Mapping brain abnormalities in boys with autism

Children with autism spectrum disorder (ASD) exhibit characteristic cognitive and behavioral differences, but no systematic pattern of neuroanatomical differences has been consistently found. Recent neurodevelopmental models posit an abnormal early surge in subcortical white matter growth in at least some autistic children, perhaps normalizing by adulthood, but other studies report subcortical white matter deficits. To investigate the profile of these alterations in 3D, we mapped brain volumetric differences using a relatively new method, tensor‐based morphometry. 3D T1‐weighted brain MRIs of 24 male children with ASD (age: 9.5 years ± 3.2 SD) and 26 age‐matched healthy controls (age: 10.3 ± 2.4 SD) were fluidly registered to match a common anatomical template. Autistic children had significantly enlarged frontal lobes (by 3.6% on the left and 5.1% on the right), and all other lobes of the brain were enlarged significantly, or at trend level. By analyzing the applied deformations statistically point‐by‐point, we detected significant gray matter volume deficits in bilateral parietal, left temporal and left occipital lobes (P = 0.038, corrected), trend‐level cerebral white matter volume excesses, and volume deficits in the cerebellar vermis, adjacent to volume excesses in other cerebellar regions. This profile of excesses and deficits in adjacent regions may (1) indicate impaired neuronal connectivity, resulting from aberrant myelination and/or an inflammatory process, and (2) help to understand inconsistent findings of regional brain tissue excesses and deficits in autism. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism

Congenital hypothyroidism is a pediatric endocrine disorder caused by insufficient endogenous thyroid hormone production. Children with congenital hypothyroidism have difficulties with episodic memory and abnormalities in hippocampal structure, suggesting deficient hippocampal functioning. To assess hippocampal activation in adolescents with congenital hypothyroidism (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years), a functional magnetic resonance imaging visuospatial memory task was used. In this task, participants had to decide if object pairings were novel or were previously studied or if object pairs were in the same location as they were at study or had switched locations. Despite no group differences in task performance, adolescents with congenital hypothyroidism showed both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls. Furthermore, the increased activation in the congenital hypothyroidism group was correlated with the severity of the hypothyroidism experienced early in life. These results suggest that perinatal deprivation of thyroid hormone has longstanding effects on hippocampal function and may account for memory problems experienced by adolescents with congenital hypothyroidism.     

Pharmacokinetics and pharmacodynamics of ampreloxetine,a novel,selective norepinephrine reuptake inhibitor,in symptomatic neurogenic orthostatic hypotension

Clinical Autonomic Research - Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic...     

Infection-associated clozapine toxicity

Three case vignettes are presented documenting the rise in serum clozapine that occurred at a time of acute infection in these patients. The literature on this phenomenon is scant. The physiological processes that occur in the acute phase of the inflammatory response are summarized and provide an explanation of how clozapine levels may rise in response to infection. The risk of clozapine toxicity occurring in association with infections is highlighted.     

Aberrant connectivity of resting-state networks in borderline personality disorder

Background

Several functional neuroimaging studies have reported regionally abnormal activation of the frontal cortex in individuals with borderline personality disorder (BPD) during cognitive and affective task performance. However, little is known about neural function in individuals with BPD during the resting state. Using functional magnetic resonance imaging (fMRI), this study investigated the functional connectivity of prefrontal and limbic networks in patients with BPD.

Methods

Between January 2009 and March 2010, we investigated patients with BPD according to DSM-IV criteria and healthy controls by means of resting-state fMRI. The data were analyzed using a spatial group independent component analysis, and random effects t tests were used to compare spatial components between groups (p < 0.005, uncorrected).

Results

There were 17 women with BPD and 17 female healthy controls enrolled in this study. Within a network comprising cortical midline regions (“default mode network”), patients with BPD showed an increase in functional connectivity in the left frontopolar cortex (FPC) and the left insula, whereas decreased connectivity was found in the left cuneus. Within a network comprising predominantly right lateral prefrontal and bilateral parietal regions, patients with BPD showed decreased connectivity of the left inferior parietal lobule and the right middle temporal cortex compared with healthy controls. Two networks comprising lateral prefrontal and cingulate regions did not exhibit significant between-group differences. We found correlations between functional connectivity of the FPC and measures of impulsivity as well as between connectivity of the insula/cuneus and dissociation tension.

Limitations

Co-occurrent axis I disorders and medication use in this sample of patients with BPD have to be considered as potential limitations.

Conclusion

These data suggest that abnormal functional connectivity of temporally coherent resting-state networks may underlie certain symptom clusters in patients with BPD.     

Mean diffusivity and fractional anisotropy as indicators of disease and genetic liability to schizophrenia

The goals of this study were to first determine whether the fractional anisotropy (FA) and mean diffusivity (MD) of major white matter pathways associate with schizophrenia, and secondly to characterize the extent to which differences in these metrics might reflect a genetic predisposition to schizophrenia. Differences in FA and MD were identified using a comprehensive atlas-based tract mapping approach using diffusion tensor imaging and high-resolution structural data from 35 patients, 28 unaffected first-degree relatives of patients, 29 community controls, and 14 first-degree relatives of controls. Schizophrenia patients had significantly higher MD in the following tracts compared to controls: the right anterior thalamic radiations, the forceps minor, the bilateral inferior fronto-occipital fasciculus (IFO), the temporal component of the left superior longitudinal fasciculus (tSLF), and the bilateral uncinate. FA showed schizophrenia effects and a linear relationship to genetic liability (represented by schizophrenia patients, first-degree relatives, and controls) for the bilateral IFO, the left inferior longitudinal fasciculus (ILF), and the left tSLF. Diffusion tensor imaging studies have previously identified white matter abnormalities in all three of these tracts in schizophrenia; however, this study is the first to identify a significant genetic liability. Thus, FA of these three tracts may serve as biomarkers for studies seeking to identify how genes influence brain structure predisposing to schizophrenia. However, differences in FA and MD in frontal and temporal white matter pathways may be additionally driven by state variables that involve processes associated with the disease.     

Depletion of cutaneous glutathione and the induction of inflammation by 8-methoxypsoralen plus UVA radiation

The purpose of this study was to examine the dose response and time course relationships between PUVA (psoralen + UVA) depletion of skin glutathione (GSH) and the induction of inflammation. Dorsal skin fold thickness (DSFT), an index of cutaneous edema, was used as a noninvasive measure of inflammation. Ornithine decarboxylase (ODC) was used as a measure of epidermal damage. Female hairless mice were given 8-methoxypsoralen (8-MOP) (dissolved in corn oil) by gavage at different doses, and 2 h later the mice were irradiated with 5 J/cm2 UVA. At 24 h, DSFT measurements were taken, the mice were killed, and reduced GSH, glutathione disulfide (GSSG), and glutathione-S-transferase were measured in the epidermis and dermis. Epidermal GSH was depleted 0, 11, 45, 87, and 98% from vehicle and/or UVA-treated levels (0.7 mM) after 0.1, 0.5, 5, 25, and 50 mg/kg, respectively. In the dermis GSH decreased from 0.3 mM by 47, 87, and 91% after 5, 25, and 50 mg/kg 8-MOP, respectively. Increases in DSFT of 20, 141, and 242% were observed after 5, 25, and 50 mg/kg doses, respectively. GSSG accounted for a small portion of total GSH in the skin after PUVA treatment. The maximal decreases in GSH were not observed until 24-48 h after PUVA treatment. PUVA treatment leads to dose-related increases in dermal edema, epidermal ODC, and depletion of GSH levels from both compartments in the skin. The time course of glutathione loss suggests that PUVA may interfere with its resynthesis or utilization from the circulation.     

Hypoactive Sexual Desire Disorder in Postmenopausal Women: Quality of Life and Health Burden

ObjectivesTo describe the health-related quality of life (HRQOL) implications of hypoactive sexual desire disorder (HSDD) in a national sample of postmenopausal women ages 30–70.MethodsThe Nationwide Survey of Female Sexual Health, a random-digit telephone survey of US households, collected information on female sexual function, demographic characteristics, HRQOL, and the presence of specific medical disorders from 1189 naturally or surgically postmenopausal women in stable relationships of ≥3 months duration. HSDD was defined as <40 on the Profile of Female Sexual Function© scale and <60 on the Personal Distress Scale©. Short Form-12 Health Survey (SF-12) summary and domain scores, and EuroQol (EQ-5D) index score and dimensions were compared with population-based norms for healthy individuals and selected chronic conditions.ResultsHSDD was associated with significant HRQOL decrements, with the largest SF-12 score differences in mental health (HSDD: 45.4 [standard error 1.9] vs. no HSDD: 51.0 [0.6], P < 0.01), vitality (HSDD: 47.7 [1.3] vs. no HSDD: 52.0 [0.7], P < 0.01), social function (HSDD: 47.3 [1.4] vs. no HSDD: 50.9 [0.7], P < 0.05), and bodily pain (HSDD: 41.4 [2.2] vs. no HSDD: 46.7 [0.9], P < 0.05). EQ-5D index was 0.08 points lower (HSDD: 0.76 [0.03] vs. no HSDD: 0.84 [0.02], P < 0.05) for those with HSDD compared with those without. HSDD was associated with a 0.1-point decrement in naturally menopausal women (HSDD: 0.78 [0.03] vs. no HSDD 0.88 [0.01], P < 0.01). Women with HSDD showed more HRQOL impairment than healthy population norms but were similar to adults with other chronic conditions such as diabetes and back pain.ConclusionsWomen with HSDD showed substantial impairment in HRQOL. Given a prevalence of 6.6% to 12.5% among US women, HSDD represents an important burden on quality of life.