0.042, standard error [SE] = 0.012, p < 0.001), and after controlling for all 7 neuropathologic markers, the association was essentially the same (estimate = -0.040, SE = 0.013, p = 0.002). In a multivariable model with 3-way interactions of neuropathologic markers with hospitalization rate and time, the association between hospitalization rate and faster cognitive decline was greater in persons with more tangle pathology (estimate for interaction = -0.007, SE = 0.002, p = 0.002) and in persons with neocortical Lewy bodies (estimate for interaction = -0.117, SE = 0.042, p = 0.005). INTERPRETATION: Older persons with more hospitalizations experienced faster rates of cognitive decline, and this association was more pronounced in persons with more tau tangle density and with neocortical Lewy body pathologies. ANN NEUROL 2019;86:844-852.

Inhibition and assessment of the biophysical gating properties of GluA2 and GluA2/A3 AMPA receptors using curcumin derivatives.

The development of efficacious and safe drugs for the treatment of neurological diseases related to glutamate toxicity has been a focus in neuropharmacological research. Specifically, discovering antagonists to modulate the activity and kinetics of AMPA receptors, which are the fastest ligand-gated ion channels involved in excitatory neurotransmission in response to glutamate. Thus, the current study investigated novel curcumin derivatives on the biophysical properties of AMPA receptors, specifically on the homomeric GluA2 and the heteromeric GluA2/A3 subunits and assessed for inhibitory actions. The biophysical parameter (i.e., desensitization, deactivation, and peak currents) were measured by using whole-cell patch clamp electrophysiology with and without the administration of the derivatives onto HEK293 cells. CR-NN, CR-NNPh, CR-MeNH, and CR-NO of the tested derivatives showed inhibition on all AMPA receptors up to 6 folds. Moreover, the inhibitory derivatives also increased desensitization and deactivation, which further intensifies the compounds' neuroprotective effects. However, CR-PhCl, CR-PhF, and CR-PhBr did not show any significant changes on the peak current, deactivation or desensitization rates. By comparison to other discovered and widely used antagonist, the prepared curcumin derivatives are not selective to a specific AMPA subunit, instead implement its effect in the same way between all types of AMPA receptors. Additionally, the obtained results provide derivatives that not only noncompetitively inhibit AMPARs but also decrease its biophysical kinetics, specifically desensitization and deactivation rates. Hence, to potentially serve as a new AMPAR inhibitor with therapeutic potential, the current study provides compounds that are non-selective and non-competitive antagonist, which also effect the desensitization and deactivation rates of the receptor.

Clinical characteristics of autoimmune GFAP astrocytopathy.

The clinical features of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy remain to be elucidated. We describe here the clinical features of 14 patients with GFAP astrocytopathy confirmed by detection of GFAP-IgG in cerebrospinal fluid (CSF). The novel findings of this study are as follows. First, over half of the patients presented with movement disorders (tremor, myoclonus, and ataxia), autonomic dysfunction (mainly urinary dysfunction), and hyponatremia. Second, most patients showed transient elevation of adenosine deaminase activity levels in CSF. Finally, some patients showed bilateral hyperintensities in the posterior part of the thalamus on brain magnetic resonance imaging.

Early detection of West Nile virus in France: quantitative assessment of syndromic surveillance system using nervous signs in horses.

West Nile virus (WNV) is a growing public health concern in Europe and there is a need to develop more efficient early detection systems. Nervous signs in horses are considered to be an early indicator of WNV and, using them in a syndromic surveillance system, might be relevant. In our study, we assessed whether or not data collected by the passive French surveillance system for the surveillance of equine diseases can be used routinely for the detection of WNV. We tested several pre-processing methods and detection algorithms based on regression. We evaluated system performances using simulated and authentic data and compared them to those of the surveillance system currently in place. Our results show that the current detection algorithm provided similar performances to those tested using simulated and real data. However, regression models can be easily and better adapted to surveillance objectives. The detection performances obtained were compatible with the early detection of WNV outbreaks in France (i.e. sensitivity 98%, specificity >94%, timeliness 2·5 weeks and around four false alarms per year) but further work is needed to determine the most suitable alarm threshold for WNV surveillance in France using cost-efficiency analysis.

Wikipedia and neurological disorders.

Our aim was to evaluate Wikipedia page visits in relation to the most common neurological disorders by determining which factors are related to peaks in Wikipedia searches for these conditions. Millions of people worldwide use the internet daily as a source of health information. Wikipedia is a popular free online encyclopedia used by patients and physicians to search for health-related information. The following Wikipedia articles were considered: Alzheimer's disease; Amyotrophic lateral sclerosis; Dementia; Epilepsy; Epileptic seizure; Migraine; Multiple sclerosis; Parkinson's disease; Stroke; Traumatic brain injury. We analyzed information regarding the total article views for 90 days and the rank of these articles among all those available in Wikipedia. We determined the highest search volume peaks to identify possible relation with online news headlines. No relation between incidence or prevalence of neurological disorders and the search volume for the related articles was found. Seven out of 10 neurological conditions showed relations in search volume peaks and news headlines. Six out of these seven peaks were related to news about famous people suffering from neurological disorders, especially those from showbusiness. Identification of discrepancies between disease burden and health seeking behavior on Wikipedia is useful in the planning of public health campaigns. Celebrities who publicly announce their neurological diagnosis might effectively promote awareness programs, increase public knowledge and reduce stigma related to diagnoses of neurological disorders.

Compensation for occupational neurological and mental disorders.

Standards for the recognition of occupational diseases (ODs) in Korea were established in 1954 and have been amended several times. In 2013, there was a significant change in these standards. On the basis of scientific evidence and causality, the International Labour Organization list, European Commission schedule, and compensated cases in Korea were reviewed to revise the previous standards for the recognition of ODs in Korea. A disease-based approach using the International Classification of Diseases (10th version) was added on the previous standards, which were agent-specific approaches. The amended compensable occupational neurological disorders and occupational mental disorders (OMDs) in Korea are acute and chronic central nervous system (CNS) disorders, toxic neuropathy, peripheral neuropathy, manganese-related disorders, and post-traumatic stress disorder. Several agents including trichloroethylene (TCE), benzene, vinyl chloride, organotin, methyl bromide, and carbon monoxide (CO) were newly included as acute CNS disorders. TCE, lead, and mercury were newly included as chronic CNS disorders. Mercury, TCE, methyl n-butyl ketone, acrylamide, and arsenic were newly included in peripheral neuropathy. Post-traumatic stress disorders were newly included as the first OMD. This amendment makes the standard more comprehensive and practical. However, this amendment does not perfectly reflect the recent scientific progress and social concerns. Ongoing effort, research, and expert consensus are needed to improve the standard.

Neurohistopathological findings at the electrode-tissue interface in long-term deep brain stimulation: systematic literature review, case report, and assessment of stimulation threshold safety.

OBJECTIVES: Despite the widespread use of deep brain stimulation (DBS) in the treatment of neurologic disorders for over a quarter of a century, there has not been a systematic review and analyses of cases in which long-term postmortem clinic-pathologic data have been collected demonstrating the effects of chronically implanted electrodes and electrical stimulation on human brain tissue. Our objective is to provide a comprehensive systematic review of the literature on clinicopathologic findings of DBS tissue-electrode interface (TEI) and to determine types and prevalences of neuropathological findings among electrode materials and stimulation parameters and to augment this with previously unpublished histopathological data, images, and analyses from a DBS case implanted for 12 years, providing the longest duration histopathological follow-up. MATERIALS AND METHODS: A Medline literature review identified DBS cases upon which postmortem clinicopathologic follow-up was performed with adequate characterization of TEI. Direct follow-up with authors augmented this with unpublished data and neuropathological details. RESULTS: We identified 40 cases, mean age 59.1 ± 13.0 (range: 21-88) years, involving 58 implanted DBS electrodes. The mean postmortem histopathological follow-up of the implanted DBS electrodes was 22.2 ± 29.2 (range: 0.067-146) months, including our case with a 12-year follow-up. The following histological changes were identified: fibrous sheaths (5-25 µm thickness) surrounding the electrode (94%), fibrillary gliosis (73%), reactive astrocytes (78%), multinucleated giant cells (75%), mononuclear leukocytes (92%), and macrophages (91%). Microglial activation (60%), axonal spheroids (64%), and neuronal loss (60%) were less common and absent at 12-year follow-up in the index case. This is seventh case reporting T cell presence at the TEI. CONCLUSIONS: Neuropathological findings from published cases and our 12-year follow-up index case confirm the long-term safety of neuromodulation and stimulation thresholds and demonstrate persistence of T cells and occasional subclinical focal tissue injury.

Continuous antihypertensive therapy throughout the initial 24 hours of intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: A short duration (<24 hours) of antihypertensive therapy (AHT) after acute intracerebral hemorrhage (ICH) may be sufficient because active bleeding generally ceases within several hours. We aimed to determine the association between sequential systolic blood pressure (SBP) levels during AHT and outcomes in ICH patients. METHODS: In 211 hyperacute ICH patients who underwent AHT based on predefined protocol, the mean of hourly SBP (mSBP) measurements was calculated over 1 to 8 hours (first mSBP), 9 to 16 hours (second mSBP), and 17 to 24 hours (third mSBP) after the initiation of AHT. Outcomes included neurological deterioration (72-hour Glasgow Coma Scale decrease ≥2 or National Instititutes of Health Stroke Scale increase ≥4), hematoma expansion (>33%), and unfavorable outcome (3-month modified Rankin Scale score 4-6). RESULTS: The median first, second, and third mSBPs were 132, 131, and 137 mm Hg, respectively. A higher first mSBP (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.34-4.69 per 10 mm Hg) or second mSBP (OR, 2.08; 95% CI, 1.20-3.80) was independently associated with neurological deterioration, and a higher second mSBP (OR, 1.40; 95% CI, 1.02-2.00) or third mSBP (OR, 1.45; 95% CI, 1.05-2.05) was associated with unfavorable outcome. None of the mSBPs was associated with hematoma expansion. CONCLUSIONS: The continuation of AHT throughout the initial 24 hours after ICH may improve outcomes.

The functional, social and economic impact of acute encephalitis syndrome in Nepal--a longitudinal follow-up study.

BACKGROUND: Over 133,000 children present to hospitals with Acute Encephalitis Syndrome (AES) annually in Asia. Japanese encephalitis (JE) accounts for approximately one-quarter of cases; in most cases no pathogen is identified and management is supportive. Although JE is known to result in neurological impairment, few studies have examined the wider impact of JE and AES on patients and their families. METHODOLOGY/PRINCIPAL FINDINGS: Children (aged 1 month-14 years) with AES were assessed 5-12 months after discharge from two Nepali hospitals. Assessment included clinical examination, the Liverpool Outcome Score (LOS) - a validated assessment of function following encephalitis, questionnaires about the child's social participation since discharge, and out-of-pocket costs to the family. Children were classified as JE or 'other AES' based on anti-JE virus antibody titres during acute illness. Contact was made with the families of 76% (73/96) of AES children. Six children had died and one declined participation. 48% (32/66) reported functional impairment at follow-up, most frequently affecting behaviour, language or limb use. Impairment was more frequent in JE compared to 'other AES' cases (68% [13/19] versus 40% [19/47]; p = 0.06). 49% (26/53) had improvement in LOS between discharge and follow-up. The median out-of-pocket cost to families, including medical bills, medication and lost earnings was US$ 1151 (10 times their median monthly income) for children with severe/moderate impairment and $524 (4.6 times their income) for those with mild/no impairment (P = 0.007). Acute admission accounted for 74% of costs. Social participation was limited in 21% of children (n = 14). CONCLUSIONS/SIGNIFICANCE: Prolonged functional impairment was common following AES. Economic impact to families was substantial. Encouragingly, almost half the children improved after discharge and most reported sustained social participation. This study highlights a need for long-term medical support following AES. Rationalisation of initial expensive hospital treatments may be warranted, especially since only supportive treatment is available.

Toxicological assessment of drugs that affect the endocrine system in puberty-related disorders.

INTRODUCTION: Toxicologists must ensure that clinical risk-to-benefit analysis should be made both for genders and age groups, with any treatment. Puberty concerns physiological changes leading to organism's maturation. Pubertal growth disorders are increasing in last decades: besides causing physical and psychological distress, they may signal underlying endocrine-metabolic abnormalities with serious health consequences later on. Therapeutic approaches for some health conditions in childhood and adolescence are considered. AREAS COVERED: The authors discuss how some diseases and treatments can impact pubertal growth. The authors look at particular immunological disorders such as asthma and how both the disease and treatment affects pubertal growth. They also discuss how the provision of available data can help to assess the dose-response of the drug, in these cases, and minimize the chance of side effects. The authors also discuss pediatric inflammatory bowel disease and how both the disease and treatment can mitigate the growth delay. Last, but not least, the authors discuss how the effects of the drugs used in the treatment of psychiatric disorders may accentuate endocrine issues in juvenile patients. Hyperprolactinemia induction by some antipsychotics is highlighted as an example. EXPERT OPINION: Appropriate risk-benefit analysis of drugs prescribed during childhood and adolescence and intended to be used in the long term is required. Furthermore, future treatment strategies and safer compounds development should be supported by the knowledge of mechanisms underlying adverse side effects in pubertal growth and development.

The economy of brain network organization.

The brain is expensive, incurring high material and metabolic costs for its size--relative to the size of the body--and many aspects of brain network organization can be mostly explained by a parsimonious drive to minimize these costs. However, brain networks or connectomes also have high topological efficiency, robustness, modularity and a 'rich club' of connector hubs. Many of these and other advantageous topological properties will probably entail a wiring-cost premium. We propose that brain organization is shaped by an economic trade-off between minimizing costs and allowing the emergence of adaptively valuable topological patterns of anatomical or functional connectivity between multiple neuronal populations. This process of negotiating, and re-negotiating, trade-offs between wiring cost and topological value continues over long (decades) and short (millisecond) timescales as brain networks evolve, grow and adapt to changing cognitive demands. An economical analysis of neuropsychiatric disorders highlights the vulnerability of the more costly elements of brain networks to pathological attack or abnormal development.

High-definition fiber tracking for assessment of neurological deficit in a case of traumatic brain injury: finding, visualizing, and interpreting small sites of damage.

For patients with traumatic brain injury (TBI), current clinical imaging methods generally do not provide highly detailed information about the location of axonal injury, severity of injury, or expected recovery. In a case of severe TBI, the authors applied a novel high-definition fiber tracking (HDFT) to directly visualize and quantify the degree of axonal fiber damage and predict functional deficits due to traumatic axonal injury and loss of cortical projections. This 32-year-old man sustained a severe TBI. Computed tomography and MRI revealed an area of hemorrhage in the basal ganglia with mass effect, but no specific information on the location of axonal injury could be obtained from these studies. Examinations of the patient at Week 3 and Week 8 after TBI revealed motor weaknesses of the left extremities. Four months postinjury, 257-direction diffusion spectrum imaging and HDFT analysis was performed to evaluate the degree of axonal damage in the motor pathway and quantify asymmetries in the left and right axonal pathways. High-definition fiber tracking was used to follow corticospinal and corona radiata pathways from the cortical surface to the midbrain and quantify projections from motor areas. Axonal damage was then localized by assessing the number of descending fibers at the level of the cortex, internal capsule, and midbrain. The motor deficit apparent in the clinical examinations correlated with the axonal losses visualized using HDFT. Fiber loss estimates at 4 months postinjury accurately predicted the nature of the motor deficits (severe, focal left-hand weakness) when other standard clinical imaging modalities did not. A repeat scan at 10 months postinjury, when edema and hemorrhage had receded, replicated the fiber loss. Using HDFT, the authors accurately identified the presence and location of damage to the underlying white matter in this patient with TBI. Detailed information of injury provided by this novel technique holds future potential for precise neuroimaging assessment of TBI.

Continuing education course #3: current practices and future trends in neuropathology assessment for developmental neurotoxicity testing.

The continuing education course on Developmental Neurotoxicity Testing (DNT) was designed to communicate current practices for DNT neuropathology, describe promising innovations in quantitative analysis and noninvasive imaging, and facilitate a discussion among experienced neuropathologists and regulatory scientists regarding suitable DNT practices. Conventional DNT neuropathology endpoints are qualitative histopathology and morphometric endpoints of particularly vulnerable sites (e.g., cerebral, cerebellar, or hippocampal thickness). Novel imaging and stereology measurements hold promise for automated analysis of factors that cannot be effectively examined in routinely processed specimens (e.g., cell numbers, fiber tract integrity). The panel recommended that dedicated DNT neuropathology data sets be acquired on a minimum of 8 sections (for qualitative assessment) or 3 sections (for quantitative linear and stereological analyses) using a small battery of stains to examine neurons and myelin. Where guidelines permit discretion, immersion fixation is acceptable for younger animals (postnatal day 22 or earlier), and peripheral nerves may be embedded in paraffin. Frequent concerns regarding DNT data sets include false-negative outcomes due to processing difficulties (e.g., lack of concordance among sections from different animals) and insensitive analytical endpoints (e.g., qualitative evaluation) as well as false-positive results arising from overinterpretation or misreading by inexperienced pathologists.