Study protocol: families and childhood transitions study (FACTS) - a longitudinal investigation of the role of the family environment in brain development and risk for mental health disorders in community based children.

BACKGROUND: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old. METHODS/DESIGN: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017. DISCUSSION: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population.

On the Use of Mixed Markov Models for Intensive Longitudinal Data.

Markov modeling presents an attractive analytical framework for researchers who are interested in state-switching processes occurring within a person, dyad, family, group, or other system over time. Markov modeling is flexible and can be used with various types of data to study observed or latent state-switching processes, and can include subject-specific random effects to account for heterogeneity. We focus on the application of mixed Markov models to intensive longitudinal data sets in psychology, which are becoming ever more common and provide a rich description of each subject's process. We examine how specifications of a Markov model change when continuous random effect distributions are included, and how mixed Markov models can be used in the intensive longitudinal research context. Advantages of Bayesian estimation are discussed and the approach is illustrated by two empirical applications.

Functional brain-imaging correlates of negative affectivity and the onset of first-episode depression.

BACKGROUND: The amygdala and subgenual anterior cingulate cortex (sACC) are key brain regions for the generation of negative affect. In this longitudinal fMRI study of adolescents we investigated how amygdala-sACC connectivity was correlated with negative affectivity (NA) both cross-sectionally and longitudinally, and examined its relationship to the onset of first-episode depression. METHOD: Fifty-six adolescents who were part of a larger longitudinal study of adolescent development were included. They had no history of mental illness at the time of their baseline scan (mean age 16.5 years) and had a follow-up scan 2 years later (mean age 18.8 years). We used resting-state functional-connectivity MRI to investigate whether cross-sectional and change measures of amygdala-sACC connectivity were (i) correlated with NA and its change over time, and (ii) related to the onset of first-episode depression. RESULTS: The magnitude of amygdala connectivity with sACC showed significant positive correlation with NA at both time-points. Further analysis confirmed that change in amygdala-sACC connectivity between assessments was correlated with change in NA. Eight participants developed a first episode of depression between the baseline and follow-up assessments: they showed increased amygdala-sACC connectivity at follow-up. CONCLUSIONS: Amygdala-sACC connectivity is associated with NA in adolescence, with change in connectivity between these regions showing positive correlation with change in NA. Our observation that the onset of depression was associated with an increase in connectivity between the regions provides support for the neurobiological 'scar' hypothesis of depression.

Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Regionally specific alterations in functional connectivity of the anterior cingulate cortex in major depressive disorder.

BACKGROUND: Depression has been associated with functional alterations in several areas of the cingulate cortex. In this study we have taken a systematic approach to examining how alterations in functional connectivity vary across the functionally diverse subregions of the rostral cingulate cortex. Method Eighteen patients with major depressive disorder, aged 15 to 24 years, were matched with 20 healthy control participants. Using resting-state functional connectivity magnetic resonance imaging (fcMRI), we systematically investigated the functional connectivity of four subregions of the rostral cingulate cortex. Voxelwise statistical maps of each subregion's connectivity with other brain areas were compared between the patient and control groups. RESULTS: The depressed participants showed altered patterns of connectivity with ventral cingulate subregions. They showed increased connectivity between subgenual anterior cingulate cortex (ACC) and dorsomedial frontal cortex, with connectivity strength showing positive correlation with illness severity. Depressed participants also showed increased connectivity between pregenual ACC and left dorsolateral frontal cortex, and decreased connectivity between pregenual ACC and the caudate nucleus bilaterally. CONCLUSIONS: The results reinforce the importance of subgenual ACC for depression, and show a close link between brain regions that support self-related processes and affective visceromotor function. The pregenual ACC also has an important role, with its increased connectivity with dorsolateral frontal cortex suggesting heightened cognitive regulation of affect; and reduced connectivity with the caudate nucleus potentially underlying symptoms such as anhedonia, reduced motivation and psychomotor dysfunction.

The ratio of morning cortisol to CRP prospectively predicts first-onset depression in at-risk adolescents.

RATIONALE: Early-onset adolescent depression is related to poor prognosis and a range of psychiatric and medical comorbidities later in life, making the identification of a priori risk factors for depression highly important. Increasingly, dysregulated levels of immune and neuroendocrine markers, such as C-reactive protein (CRP) and cortisol, have been demonstrated as both precursors to and consequences of depression. However, longitudinal research with adolescent populations is limited and demonstrates mixed immuno-endocrine-depression links. OBJECTIVE: This study explored the putative bidirectional relationship between salivary measures of cortisol (Cort) and CRP, including the novel Cort:CRP ratio and depression. METHODS: Participants from the randomized control trial 'Sleep and Education: learning New Skills Early' (SENSE) Study were 122 adolescents at risk for depression (73 females) aged 12-16 years (M = 12.71 years, SD = 1.01 years) assessed at baseline (T1), post-intervention (T2), and a two-year follow-up (T3). RESULTS: Logistic regression results demonstrated that adolescents with higher T1 Cort:CRPmorn ratio levels were two-fold more likely to develop a first-onset depressive disorder from T2 to T3 as compared to adolescents with lower Cort:CRPmorn ratio levels, ß = 0.73, t (36) = 2.15, p = .04, OR = 2.08. This effect was not moderated by treatment condition (ß = -1.38, t (13) = -1.33, p = .20) and did not change when controlling for known risk factors for depression, including sex, age, body-mass index, socio-economic status, T1 anxiety disorder, nor T1 sleep disturbance, anxiety, or depressive symptoms (ß = 0.91, t (31) = 2.14, p = .04). CONCLUSION: Results highlight potential immuno-endocrine dysregulation as an underlying risk factor for adolescent first-onset depression, and may inform the development of targeted, preventative biobehavioral treatment strategies for youth depression.

Salivary C-reactive protein among at-risk adolescents: A methods investigation of out of range immunoassay data.

Inflammatory markers including C-Reactive Protein (CRP) are increasingly used within research and clinical settings. Yet, varying methodologies for cleaning immunoassay data with out of range (OOR) samples may alter characteristic levels of CRP, thereby obscuring interpretation and reliability. This study investigated the influence of eight immunoassay OOR data treatment techniques on salivary CRP (sCRP) samples from at-risk adolescents. Participants from the 'Sleep and Education: learning New Skills Early' (SENSE) Study were 86 adolescents at-risk for depression (50 female), aged 14.29 years (SD = 1.04). ANOVA results showed no statistically significant differences in average morning (F(7, 590) = 1.24, p = .28) and evening (F(7, 599)=1.29, p = .25) values produced by each OOR data cleaning technique. However, varying techniques produced differences in the magnitude of Pearson's correlations between consecutive saliva samples (r's between 0.27-0.78), and influenced the significance of a sCRP diurnal pattern; two techniques produced statistically higher morning than evening sCRP levels (t(85) = 2.70, p = .01 and t(85) = 2.67, p = .01), whereas six techniques failed to find statistical differences between morning and evening sCRP levels (p's >.05). Varying techniques also produced statistically divergent associations between sCRP and age and depressive symptoms. Results from this study provide evidence for the temporal stability of sCRP among adolescents, show winsorization as an effective OOR data management technique, and highlight the influence of methodological decisions in cleaning salivary biomarker data and the need for consistency within the field.

Electrophysiological evidence that drug cues have greater salience than other affective stimuli in opiate addiction.

Previous research has demonstrated that drug cues are able to capture attentional resources in addicted populations. However, few studies have controlled for the possibility that drug users find all motivationally significant (i.e., affective) stimuli particularly salient. We examined this issue in opiate addiction, by exploring the impact of drug-related and affective stimuli on central attentional processes. Sixteen male heroin addicts (seven on opiate pharmacotherapy and nine recently detoxified subjects) and 12 matched controls were studied. Subjects were fitted with a 32-channel electrode cap and were instructed to passively view a series of neutral, affective and opiate-related images. The P300 elicited by drug-related stimuli was significantly larger than that elicited by affective and neutral stimuli in opiate users but not controls. Baseline ratings of craving were also found to predict the degree of P300 facilitation to the drug-related stimuli in the addicted group. Further, the opiate group demonstrated an absence of the typical enhancement of ERP responses to non-drug affective stimuli. These results suggest that opiate addicts demonstrate greater cortical processing of drug cues than other types of affective stimuli. Further research is required to assess whether addiction is specifically associated with reduced sensitivity to natural rewards, aversive stimuli or affective cues in general.

Trajectories of adolescent conduct problems in relation to cortical thickness development: a longitudinal MRI study.

Multiple cross-sectional imaging studies have identified structural abnormalities in prefrontal, temporal and limbic regions related to conduct problems (CPs). However, the relationship between development of such neurobiological deficits and developmental pathways of CPs has remained unclear. The current study investigated distinct trajectories of CP and related trajectories of cortical thickness within a community-based sample of adolescents (n=239), age range 12-19, to address this gap. Three trajectory classes were revealed using latent class growth analyses (LCGAs), comprising a 'desisting' CP group, an 'intermediate' CP group and a 'stable low' CP group. Structural magnetic resonance imaging (MRI) scans were collected with a subgroup of 171 adolescents at three waves throughout adolescence (ages 12, 16 and 19). Generalized estimating equation (GEE) analysis-comparing longitudinal changes in cortical thickness and subcortical volume between CP groups for several regions of interest (ROIs)-showed that these CP groups had differential trajectories of cortical thickness in the dorsolateral prefrontal cortex (dl-PFC), and the anterior cingulate cortex (ACC), and volume of the hippocampus. Adolescents in the desisting CP group showed an attenuation of the typical pattern of cortical thinning as present in the intermediate and stable low CP groups, in addition to an exaggeration of the typical pattern of hippocampal volume increase. These findings suggest that a deviant cortical thickness trajectory was related to a desisting CP pathway across adolescence. Such deviant neurodevelopmental growth trajectories may act as an underlying mechanism for developmental CP pathways, and possibly distinguish desisting antisocial adolescents.

Dispositional mindfulness is predicted by structural development of the insula during late adolescence.

Adolescence is a critical period of development, in which the increasing social and cognitive demands of independence need to be met by enhanced self-regulatory abilities. The cultivation of mindfulness has been associated with improved self-regulation in adult populations, and it is theorized that one neurodevelopmental mechanism that supports this capacity is the development of the prefrontal cortex. The current study examined the neurodevelopmental mechanisms associated with dispositional mindfulness in adolescence. Using a longitudinal within-persons design, 82 participants underwent structural magnetic resonance imaging (MRI) assessments at approximately ages 16 and 19, and also completed self-reported measurements of mindfulness at age 19. It was hypothesized that adolescents who demonstrated greater thinning of frontal cortical regions between the age of 16 and 19 would exhibit higher dispositional mindfulness levels at age 19. Results indicated that, contrary to predictions, adolescents with higher levels of mindfulness demonstrated less thinning in the left anterior insula. By contrast, higher IQ was associated with greater thinning of the right caudal middle frontal and right superior frontal regions. The involvement of insula development in mindfulness is consistent with a direct role for this structure in managing self-regulation, and in doing so concords with recent models of self-referential interoceptive awareness.

Online mindfulness-based intervention for late-stage bipolar disorder: pilot evidence for feasibility and effectiveness.

OBJECTIVES: People in the late stage of bipolar disorder (BD) experience elevated relapse rates and poorer quality of life (QoL) compared with those in the early stages. Existing psychological interventions also appear less effective in this group. To address this need, we developed a new online mindfulness-based intervention targeting quality of life (QoL) in late stage BD. Here, we report on an open pilot trial of ORBIT (online, recovery-focused, bipolar individual therapy). METHODS: Inclusion criteria were: self-reported primary diagnosis of BD, six or more episodes of BD, under the care of a medical practitioner, access to the internet, proficient in English, 18-65 years of age. Primary outcome was change (baseline - post-treatment) on the Brief QoL.BD (Michalak and Murray, 2010). Secondary outcomes were depression, anxiety, and stress measured on the DASS scales (Lovibond and Lovibond, 1993). RESULTS: Twenty-six people consented to participate (Age M=46.6 years, SD=12.9, and 75% female). Ten participants were lost to follow-up (38.5% attrition). Statistically significant improvement in QoL was found for the completers, t(15)=2.88, 95% CI:.89-5.98, p=.011, (Cohen׳s dz=.72, partial η(2)=.36), and the intent-to-treat sample t(25)=2.65, 95% CI:.47-3.76, (Cohen׳s dz=.52; partial η(2)=.22). A non-significant trend towards improvement was found on the DASS anxiety scale (p=.06) in both completer and intent-to-treat samples, but change on depression and stress did not approach significance. LIMITATIONS: This was an open trial with no comparison group, so measured improvements may not be due to specific elements of the intervention. Structured diagnostic assessments were not conducted, and interpretation of effectiveness was limited by substantial attrition. CONCLUSION: Online delivery of mindfulness-based psychological therapy for late stage BD appears feasible and effective, and ORBIT warrants full development. Modifications suggested by the pilot study include increasing the 3 weeks duration of the intervention, adding cautions about the impact of extended meditations, and addition of coaching support/monitoring to optimise engagement.

Affective startle modulation in clinical depression: preliminary findings.

BACKGROUND: Modulation of the startle reflex by affective foreground stimuli was investigated in a group receiving inpatient treatment for major depressive episodes (n = 14) and an age and gender matched nondepressed group (n = 14). METHODS: Participants viewed 27 pleasant, neutral, and unpleasant pictures chosen from the International Affective Picture System. Acoustic startle probes were presented during picture viewing, and participants also rated the affective qualities of the pictures. RESULTS: While ratings of the pictures were largely similar between the depressed and nondepressed groups, they displayed dissimilar patterns of startle modulation. In the nondepressed group, blinks elicited during unpleasant pictures were significantly larger than during pleasant pictures, whereas the depressed group failed to show this effect. Analyses, which separated the depressed participants into moderate and severe groups based on Beck Depression Inventory scores, revealed that while the moderately depressed group also showed a normal pattern of startle modulation, the severely depressed showed potentiated startles during the pleasant pictures. CONCLUSIONS: These preliminary results suggest that severely depressed patients may respond to some pleasant stimuli as if they are aversive, possibly because such stimuli are seen as signals of frustrative nonreward.

Neuro-Behçet's disease: factors hampering proper diagnosis.

We reviewed the clinical course of nine patients with neuro-Behçet's disease to assess difficulties in making this diagnosis. Factors delaying proper diagnosis included lack of accurate history and physical examination, lack of recognition of an underlying systemic syndrome and its relationship to the neurologic symptoms, presence of intermittently normal CSF studies, and use of noncontrasted neuroimaging techniques.

Wegener's granulomatosis involving the breast. Report of three cases and review of the literature.

Three cases of necrotizing granulomatous vasculitis of the Wegener's type involving the breast are described. In each, the presumed diagnosis was localized or metastatic carcinoma. The breast lesion and other manifestations of Wegener's granulomatosis developed concomitantly in one patient, and the breast lesion appeared several months before classic pulmonary symptoms in another. In the third patient, not only were her upper and lower airway symptoms explained only in retrospect, but even the significance of the breast biopsy findings was clarified only after other aspects of Wegener's granulomatosis developed. All patients ultimately demonstrated a good response to corticosteroids and cyclophosphamide therapy. Wegener's granulomatosis is a rare lesion affecting the breast but should nonetheless be considered in the evaluation of any breast mass.

Isolated atlantoaxial subluxation as the presenting manifestation of inflammatory bowel disease.

A previously healthy 21-year-old black woman is described in whom erosive cervical spine disease with C1-C2 subluxation spontaneously developed. Various investigations led to the discovery of Crohn's disease, a heretofore unreported association. Thus, clinically silent or undiagnosed inflammatory bowel disease should be considered in the cause of atlantoaxial subluxation.

Defective release of tissue plasminogen activator in systemic and cutaneous vasculitis.

The fibrinolytic system in a group of 23 patients with vasculitis and 10 patients with the cutaneous vasculitis atrophie blanche were studied. These patients were found to have markedly suppressed release of vascular tissue plasminogen activator (t-PA) stores whether the disease was active or in remission. The control group had releasable t-PA levels of 0.70 +/- 0.10 IU/ml of plasma. Levels of releasable t-PA in the patient population were 0.09 +/- 0.03 IU/ml for those with active vasculitis (p less than 0.0001 compared with the control group by the Student t test), 0.23 +/- 0.12 IU/ml for those with inactive vasculitis (p less than 0.001), and 0.03 +/- 0.01 IU/ml for those with atrophie blanche (p less than 0.0001). It is concluded that there is a generalized defect in plasminogen activator in a variety of vasculitides. Such a defect may contribute to the pathogenesis of lesions as well as the thromboembolic disease that may be observed in these patients.

Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis.

PURPOSE: Beginning in the 1980s, methotrexate has been used successfully to treat rheumatoid arthritis. The magnitude and severity of short- and long-term methotrexate toxicity, however, have not been adequately investigated. Our study was performed to determine the prevalence of hepatotoxicity in patients with rheumatoid arthritis receiving long-term methotrexate therapy. PATIENTS AND METHODS: We conducted a retrospective, computer-assisted review of all Duke University Medical Center patients undergoing liver biopsy for methotrexate monitoring from January 1979 to January 1988. A total of 538 biopsies were performed in 399 patients, 259 of whom had inflammatory arthritis (210 with rheumatoid arthritis, 47 with psoriatic arthritis, and two with seronegative spondyloarthropathy). RESULTS: No evidence of cirrhosis was defined in the cohort with rheumatoid arthritis; however, six patients with rheumatoid arthritis had histologic changes of fibrotic liver disease (prevalence of 2.9 percent in the group with rheumatoid arthritis) while taking methotrexate. Five of the six patients were obese and three had glucose intolerance or overt diabetes mellitus, and one person admitted to alcohol usage. Only one patient with fibrotic liver disease had elevated liver function test results, and no person showed a declining serum albumin level at the time of biopsy. Sixty-one patients with rheumatoid arthritis underwent multiple samplings (44 with two, 13 with three, and four with four biopsies). Fourteen of these patients showed progressive hepatic disease, whereas four patients improved. CONCLUSION: Although the prevalence of methotrexate hepatotoxicity in this large cohort of patients with rheumatoid arthritis was low, a small but definite risk of hepatic fibrosis, not predictable by laboratory screening, still exists.

Trazodone-related exercise-induced nonsustained ventricular tachycardia.

A 79-year-old woman in the course of a syncope evaluation is shown to have a trazodone-related cardiac arrhythmia confirmed by drug rechallenge. This nontricyclic antidepressant should be considered as potentially arrhythmogenic despite its generally favorable cardiovascular profile.

Retroperitoneal fibrosis. A true connective tissue disease.

Retroperitoneal fibrosis, a disease that can occur at any age, is characterized by a periaortic fibrous mass that often surrounds the ureters, leading to ureteral obstruction. Patients who present with this disease may complain of flank pain and acute renal failure. There is a high correlation with atherosclerotic disease of the aorta, although the pathogenesis of this disease remains unknown. Although recommendations for therapy remain empiric, prednisone seems to be efficacious in treatment; tamoxifen also may be effective. Retroperitoneal fibrosis usually does not lead to long-term morbidity or affect survival.

Neuroradiologic findings in polyarteritis nodosa.

PURPOSE: To demonstrate the neuroradiologic findings in patients with polyarteritis nodosa. METHODS: A review of hospital records for a 10-year period revealed 50 patients with a discharge diagnosis of polyarteritis nodosa. Thirteen patients had undergone neuroimaging, and abnormal findings were found in 5 cases; these were the subjects of this study. RESULTS: All 5 patients had abnormal findings on CT scans, 3 had abnormal findings on MR images, and 1 had an abnormal finding on a cerebral angiogram. All patients had cerebral cortical or subcortical infarctions, and 1 also had small infarctions within the brain stem and cerebellum. One patient had cerebral angiographic findings of arteritis. The diagnosis of arteritis was considered probable or possible in 3 other patients. Three patients had echocardiographic evidence of concentric hypertrophy and a hypocontractile left ventricle resulting from polyarteritis nodosa-related hypertension. Cardiogenic embolism was considered the likely cause in 1 patient. CONCLUSION: Small peripheral cerebral infarctions, consistent with an arteritis involving medium-sized and small arteries, were the most common finding. However, cardiogenic embolism should also be considered as a possible cause of cerebral infarction in patients with polyarteritis nodosa who have left ventricular dysfunction.