Testing anxiety and reward processing in anorexia nervosa as predictors of longitudinal clinical outcomes.

Anorexia nervosa (AN) is a psychiatric disorder with a tenuous longitudinal course marked by a high risk of relapse. Previous studies suggest that aberrant threat perception and reward processing operate in many with AN, and may produce obstacles to treatment engagement; therefore, these could potentially represent predictors for longitudinal clinical outcomes. In this study, anxiety and reward symptoms, behaviors, and neural circuit connectivity were measured in intensively treated AN-restrictive subtype patients (n = 33) and healthy controls (n = 31). Participants underwent an fMRI experiment using a monetary reward task in combination with either overlapping individually tailored anxiety-provoking words or neutral words. Behavioral/psychometric measures consisted of reaction times on the monetary reward task and self-ratings on anxiety symptoms at study entry. We tested multimodal, multivariate models based on neural, behavioral, and psychometric measures of reward and anxiety to predict physiological (Body Mass Index; BMI) and psychological (eating disorder symptom severity) longitudinal outcomes in AN over six months. Our results indicated that higher anxiety symptom psychometric scores significantly predicted BMI reductions at follow-up. Untreated anxiety after intensive treatment could put individuals with AN at heightened risk for weight loss. This represents a potentially modifiable risk factor that could be targeted more aggressively to help reduce the chance of future clinical worsening.

Mechanisms of cognitive-behavioral therapy for obsessive-compulsive disorder involve robust and extensive increases in brain network connectivity.

Cognitive-behavioral therapy (CBT) is effective for obsessive compulsive disorder (OCD); however, little is understood about its mechanisms related to brain network connectivity. We examined connectivity changes from resting-state functional magnetic resonance imaging data pre-to-post-CBT in 43 OCD participants, randomized to receive either 4 weeks of intensive CBT or 4 weeks waitlist followed by 4 weeks of CBT, and 24 healthy controls before and after 4 weeks of no treatment. Network-based-statistic analysis revealed large-magnitude increases in OCD connectivity in eight networks. Strongest increases involved connectivity between the cerebellum and caudate/putamen, and between the cerebellum and dorsolateral/ventrolateral prefrontal cortices. Connectivity increases were associated with increased resistance to compulsions. Mechanisms of CBT may involve enhanced cross-network integration, both within and outside of classical cortico-striatal-thalamo-cortical regions; those involving cerebellar to striatal and prefrontal regions may reflect acquisition of new non-compulsive goal-directed behaviors and thought patterns. Our findings have implications for identifying targets for enhancing treatment efficacy and monitoring treatment progress.

Brain connectome modularity in weight-restored anorexia nervosa and body dysmorphic disorder.

BACKGROUND: Anorexia nervosa (AN) and body dysmorphic disorder (BDD) frequently co-occur, and have several overlapping phenomenological features. Little is known about their shared neurobiology. The aim of the study was to compare modular organization of brain structural connectivity. METHOD: We acquired diffusion-weighted magnetic resonance imaging data on unmedicated individuals with BDD (n = 29), weight-restored AN (n = 24) and healthy controls (HC) (n = 31). We constructed connectivity matrices using whole-brain white matter tractography, and compared modular structures across groups. RESULTS: AN showed abnormal modularity involving frontal, basal ganglia and posterior cingulate nodes. There was a trend in BDD for similar abnormalities, but no significant differences compared with AN. In AN, poor insight correlated with longer path length in right caudal anterior cingulate and right posterior cingulate. CONCLUSIONS: Abnormal network organization patterns in AN, partially shared with BDD, may have implications for understanding integration between reward and habit/ritual formation, as well as conflict monitoring/error detection.

Single nucleotide polymorphism in IL1B is associated with infection risk in paediatric acute myeloid leukaemia.

We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged ≤18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments.

Functional connectivity for face processing in individuals with body dysmorphic disorder and anorexia nervosa.

BACKGROUND: Body dysmorphic disorder (BDD) and anorexia nervosa (AN) are both characterized by distorted perception of appearance. Previous studies in BDD suggest abnormalities in visual processing of own and others' faces, but no study has examined visual processing of faces in AN, nor directly compared the two disorders in this respect. METHOD: We collected functional magnetic resonance imaging data on 60 individuals of equivalent age and gender in each of three groups--20 BDD, 20 weight-restored AN, and 20 healthy controls (HC)--while they viewed images of others' faces that contained only high or low spatial frequency information (HSF or LSF). We tested hypotheses about functional connectivity within specialized sub-networks for HSF and LSF visual processing, using psychophysiological interaction analyses. RESULTS: The BDD group demonstrated increased functional connectivity compared to HC between left anterior occipital face area and right fusiform face area (FFA) for LSF faces, which was associated with symptom severity. Both BDD and AN groups had increased connectivity compared to HC between FFA and precuneous/posterior cingulate gyrus for LSF faces, and decreased connectivity between FFA and insula. In addition, we found that LSF connectivity between FFA and posterior cingulate gyrus was significantly associated with thoughts about own appearance in AN. CONCLUSIONS: Results suggest similar abnormal functional connectivity within higher-order systems for face processing in BDD and AN, but distinct abnormal connectivity patterns within occipito-temporal visual networks. Findings may have implications for understanding relationships between these disorders, and the pathophysiology underlying perceptual distortions.

Anorexia nervosa and body dysmorphic disorder are associated with abnormalities in processing visual information.

BACKGROUND: Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are characterized by distorted body image and are frequently co-morbid with each other, although their relationship remains little studied. While there is evidence of abnormalities in visual and visuospatial processing in both disorders, no study has directly compared the two. We used two complementary modalities--event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI)--to test for abnormal activity associated with early visual signaling. METHOD: We acquired fMRI and ERP data in separate sessions from 15 unmedicated individuals in each of three groups (weight-restored AN, BDD, and healthy controls) while they viewed images of faces and houses of different spatial frequencies. We used joint independent component analyses to compare activity in visual systems. RESULTS: AN and BDD groups demonstrated similar hypoactivity in early secondary visual processing regions and the dorsal visual stream when viewing low spatial frequency faces, linked to the N170 component, as well as in early secondary visual processing regions when viewing low spatial frequency houses, linked to the P100 component. Additionally, the BDD group exhibited hyperactivity in fusiform cortex when viewing high spatial frequency houses, linked to the N170 component. Greater activity in this component was associated with lower attractiveness ratings of faces. CONCLUSIONS: Results provide preliminary evidence of similar abnormal spatiotemporal activation in AN and BDD for configural/holistic information for appearance- and non-appearance-related stimuli. This suggests a common phenotype of abnormal early visual system functioning, which may contribute to perceptual distortions.

Global characteristics of childhood acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) comprises approximately 5-10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent-de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed.

MEASURING INTER-HEMISPHERIC INTEGRATION IN BIPOLAR AFFECTIVE DISORDER USING BRAIN NETWORK ANALYSES AND HARDI.

Bipolar disorder is characterized by extreme mood swings, including both manic and depressive episodes commonly accompanied by psychosis. Many imaging studies have investigated white matter changes in bipolar illness, and the results have suggested abnormal intra- and inter-hemispheric white matter structures, particularly in the fronto-limbic and callosal systems. However, some inconsistency remains in the literature, and no study to-date has utilized brain network analysis using graph theory. Here, we acquired 64-direction diffusion weighted imaging (DWI) on 25 euthymic bipolar I subjects and 25 gender/age matched healthy subjects. White matter integrity measures were computed and compared in 50 white matter ROIs. The results indicated impaired integrity in the corpus callosum. Guided by this, we constructed whole brain structural connectivity networks using graph theory. We devised brain network metrics (inter-hemispheric path length and efficiency) to further probe inter-hemispheric integration, and demonstrated relatively preserved intra-hemispheric but significantly impaired inter-hemispheric integration in our bipolar subjects.

Computational non-linear dynamical psychiatry: a new methodological paradigm for diagnosis and course of illness.

The goal of this article is to highlight the significant potential benefits of applying computational mathematical models to the field of psychiatry, specifically in relation to diagnostic conceptualization. The purpose of these models is to augment the current diagnostic categories that utilize a "snapshot" approach to describing mental states. We hope to convey to researchers and clinicians that non-linear dynamics can provide an additional useful longitudinal framework to understand mental illness. Psychiatric phenomena are complex processes that evolve in time, similar to many other processes in nature that have been successfully described and understood within deterministic chaos and non-linear dynamic computational models. Dynamical models describe mental processes and phenomena that change over time, more like a movie than a photograph, with multiple variables interacting over time. The use of these models may help us understand why and how current diagnostic categories are insufficient. They may also provide a new, more descriptive and ultimately more predictive approach leading to better understanding of the interrelationship between psychological, neurobiological, and genetic underpinnings of mental illness.

Abnormalities of object visual processing in body dysmorphic disorder.

BACKGROUND: Individuals with body dysmorphic disorder (BDD) may have perceptual distortions for their appearance. Previous studies suggest imbalances in detailed relative to configural/holistic visual processing when viewing faces. No study has investigated the neural correlates of processing non-symptom-related stimuli. The objective of this study was to determine whether individuals with BDD have abnormal patterns of brain activation when viewing non-face/non-body object stimuli. METHOD: Fourteen medication-free participants with DSM-IV BDD and 14 healthy controls participated. We performed functional magnetic resonance imaging (fMRI) while participants matched photographs of houses that were unaltered, contained only high spatial frequency (HSF, high detail) information or only low spatial frequency (LSF, low detail) information. The primary outcome was group differences in blood oxygen level-dependent (BOLD) signal changes. RESULTS: The BDD group showed lower activity in the parahippocampal gyrus, lingual gyrus and precuneus for LSF images. There were greater activations in medial prefrontal regions for HSF images, although no significant differences when compared to a low-level baseline. Greater symptom severity was associated with lower activity in the dorsal occipital cortex and ventrolateral prefrontal cortex for normal spatial frequency (NSF) and HSF images. CONCLUSIONS: Individuals with BDD have abnormal brain activation patterns when viewing objects. Hypoactivity in visual association areas for configural and holistic (low detail) elements and abnormal allocation of prefrontal systems for details are consistent with a model of imbalances in global versus local processing. This may occur not only for appearance but also for general stimuli unrelated to their symptoms.

Antidepressants and suicidal behaviour in unipolar depression.

OBJECTIVE: To compare the rates of suicidal behaviour during vs. after discontinuation of treatment with antidepressants, and to determine the comparative rates of suicidal behaviour for patients maintained on tricyclic (TCA) vs. selective serotonin reuptake inhibitor (SSRI) antidepressants. METHOD: Charts were reviewed for 521 patients with major depressive disorder and/or dysthymic disorder. Periods of active treatment or discontinuation with SSRIs or TCAs were determined. Rates of completed suicide, suicide attempts, and hospitalization for suicidality were analyzed. RESULTS: There was greater than a five-fold increase in risk for suicidal behaviour after discontinuation of antidepressant treatment (P < 0.0001). The rates of suicidal behavior during treatment with SSRIs or TCAs were similar. CONCLUSION: Suicidal behaviour in unipolar depressed patients treated with antidepressants increases substantially after medication discontinuation. This effect occurred in both patients who were maintained on SSRIs and TCAs. The findings support a possible protective effect on suicidal behaviour for both SSRIs and TCAs.

Small cell undifferentiated histology in hepatoblastoma may be unfavorable.

BACKGROUND: Chemotherapy has improved the prognosis of hepatoblastoma demonstrably. It renders seemingly unresectable primary tumors amenable to surgery and can cure metastases. Some authors advocate preoperative chemotherapy for patients with tumors that are deemed resectable, relying solely on percutaneous biopsy or even on diagnostic imaging and elevated serum alpha-fetoprotein levels for diagnosis. However, certain cytologic features of hepatoblastoma appear to have important prognostic consequences. Well differentiated fetal hepatoblastomas that are confined to the liver and that have minimal mitotic activity may not require additional therapy if they are resected totally. METHODS: In the current study 16 completely resected hepatoblastomas that exhibited partial or predominant small cell undifferentiated histology were identified retrospectively and correlated with patient outcome. RESULTS: Ten of 16 patients with completely resected tumors exhibiting small cell undifferentiated histology developed a disease recurrence. Five of these recurrences were fatal. CONCLUSIONS: Small cell undifferentiated histology may have an unfavorable effect on outcome in patients with completely resected hepatoblastoma. The focal distribution of small cell histology in the majority of these tumors suggests that treating hepatoblastoma based on limited preexcision biopsies may deprive some patients of appropriate therapy.

GABA(A) receptor beta 3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population.

GABAergic systems have been implicated in the pathogenesis of anxiety, depression and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in post-traumatic stress disorder (PTSD). In a sample of Caucasian male PTSD patients, dinucleotide repeat polymorphisms of the GABA(A) receptor beta 3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ). As the major allele at this gene locus (GABRB3) was G1, the alleles were divided into G1 and non-G1 groups. On the total score of the GHQ, which comprises the somatic symptoms, anxiety/insomnia, social dysfunction and depression subscales, patients with the G1 non-G1 genotype had a significantly higher score when compared to either the G1G1 genotype (alpha=0.01) or the non-G1 non-G1 genotype (alpha=0.05). No significant difference was found between the G1G1 and non-G1 non-G1 genotypes. When the G1 non-G1 heterozygotes were compared to the combined G1G1 and non-G1 non-G1 homozygotes, a significantly higher total GHQ score was found in the heterozygotes (P=0.002). These observations suggest a heterosis effect. Further analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P=0.006), anxiety/insomnia (P=0.003), social dysfunction (P=0.054) and depression (P=0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.

Itraconazole-enhanced vincristine neurotoxicity in a child with acute lymphoblastic leukemia.

A boy with acute lymphoblastic leukemia (ALL) experienced life-threatening vincristine neurotoxicity while simultaneously exposed to itraconazole. Five pediatric and six adult cases of itraconazole-enhanced vincristine toxicity have been reported, all with ALL. Upon cessation of the itraconazole, the patient's symptoms resolved, which is similar to the outcome of the previously reported cases: 10 of 11 patients had complete resolution of symptoms.

Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group.

PURPOSE: Previous studies demonstrated that chemotherapy with either cisplatin, vincristine, and fluorouracil (regimen A) or cisplatin and continuous infusion doxorubicin (regimen B) improved survival in children with hepatoblastoma. The current trial is a randomized comparison of these two regimens. PATIENTS AND METHODS: Patients (N = 182) were enrolled onto study between August 1989 and December 1992. After initial surgery, patients with stage I-unfavorable histology (UH; n = 43), stage II (n = 7), stage III (n = 83), and stage IV (n = 40) hepatoblastoma were randomized to receive regimen A (n = 92) or regimen B (n = 81). Patients with stage I-favorable histology (FH; n = 9) were treated with four cycles of doxorubicin alone. RESULTS: There were no events among patients with stage I-FH disease. Five-year event-free survival (EFS) estimates were 57% (SD = 5%) and 69% (SD = 5%) for patients on regimens A and B, respectively (P =.09) with a relative risk of 1.54 (95% confidence interval, 0.93 to 2.5) for regimen A versus B. Toxicities were more frequent on regimen B. Patients with stage I-UH, stage II, stage III, or stage IV disease had 5-year EFS estimates of 91% (SD = 4%), 100%, 64% (SD = 5%), and 25% (SD = 7%), respectively. Outcome was similar for either regimen within disease stages. At postinduction surgery I, patients with stage III or IV disease who were found to be tumor-free had no events; those who had complete resections achieved a 5-year EFS of 83% (SD = 6%); other patients with stage III or IV disease had worse outcome. CONCLUSION: Treatment outcome was not significantly different between regimen A and regimen B. Excellent outcome was achieved for patients with stage I-UH and stage II hepatoblastoma and for subsets of patients with stage III disease. New treatment strategies are needed for the majority of patients with advanced-stage hepatoblastoma.