Faculty Bibliography

OBJECTIVE: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the present study examines this issue in adolescents with GAD. METHOD: Resting state fMRI scans were obtained from 15 adolescents with GAD and 20 adolescents without anxiety who were group matched on age, sex, scanner, and intelligence. Functional connectivity of the centromedial, basolateral, and superficial amygdala subdivisions was compared between groups. We also assessed the relationship between amygdala network dysfunction and anxiety severity. RESULTS: Adolescents with GAD exhibited disruptions in amygdala-based intrinsic functional connectivity networks that included regions in medial prefrontal cortex, insula, and cerebellum. Positive correlations between anxiety severity scores and amygdala functional connectivity with insula and superior temporal gyrus were also observed within the GAD group. There was some evidence of greater overlap (less differentiation of connectivity patterns) of the right basolateral and centromedial amygdala networks in the adolescents with, relative to those without, GAD. CONCLUSIONS: These findings suggest that adolescents with GAD manifest alterations in amygdala circuits involved in emotion processing, similar to findings in adults. In addition, disruptions were observed in amygdala-based networks involved in fear processing and the coding of interoceptive states.

Seizures in patients with Alzheimer's disease (AD) have been examined by many investigators over the last several decades, and there are diverse opinions about their potential relevance to AD pathophysiology. Some studies suggest that seizures appear to be a fairly uncommon co-morbidity, whereas other studies report a higher incidence of seizures in patients with AD. It was previously thought that seizures play a minor role in AD pathophysiology because of their low frequency, and also because they may only be noticed during late stages of AD, suggesting that seizures are likely to be a consequence of neurodegeneration rather than a contributing factor. However, clinical reports indicate that seizures can occur early in the emergence of AD symptoms, particularly in familial AD. In this case, seizures may be an integral part of the emerging pathophysiology. This view has been supported by evidence of recurrent spontaneous seizures in transgenic mouse models of AD in which familial AD is simulated. Additional data from transgenic animals suggest that there may be a much closer relationship between seizures and AD than previously considered. There is also evidence that seizures facilitate production of amyloid beta (Abeta) and can cause impairments in cognition and behavior in both animals and humans. However, whether seizures play a role in the early stages of AD pathogenesis is still debated. Therefore, it is timely to review the similarities and differences between AD and epilepsy, as well as data suggesting that seizures may contribute to cognitive and behavioral dysfunction in AD. Here we focus on AD and temporal lobe epilepsy (TLE), a particular type of epilepsy that involves the temporal lobe, a region that influences behavior and is critical to memory. We also consider potential neurobiological mechanisms that support the view that the causes of seizures in TLE may be related to the causes of cognitive dysfunction in AD. We suggest that similar underlying mechanisms may exist for at least some of the aspects of AD that are also found in TLE.

OBJECTIVE: The primary aim of this study was to compare the sleep macroarchitecture of children and adolescents whose mothers have a history of depression with children and adolescents whose mothers do not. METHOD: Polysomnography (PSG) and Holter electroencephalogram (EEG) were used to compare the sleep architecture of 35 children whose mothers had at least one previous depressive episode (19 boys, aged 4-18years, "high-risk" group) and 25 controls (13 males, aged 4-18years, "low-risk" group) whose mothers had never had a depressive episode. The total sleep time, wakefulness after sleep onset (WASO), sleep latency, sleep efficiency, number of awakenings per hour of sleep, percentages of time spent in each sleep stage, rapid eye movement (REM) latency and the depressive symptoms of participants were measured. RESULTS: In children (4-12years old), the high-risk group exhibited significantly more depressive symptoms than controls (P=0.02). However, PSG parameters were not significantly different between high-risk children and controls. In adolescents (13-18years old), the high-risk subjects presented with significantly more depressive symptoms (P=0.003), a significant increase in WASO (P=0.019) and a significant decrease in sleep efficiency compared to controls (P=0.009). CONCLUSION: This study shows that children and adolescents born from mothers with a history of at least one depressive episode had significantly more depressive symptoms than controls. However, only high-risk adolescents presented with concurrent alterations of sleep macroarchitecture.

BACKGROUND: Medication is an important element of therapeutic strategies for ADHD. While medications for ADHD are generally well-tolerated, there are common, although less severe, as well as rare but severe adverse events AEs during treatment with ADHD drugs. The aim of this review is to provide evidence- and expert-based guidance concerning the management of (AEs) with medications for ADHD. METHODS: For ease of use by practitioners and clinicians, the article is organized in a simple question and answer format regarding the prevalence and management of the most common AEs. Answers were based on empirical evidence from studies (preferably meta-analyses or systematic reviews) retrieved in PubMed, Ovid, EMBASE and Web of Knowledge through 30 June 2012. When no empirical evidence was available, expert consensus of the members of the European ADHD Guidelines Group is provided. The evidence-level of the management recommendations was based on the SIGN grading system. RESULTS: The review covers monitoring and management strategies of loss of appetite and growth delay, cardiovascular risks, sleep disturbance, tics, substance misuse/abuse, seizures, suicidal thoughts/behaviours and psychotic symptoms. CONCLUSION: Most AEs during treatment with drugs for ADHD are manageable and most of the times it is not necessary to stop medication, so that patients with ADHD may continue to benefit from the effectiveness of pharmacological treatment.

OBJECTIVE: Youths with disruptive behavior disorders, including conduct disorder and oppositional defiant disorder, show major impairments in reinforcement-based decision making. However, the neural basis of these difficulties remains poorly understood. This partly reflects previous failures to differentiate responses during decision making and feedback processing and to take advantage of computational model-based functional MRI (fMRI). METHOD: Participants were 38 community youths ages 10-18 (20 had disruptive behavior disorders, and 18 were healthy comparison youths). Model-based fMRI was used to assess the computational processes involved in decision making and feedback processing in the ventromedial prefrontal cortex, insula, and caudate. RESULTS: Youths with disruptive behavior disorders showed reduced use of expected value information within the ventromedial prefrontal cortex when choosing to respond and within the anterior insula when choosing not to respond. In addition, they showed reduced responsiveness to positive prediction errors and increased responsiveness to negative prediction errors within the caudate during feedback. CONCLUSIONS: This study is the first to determine impairments in the use of expected value within the ventromedial prefrontal cortex and insula during choice and in prediction error-signaling within the caudate during feedback in youths with disruptive behavior disorders.

Elucidating the neural basis of joint attention in infancy promises to yield important insights into the development of language and social cognition, and directly informs developmental models of autism. We describe a new method for evaluating responding to joint attention performance in infancy that highlights the 9- to 10-month period as a time interval of maximal individual differences. We then demonstrate that fractional anisotropy in the right uncinate fasciculus, a white matter fiber bundle connecting the amygdala to the ventral-medial prefrontal cortex and anterior temporal pole, measured in 6-month-olds predicts individual differences in responding to joint attention at 9 months of age. The white matter microstructure of the right uncinate was not related to receptive language ability at 9 months. These findings suggest that the development of core nonverbal social communication skills in infancy is largely supported by preceding developments within right lateralized frontotemporal brain systems.

The human brain undergoes rapid and dynamic development early in life. Assessment of brain growth patterns relevant to neurological disorders and disease requires a normative population model of growth and variability in order to evaluate deviation from typical development. In this paper, we focus on maturation of brain white matter as shown in diffusion tensor MRI (DT-MRI), measured by fractional anisotropy (FA), mean diffusivity (MD), as well as axial and radial diffusivities (AD, RD). We present a novel methodology to model temporal changes of white matter diffusion from longitudinal DT-MRI data taken at discrete time points. Our proposed framework combines nonlinear modeling of trajectories of individual subjects, population analysis, and testing for regional differences in growth pattern. We first perform deformable mapping of longitudinal DT-MRI of healthy infants imaged at birth, 1 year, and 2 years of age, into a common unbiased atlas. An existing template of labeled white matter regions is registered to this atlas to define anatomical regions of interest. Diffusivity properties of these regions, presented over time, serve as input to the longitudinal characterization of changes. We use non-linear mixed effect (NLME) modeling where temporal change is described by the Gompertz function. The Gompertz growth function uses intuitive parameters related to delay, rate of change, and expected asymptotic value; all descriptive measures which can answer clinical questions related to quantitative analysis of growth patterns. Results suggest that our proposed framework provides descriptive and quantitative information on growth trajectories that can be interpreted by clinicians using natural language terms that describe growth. Statistical analysis of regional differences between anatomical regions which are known to mature differently demonstrates the potential of the proposed method for quantitative assessment of brain growth and differences thereof. This will eventually lead to a prediction of white matter diffusion properties and associated cognitive development at later stages given imaging data at early stages.

Re-exposure to drug-associated cues causes significant drug craving in recovering addicts, which may precipitate relapse. In animal models of craving, drug-seeking responses for contingent delivery of drug-associated cues sensitizes or "incubates" across drug withdrawal. To date there is limited evidence supporting an incubation effect for behaviors mediated by non-contingent presentation of drug-associated cues. Here we used a model of cue-induced conditioned activity to determine if the conditioned locomotor response to a non-contingent presentation of a drug-associated cue sensitizes across drug withdrawal. In addition, because cue-induced drug-seeking responses are mediated by the rostral basolateral amygdala (BLA), we investigated whether this structure is critical for the expression of cue-induced conditioned activity. A conditioned association between cocaine (15mg/kg) and a compound discrete cue (flashing bicycle light+a metronome) was established over 12 conditioning sessions in male Sprague-Dawley rats. In experiment 1, cue-induced conditioned activity was assessed on 3 occasions: 3, 14 and 28days following the final drug-cue conditioning session. Cocaine-conditioned rats demonstrated reliable cue-induced conditioned activity across all 3 test sessions, however there was no evidence of an incubation effect. To determine whether repeated testing prevented the observation of an incubation effect, rats in experiment 2 were tested either 3days or 28days following conditioning; again no incubation effect was observed. In experiment 3, either saline or the GABAA receptor agonist muscimol was infused prior to testing. Intra-BLA infusions of muscimol prevented the expression of cue-induced conditioned activity. These data support the role of the rBLA in mediating conditioned responses to drug-associated cues. The failure to observe an incubation effect for cue-induced conditioned activity may point to a fundamental difference in the manner by which contingent and non-contingent presentations of drug-associated cues influence behavior.

OBJECTIVE:  We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. METHODS:  Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low-frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. RESULTS:  The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). CONCLUSIONS:  Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically important imaging biomarker.

With increased interest in the early diagnosis and treatment of children with autism spectrum disorders (ASD), more attention has been called to the motor skills of very young children with ASD. This study describes the gross and fine motor skills of a cross-sectional group of 162 children with ASD between the ages of 12 and 36 months, as well as a subset of 58 children followed longitudinally. Gross motor and fine motor age equivalent scores were obtained for all children. A 'motor difference' variable was calculated for each child's gross and fine motor skills by taking the absolute difference of the children's age equivalent motor score and their respective chronological age. In Study 1 (the cross-sectional analysis), ANCOVA (co-varied for nonverbal problem solving) revealed significant group differences in the gross motor and fine motor age difference variables. Post-hoc analysis revealed that gross motor and fine motor differences became significantly greater with each 6-month period of chronological age. In Study 2, 58 children were measured twice, an average of 12 months apart. Results indicate that the gross motor and fine motor difference scores significantly increased between the first and second measurements. The importance of addressing motor development in early intervention treatments is discussed