Adverse Neuropsychiatric Outcomes Research Articles

The Bidirectional Association of TBI and Dementia/MCI among older US Veterans

AbstractBackgroundPrior studies have reported a link between traumatic brain injury (TBI) and risk of adverse neuropsychiatric outcomes including dementia. However it is unclear how prevalent these conditions are prior to TBI and if they are predisposing factors in addition to sequalae.MethodsWe studied older (age >55 years) US veterans who were followed for care at Veterans Affairs Medical Centers across the nation from 2000 to 2019. We first identified all veterans with an incident TBI diagnoses defined as no prior TBI diagnosis, having been seen in an emergency department (ED), having a brain imaging scan (primarily CT) within one day of ED visit and with a subsequent new TBI diagnosis in the electronic medical record (EMR). We then determined 2‐year age‐adjusted prevalence rates (rate per 1000 person‐years and 95% confidence interval or CI) for dementia and mild cognitive impairment (MCI) prior to and post incident TBI. We also compared prior TBI prevalence to prevalence among 1:3 matched (on age and index date) veterans without TBI.ResultsThere were 13,709 primarily male veterans with incident TBI with mean age of 77.7 sd 9.1 years, 81% were non‐Hispanic White. Compared to the 41,127 veterans without TBI (mean age = 77.9, sd 9.1), veterans prior to having an incident TBI had almost a six‐fold greater pre‐TBI age‐adjusted prevalence of dementia (104.9; 95% CI 100.8‐109.0 vs 18.6; 95% CI 17.6‐19.7, p<0.001) and MCI (48.0; 95% CI 45.2‐50.7 vs 8.1; 95% CI 7.4‐8.8, p<0.001). After the incident TBI diagnosis, the age‐adjusted prevalence rates were even higher: dementia (193.5; 95% CI 187.7‐199.2) and MCI (59.3; 95% CI 56.0‐62.6).ConclusionsAmong older US veterans, there is a bidirectional association with dementia/ MCI and TBI with very high prevalence prior to TBI (compared to those without TBI) and even greater prevalence after TBI. These findings highlight the importance of prevention strategies for both pre‐ and post‐TBI cognitive impairment.

Examining the relationship between fetal cortical thickness, gestational age, and maternal psychological distress

In utero exposure to maternal stress, anxiety, and depression has been associated with reduced cortical thickness (CT), and CT changes, in turn, to adverse neuropsychiatric outcomes. Here, we investigated global and regional (G/RCT) changes associated with fetal exposure to maternal psychological distress in 265 brain MRI studies from 177 healthy fetuses of low-risk pregnant women. GCT was measured from cortical gray matter (CGM) voxels; RCT was estimated from 82 cortical regions. GCT and RCT in 87% of regions strongly correlated with GA. Fetal exposure was most strongly associated with RCT in the parahippocampal region, ventromedial prefrontal cortex, and supramarginal gyrus suggesting that cortical alterations commonly associated with prenatal exposure could emerge in-utero. However, we note that while regional fetal brain involvement conformed to patterns observed in newborns and children exposed to prenatal maternal psychological distress, the reported associations did not survive multiple comparisons correction. This could be because the effects are more subtle in this early developmental window or because majority of the pregnant women in our study did not experience high levels of maternal distress. It is our hope that the current findings will spur future hypothesis-driven studies that include a full spectrum of maternal mental health scores.

Evaluation of Archival HIV DNA in Brain and Lymphoid Tissues.

HIV reservoirs persist in anatomic compartments despite antiretroviral therapy (ART). Characterizing archival HIV DNA in the central nervous system (CNS) and other tissues is crucial to inform cure strategies. We evaluated paired autopsy brain-frontal cortex (FC), occipital cortex (OCC), and basal ganglia (BG)-and peripheral lymphoid tissues from 63 people with HIV. Participants passed away while virally suppressed on ART at the last visit and without evidence of CNS opportunistic disease. We quantified total HIV DNA in all participants and obtained full-length HIV-envelope (FL HIV-env) sequences from a subset of 14 participants. We detected HIV DNA (gag) in most brain (65.1%) and all lymphoid tissues. Lymphoid tissues had higher HIV DNA levels than the brain (P < 0.01). Levels of HIV gag between BG and FC were similar (P > 0.2), while OCC had the lowest levels (P = 0.01). Females had higher HIV DNA levels in tissues than males (gag, P = 0.03; 2-LTR, P = 0.05), suggesting possible sex-associated mechanisms for HIV reservoir persistence. Most FL HIV-env sequences (n = 143) were intact, while 42 were defective. Clonal sequences were found in 8 out of 14 participants, and 1 participant had clonal defective sequences in the brain and spleen, suggestive of cell migration. From 10 donors with paired brain and lymphoid sequences, we observed evidence of compartmentalized sequences in 2 donors. Our data further the idea that the brain is a site for archival HIV DNA during ART where compartmentalized provirus may occur in a subset of people. Future studies assessing FL HIV-provirus and replication competence are needed to further evaluate the HIV reservoirs in tissues. IMPORTANCE HIV infection of the brain is associated with adverse neuropsychiatric outcomes, despite efficient antiretroviral treatment. HIV may persist in reservoirs in the brain and other tissues, which can seed virus replication if treatment is interrupted, representing a major challenge to cure HIV. We evaluated reservoirs and genetic features in postmortem brain and lymphoid tissues from people with HIV who passed away during suppressed HIV replication. We found a differential distribution of HIV reservoirs across brain regions which was lower than that in lymphoid tissues. We observed that most HIV reservoirs in tissues had intact envelope sequences, suggesting they could potentially generate replicative viruses. We found that women had higher HIV reservoir levels in brain and lymphoid tissues than men, suggesting possible sex-based mechanisms of maintenance of HIV reservoirs in tissues, warranting further investigation. Characterizing the archival HIV DNA in tissues is important to inform future HIV cure strategies.

Response to ‘Isotretinoin and adverse neuropsychiatric outcomes: retrospective cohort study using routine data’

Abstract Linked Article: Paljarvi et al. Br J Dermatol 2022; 187:64–72.

Paracetamol perturbs neuronal arborization and disrupts the cytoskeletal proteins SPTBN1 and TUBB3 in both human and chicken in vitro models

Epidemiological studies have linked long-term/high-dose usage of paracetamol (N-acetyl-para-aminophenol, APAP) during pregnancy to adverse neuropsychiatric outcomes, primarily attention-deficit hyperactive disorder (ADHD), in the offspring. Though variable, ADHD has been associated with phenotypic alterations characterized by reductions in grey matter densities and aberrations in structural connectivity, effects which are thought to originate in neurodevelopment. We used embryonic chicken cerebellar granule neurons (CGNs) and neuronally differentiating human NTERA2 cells (NT2Ns) to investigate the in vitro effects of APAP on cell viability, migration, neuritogenesis, and the intracellular levels of various proteins involved in neurodevelopment as well as in the maintenance of the structure and function of neurites. Exposure to APAP ranging from 100 to 1600 μM yielded concentration- and time-dependent reductions in cell viability and levels of neurite arborization, as well as reductions in the levels of the cytoskeletal protein β2-spectrin, with the highest APAP concentration resulting in between 50 and 75% reductions in the aforementioned metrics over the course of 72 h. Exposure to APAP also reduced migration in the NT2Ns but not CGNs. Moreover, we found concentration- and time-dependent increases in punctate aggregation of the cytoskeletal protein β3-tubulin following exposure to APAP in both cell model systems, with the highest APAP concentration approximately doubling the number of aggregates over 72–120 h. Our findings demonstrate that APAP negatively perturbs neurite arborization degree, with concurrent reductions in the protein levels of β2-spectrin and disruption of the integrity of β3-tubulin, both proteins of which play important roles in neuronal structure and function.

Analysis of Neuropsychiatric Diagnoses After Montelukast Initiation

The evidence base for the association between montelukast and adverse neuropsychiatric outcomes is mixed and inconclusive. Several methodological limitations have been identified in the evidence base on the safety of montelukast in observational studies. To investigate the association between new montelukast exposure and 1-year incident neuropsychiatric diagnoses with improved precision and control for baseline confounders. This propensity score-matched cohort study was conducted using electronic health records from 2015 to 2019 in the TriNetX Analytics Network patient repository of more than 51 million patients from 56 health care organizations, mainly in the US. Included patients were those aged 15 to 64 years at index prescription for montelukast or for control prescription who had a history of asthma or allergic rhinitis. After propensity score matching for various baseline confounders, including comorbidities and dispensed prescription medicines, we included 154 946 patients, of whom 77 473 individuals were exposed to montelukast. Patients were followed up for 12 months. Data were analyzed from June through November 2021. New dispensed prescription for leukotriene receptor antagonist montelukast or control medication. Incident neuropsychiatric diagnoses at 12 months identified using International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. There were 72 490 patients with asthma (44 726 [61.7%] women; mean [SD] age at index prescription, 35 [15] years) and 82 456 patients with allergic rhinitis (54 172 [65.7%] women; mean [SD] age at index prescription, 40 [14] years). In patients exposed to montelukast, the odds ratio [OR] for any incident neuropsychiatric outcome was 1.11 (95% CI, 1.04-1.19) in patients with asthma and 1.07 (95% CI, 1.01-1.14) in patients with allergic rhinitis compared with patients who were unexposed. The highest OR was for anxiety disorders (OR, 1.21; 95% CI, 1.05-1.20) among patients with asthma exposed to montelukast and insomnia (OR, 1.15; 95% CI, 1.05-1.27) among patients with allergic rhinitis exposed to montelukast. This study found that patients with asthma or allergic rhinitis had increased odds of adverse neuropsychiatric outcomes after montelukast initiation. These findings suggest that clinicians should consider monitoring potential adverse mental health symptoms during montelukast treatment, particularly in individuals with a history of mental health or sleep problems.

Isotretinoin and adverse neuropsychiatric outcomes: retrospective cohort study using routine data.

BackgroundSevere neuropsychiatric outcomes have been reported in individuals exposed to isotretinoin, but the evidence is inconclusive and complicated by several methodological limitations.ObjectivesTo establish and quantify the association between isotretinoin use for acne and 1‐year incident neuropsychiatric adverse outcomes.MethodsA propensity score‐matched cohort study of electronic medical records between the years 2013 and 2019 with patients followed up for 1 year after their index dispensed prescription was conducted. The database included over 12 million patients aged 12–27 years. We analysed data for individuals with acne in this age range with a dispensed prescription for isotretinoin or a control prescription. Outcomes included diagnoses of any incident sleep or mental health disorder, or nonfatal self‐harm within 1 year of the index prescription.ResultsWe included 30 866 patients prescribed isotretinoin for their acne, 44 748 prescribed oral antibiotics, 108 367 prescribed topical anti‐acne agents and 78 666 patients with acne but without an anti‐acne prescription. After propensity score matching for baseline confounders, the odds ratio (OR) for any incident neuropsychiatric outcomes in patients with acne exposed to isotretinoin was 0·80 [95% confidence interval (CI) 0·74–0·87] compared with those on oral antibiotics; 0·94 (95% CI 0·87–1·02) compared with those using topical anti‐acne medicines; and 1·06 (95% CI 0·97–1·16) compared with those without a prescription for anti‐acne medicines. Patients exposed to isotretinoin experienced significantly more incident physical symptoms than patients in any of the three comparison cohorts.ConclusionsIsotretinoin was not independently associated with excess adverse neuropsychiatric outcomes at the population level. When monitoring potential adverse outcomes during isotretinoin treatment, clinicians should also consider the high mental health burden associated with treatment‐resistant acne and the potential contribution of physical side‐effects of prescribed medication on mental health.

Isotretinoin not associated with increased risk of adverse neuropsychiatric outcomes

Isotretinoin not associated with increased risk of adverse neuropsychiatric outcomes

Psychiatric Adverse Effects of Levetiracetam in Malignant Glioma Populations; a Retrospective Cohort Study

Objective: Levetiracetam is commonly used in malignant glioma populations because of its efficacy, limited drug-drug interactions and adverse effects. Although, there has been growing evidence of adverse neuropsychiatric side effects from levetiracetam; however, such evidence in malignant brain tumor settings is limited. Hence, we hypothesized that malignant glioma patients exposed to levetiracetam would also experience more adverse neuropsychiatric effects compared to patients not receiving this medication.Material and Methods: A retrospective cohort analysis was conducted in 150 high grade malignant glioma patients at our Cleveland Clinic Cancer Center; from 2013-2014, comparing the accumulative adverse neuropsychiatric outcomes between patients who received levetiracetam and patients who did not (n=108 and 42, respectively). A sub-analysis of each specific neuropsychiatric side effect between these two groups was performed.Results: Patients with malignant glioma receiving levetiracetam had increased risk of developing neuropsychiatric adverse effects compared to the non-levetiracetam group (odds ratio=2.08, p-value=0.040, 95% confidence interval=1.00-4.36). After adjusting for confounding factors, past psychiatric history and the interaction between seizure and levetiracetam use was significantly associated with neuropsychiatric problems. Delirium, psychosis, and irritability were more common in the levetiracetam group, and likely led to more psychiatric referrals, starting of psychotropic medications, and vitamin B6 use.Conclusion: Incidence of neuropsychiatric presentations in malignant glioma patients was higher in the levetiracetam exposed group than the non-exposed group. The changes, or emergence of new neuropsychiatric behaviors should prompt clinicians to search for possible causes; including levetiracetam adverse effects, so they can be managed accordingly.

Impact of the COVID-19 Pandemic on Adverse Neuropsychiatric Outcomes After Trauma Exposure

Impact of the COVID-19 Pandemic on Adverse Neuropsychiatric Outcomes After Trauma Exposure

COVID-19-related anxiety in phenylketonuria patients.

Phenylketonuria (PKU) is an inherited disorder of amino acid metabolism, the treatment of which often requires a special diet to prevent adverse neuropsychiatric outcomes. In the COVID-19 pandemic, which has had a substantial effect on the whole world since the beginning of 2020, PKU patients represent a vulnerable population because they may be dependent on special nutritional products, have limited access to routine care and display increased levels of anxiety. For this reason, an online questionnaire assessing the anxiety levels and various personal opinions and practices regarding the pandemic was sent to the PKU patients managed at our clinic, who were 12 years of age or older. Ninety-eight patients responded to the questionnaire. Median age of the participants was 19 years. Most patients were compliant with the hygiene and social distancing recommendations regarding the spread of COVID-19. Of the patients, 61.2% felt more anxious since the pandemic. The most common concern was the possibility of not being able to obtain special nutritional products (58.2%). Anxiety level was significantly higher in females. These data suggest that food security is an important issue of concern in PKU patients. In line with the changing world after the pandemic, different strategies should be considered in the management of patients with inborn errors of metabolism, including PKU.

Association of Gestational Age at Birth With Brain Morphometry

Preterm and postterm births are associated with adverse neuropsychiatric outcomes. However, it remains unclear whether variation of gestational age within the 37- to 42-week range of term deliveries is associated with neurodevelopment. To investigate the association of gestational age at birth (GAB) with structural brain morphometry in children aged 10 years. This population-based cohort study included pregnant women living in Rotterdam, the Netherlands, with an expected delivery date between April 1, 2002, and January 31, 2006. The study evaluated 3079 singleton children with GAB ranging from 26.3 to 43.3 weeks and structural neuroimaging at 10 years of age from the Generation R Study, a longitudinal, population-based prospective birth cohort from early pregnancy onward in Rotterdam. Data analysis was performed from March 1, 2019, to February 28, 2020, and at the time of the revision based on reviewer suggestions. The GAB was calculated based on ultrasonographic assessment of crown-rump length (<12 weeks 5 days) or biparietal diameter (≥12 weeks 5 days) in dedicated research centers. Brain structure, including global and regional brain volumes and surface-based cortical measures (thickness, surface area, and gyrification), was quantified by magnetic resonance imaging. In the 3079 children (1546 [50.2%] female) evaluated at 10 years of age, GAB was linearly associated with global and regional brain volumes. Longer gestational duration was associated with larger brain volumes; for example, every 1-week-longer gestational duration corresponded to an additional 4.5 cm3/wk (95% CI, 2.7-6.3 cm3/wk) larger total brain volume. These associations persisted when the sample was restricted to children born at term (GAB of 37-42 weeks: 4.8 cm3/wk; 95% CI, 1.8-7.7 cm3/wk). No evidence of nonlinear associations between GA and brain morphometry was observed. In this cohort study, gestational duration was linearly associated with brain morphometry during childhood, including within the window of term delivery. These findings may have marked clinical importance, particularly given the prevalence of elective cesarean deliveries.

Risk of childhood cerebral palsy following prenatal exposure to ß2-adrenergic receptor agonist: A nationwide cohort study.

BackgroundCerebral palsy (CP) is the most common physical developmental disability in childhood with a prevalence of 2 to 3 per 1000 live births. β2-adrenoreceptor agonist (β2AA) are widely used for the treatment of asthma. Maternal use of β2AAs may increase the risk of adverse neuro-psychiatric health outcomes in the offspring. No study, however, has evaluated the effect of prenatal exposure to β2AAs on the risk of CP.ObjectiveTo examine the association between prenatal exposure to β2AAs and the risk of childhood cerebral palsy.MethodsThis population-based cohort study included all live singleton births in Denmark from January 1, 1997 to December 31, 2003. The information on outpatient prescriptions of β2AAs was extracted from Danish National Prescription Registry. Children born to mothers who used β2AAs from 30 days before pregnancy until delivery were categorized as the exposed. To differentiate the effect of β2AAs from the underlying indications, the exposure window was further extended to 2 years before pregnancy and the exposed groups were re-defined to represent different periods of exposure to maternal use of β2AAs (use only before pregnancy, use only during pregnancy, and use both before and during pregnancy). Cases of CP were identified from the Danish Cerebral Palsy Register. Logistic regression was used to estimate incidence odds ratio (OR) of CP.ResultsAmong all the 442,278 singletons, 19,616 (4.44%) were exposed to β2AAs in utero (from 30 days before pregnancy until delivery). The risk of childhood CP was 0.21% in exposed and 0.19% in unexposed group, yielding an adjusted OR (aOR) 1.12 (95% confidence interval (CI): 0.82, 1.53). When extending the exposure time window to 2 years prior to pregnancy, no overall significant association was observed regardless of the exposure period. However, an increased risk of CP (aOR = 1.41, 95%CI: 0.92, 2.18) for maternal β2AAs use during pregnancy was observed in female offspring, especially in those born at term (aOR = 1.65, 95%CI: 1.02, 2.67). This increase was mainly attributed to an increased risk in those born to mothers who used β2AAs both before and during pregnancy (aOR = 1.81, 95%CI: 0.99, 3.33).ConclusionsWe observed an association between maternal β2AAs use during pregnancy and an increased risk of CP in female offspring, but we could not rule out confounding by the underlying indications for β2AAs.

Prenatal Obesity and Childhood Neuropsychiatric Symptoms

Evidence of a link between prenatal maternal obesity and adverse neuropsychiatric outcomes in children has been inconsistent, and previous researchers

Prenatal exposure to very severe maternal obesity is associated with adverse neuropsychiatric outcomes in children.

Prenatal maternal obesity has been linked to adverse childhood neuropsychiatric outcomes, including increased symptoms of attention deficit hyperactivity disorder (ADHD), internalizing and externalizing problems, affective disorders and neurodevelopmental problems but few studies have studied neuropsychiatric outcomes among offspring born to very severely obese women or assessed potential familial confounding by maternal psychological distress. We evaluated neuropsychiatric symptoms in 112 children aged 3-5 years whose mothers had participated in a longitudinal study of obesity in pregnancy (50 very severe obesity, BMI ⩾40 kg/m2, obese class III and 62 lean, BMI 18.5-25 kg/m2). The mothers completed the Conners' Hyperactivity Scale, Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examination Questionnaire (ESSENCE-Q), Child's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), and Child Behavior Checklist (CBCL) to assess child neuropsychiatric symptoms. Covariates included child's sex, age, birthweight, gestational age, socioeconomic deprivation levels, maternal age, parity, smoking status during pregnancy, gestational diabetes and maternal concurrent symptoms of anxiety and depression assessed using State Anxiety of Spielberger State-Trait Anxiety Index (STAI) and General Health Questionnaire (GHQ), respectively. Children exposed to prenatal maternal very severe obesity had significantly higher scores in the Conners' Hyperactivity Scale; ESSENCE-Q; total sleep problems in CSHQ; hyperactivity, conduct problems and total difficulties scales of the SDQ; higher externalizing and total problems, anxious/depressed, aggressive behaviour and other problem syndrome scores and higher DSM-oriented affective, anxiety and ADHD problems in CBCL. Prenatal maternal very severe obesity remained a significant predictor of child neuropsychiatric problems across multiple scales independent of demographic factors, prenatal factors and maternal concurrent symptoms of anxiety and depression. Prenatal maternal very severe obesity is a strong predictor of increased neuropsychiatric problems in early childhood.

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia.

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular–metabolic, neuropsychiatric, physiological–anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.

The neurotoxicology of carbon monoxide – Historical perspective and review

Carbon monoxide (CO) has been recognized as a poison for centuries, and remains one of the most common causes of both accidental and deliberate poisoning worldwide. Despite this, there are widespread misconceptions with regards to the mechanisms, diagnosis and outcomes of CO induced poisoning such as the idea that CO poisoning is rare; that carboxyhaemoglobin levels above 20% and loss of consciousness are required before nervous system damage ensues; and that the binding of CO to haemoglobin is the only mechanism of toxicity. Prevention and diagnosis of CO poisoning is hampered by the lack of awareness of CO as a cause of illness, among both the general public and healthcare professionals. To complicate matters further there is no standardized definition of CO poisoning. Carboxyhaemoglobin levels are often used as a marker of CO poisoning, yet plasma levels rapidly reduce upon removal of the source and are therefore an unreliable biomarker of exposure and tissue damage. Adverse neuropsychiatric outcomes after CO poisoning are difficult to define, especially as they fluctuate, mimic other non-specific complaints, and are not present in all survivors. This paper challenges a number of misconceptions about CO poisoning which can result in misdiagnosis, and consequently in mismanagement. We illustrate how recent developments in the understanding of CO toxicology explain the particular susceptibility of the central nervous system to the effects of CO exposure.

Anxiety is related to indices of cortical maturation in typically developing children and adolescents.

Anxiety is a risk factor for many adverse neuropsychiatric and socioeconomic outcomes, and has been linked to functional and structural changes in the ventromedial prefrontal cortex (VMPFC). However, the nature of these differences, as well as how they develop in children and adolescents, remains poorly understood. More effective interventions to minimize the negative consequences of anxiety require better understanding of its neurobiology in children. Recent research suggests that structural imaging studies may benefit from clearly delineating between cortical surface area and thickness when examining these associations, as these distinct cortical phenotypes are influenced by different cellular mechanisms and genetic factors. The present study examined relationships between cortical surface area and thickness of the VMPFC and a self-report measure of anxiety (SCARED-R) in 287 youths aged 7-20years from the Pediatric Imaging, Neurocognition, and Genetics (PING) study. Age and gender interactions were examined for significant associations in order to test for developmental differences. Cortical surface area and thickness were also examined simultaneously to determine whether they contribute independently to the prediction of anxiety. Anxiety was negatively associated with relative cortical surface area of the VMPFC as well as with global cortical thickness, but these associations diminished with age. The two cortical phenotypes contributed additively to the prediction of anxiety. These findings suggest that higher anxiety in children may be characterized by both delayed expansion of the VMPFC and an altered trajectory of global cortical thinning. Further longitudinal studies will be needed to confirm these findings.

Possible Association Between Alice In Wonderland Syndrome And Influenza A Infection

Possible Association Between Alice In Wonderland Syndrome And Influenza A Infection

Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain

The induction of neuronal apoptosis throughout many regions of the developing rat brain by phenobarbital and phenytoin, two drugs commonly used for the treatment of neonatal seizures, has been well documented. However, several limbic regions have not been included in previous analyses. Because drug-induced damage to limbic brain regions in infancy could contribute to emotional and psychiatric sequelae, it is critical to determine the extent to which these regions are vulnerable to developmental neurotoxicity. To evaluate the impact of antiepileptic drug (AED) exposure on limbic nuclei, we treated postnatal day 7 rat pups with phenobarbital, phenytoin, carbamazepine, or vehicle, and examined nucleus accumbens, septum, amygdala, piriform cortex, and frontal cortex for cell death. Histologic sections were processed using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay to label apoptotic cells. Nucleus accumbens displayed the highest level of baseline cell death (vehicle group), as well as the greatest net increase in cell death following phenobarbital or phenytoin. Phenobarbital exposure resulted in a significant increase in cell death in all brain regions, whereas phenytoin exposure increased cell death only in the nucleus accumbens. Carbamazepine was without effect on cell death in any brain region analyzed, suggesting that the neurotoxicity observed is not an inherent feature of AED action. Our findings demonstrate pronounced cell death in several important regions of the rat limbic system following neonatal administration of phenobarbital, the first-line treatment for neonatal seizures in humans. These findings raise the possibility that AED exposure in infancy may contribute to adverse neuropsychiatric outcomes later in life.