Faculty Bibliography

Brain operation is profoundly rhythmic. Oscillations of neural excitability shape sensory, motor, and cognitive processes. Intrinsic oscillations also entrain to external rhythms, allowing the brain to optimize the processing of predictable events such as speech. Moreover, selective attention to a particular rhythm in a complex environment entails entrainment of neural oscillations to its temporal structure. Entrainment appears to form one of the core mechanisms of selective attention, which is likely to be relevant to certain psychiatric disorders. Deficient entrainment has been found in schizophrenia and dyslexia and mounting evidence also suggests that it may be abnormal in attention-deficit/hyperactivity disorder (ADHD). Accordingly, we suggest that studying entrainment in selective-attention paradigms is likely to reveal mechanisms underlying deficits across multiple disorders.

In the accompanying Annual Research Review, Horga and colleagues provide a comprehensive overview of the current limitations of magnetic resonance imaging (MRI) of developmental psychopathologies focusing particularly on experimental design. Horga et al. are unsparing in their assessment of the problems that plague current clinical neuroimaging studies. We will not reiterate the long list of deficiencies in the imaging literature, which persist despite its impressive volume (PubMed lists more than 135,000 papers with the terms 'magnetic resonance imaging' and 'brain'). Rather, in this Commentary, while we agree with Horga et al. that neuroimaging approaches merely represent one more types of tool, we look at where this leave us and the prospects (by attending to the lessons thoughtfully laid out by Horga and colleagues on how to place research design at the forefront in clinical neuroimaging) of better times ahead for our understanding of the pathophysiology of child- and adult-onset developmental psychiatric conditions.

The identification of phenotypic associations in high-dimensional brain connectivity data represents the next frontier in the neuroimaging connectomics era. Exploration of brain-phenotype relationships remains limited by statistical approaches that are computationally intensive, depend on a priori hypotheses, or require stringent correction for multiple comparisons. Here, we propose a computationally efficient, data-driven technique for connectome-wide association studies (CWAS) that provides a comprehensive voxel-wise survey of brain-behavior relationships across the connectome; the approach identifies voxels whose whole-brain connectivity patterns vary significantly with a phenotypic variable. Using resting state fMRI data, we demonstrate the utility of our analytic framework by identifying significant connectivity-phenotype relationships for full-scale IQ and assessing their overlap with existent neuroimaging findings, as synthesized by openly available automated meta-analysis (www.neurosynth.org). The results appeared to be robust to the removal of nuisance covariates (i.e., mean connectivity, global signal, and motion) and varying brain resolution (i.e., voxelwise results are highly similar to results using 800 parcellations). We show that CWAS findings can be used to guide subsequent seed-based correlation analyses. Finally, we demonstrate the applicability of the approach by examining CWAS for three additional datasets, each encompassing a distinct phenotypic variable: neurotypical development, Attention-Deficit/Hyperactivity Disorder diagnostic status, and L-DOPA pharmacological manipulation. For each phenotype, our approach to CWAS identified distinct connectome-wide association profiles, not previously attainable in a single study utilizing traditional univariate approaches. As a computationally efficient, extensible, and scalable method, our CWAS framework can accelerate the discovery of brain-behavior relationships in the connectome.

PURPOSE: To examine thalamic and cortical injuries using fractional amplitude of low-frequency fluctuations (fALFFs) and functional connectivity MRI (fcMRI) based on resting state (RS) and task-related fMRI in patients with mild traumatic brain injury (MTBI). MATERIALS AND METHODS: Twenty-seven patients and 27 age-matched controls were recruited. The 3 Tesla fMRI at RS and finger tapping task were used to assess fALFF and fcMRI patterns. fALFFs were computed with filtering (0.01-0.08 Hz) and scaling after preprocessing. fcMRI was performed using a standard seed-based correlation method, and delayed fcMRI (coherence) in frequency domain were also performed between thalamus and cortex. RESULTS: In comparison with controls, MTBI patients exhibited significantly decreased fALFFs in the thalamus (and frontal/temporal subsegments) and cortical frontal and temporal lobes; as well as decreased thalamo-thalamo and thalamo-frontal/ thalamo-temporal fcMRI at rest based on RS-fMRI (corrected P < 0.05). This thalamic and cortical disruption also existed at task-related condition in patients. CONCLUSION: The decreased fALFFs (i.e., lower neuronal activity) in the thalamus and its segments provide additional evidence of thalamic injury in patients with MTBI. Our findings of fALFFs and fcMRI changes during motor task and resting state may offer insights into the underlying cause and primary location of disrupted thalamo-cortical networks after MTBI. J. Magn. Reson. Imaging 2013. (c) 2013 Wiley Periodicals, Inc.

Data on the relationship between sleep disturbances and refractory epileptic encephalopathies (EEs) are scarce. Our aim was to assess, by means of nocturnal polysomnography, if children with EEs present with objective alterations in sleep organization. Twenty-three children with EEs (12 males; mean age: 8.7+/-1.4years) and 40 healthy controls (22 males; mean age: 8.8+/-1.1years) underwent an overnight full polysomnography (PSG). Relative to controls, children with EEs showed a significant reduction in all PSG parameters related to sleep duration time in bed (TIB-min p<0.001), total sleep time (TST-min p<0.001), and sleep percentage (SPT-min p<0.001), as well as significantly higher REM latency (FRL-min p<0.001), rate in stage shifting (p=0.005), and number of awakenings/hour (p=0.002). Relative to controls, children with EEs also showed significant differences in respiratory parameters (AHI/h p<0.001, ODI/h p<0.001, SpO2% p<0.001, SpO2 nadir% p<0.001) and a higher rate of periodic limb movements (PLMs% p<0.001). Our findings suggest that sleep evaluation could be considered mandatory in children with refractory epileptic encephalopathy in order to improve the clinical management and the therapeutic strategies.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD) is a new disorder for DSM-5 that is uncommon and frequently co-occurs with other psychiatric disorders. Here, the authors test whether meeting diagnostic criteria for this disorder in childhood predicts adult diagnostic and functional outcomes. METHOD: In a prospective, population-based study, individuals were assessed with structured interviews up to six times in childhood and adolescence (ages 10 to 16 years; 5,336 observations of 1,420 youths) for symptoms of DMDD and three times in young adulthood (ages 19, 21, and 24-26 years; 3,215 observations of 1,273 young adults) for psychiatric and functional outcomes (health, risky/illegal behavior, financial/educational functioning, and social functioning). RESULTS: Young adults with a history of childhood DMDD had elevated rates of anxiety and depression and were more likely to meet criteria for more than one adult disorder relative to comparison subjects with no history of childhood psychiatric disorders (noncases) or individuals meeting criteria for psychiatric disorders other than DMDD in childhood or adolescence (psychiatric comparison subjects). Participants with a history of DMDD were more likely to have adverse health outcomes, be impoverished, have reported police contact, and have low educational attainment as adults compared with either psychiatric or noncase comparison subjects. CONCLUSIONS: The long-term prognosis of children with DMDD is one of pervasive impaired functioning that in many cases is worse than that of other childhood psychiatric disorders.

Purpose Given the metabolic and neurologic side effects of antipsychotics and concerns about the increased risks associated with concomitant use, antipsychotic polypharmacy is a quality concern. This study assessed the operating characteristics of a Medicaid claims-based measure of antipsychotic polypharmacy. Methods A random sample from 10 public mental health clinics and 312 patients met criteria for this study. Medical record extractors were blind to measure status. We examined the prevalence, sensitivity, specificity, and positive predictive value (PPV) in Medicaid claims, testing nine different definitions of antipsychotic polypharmacy, including >14, >60, or >90 days concurrent use of >/=2 antipsychotic agents, each with allowable gaps of up to 0, 14, or 32 days in days' supply of antipsychotic medications. Results All Medicaid claims measure definitions tested had excellent specificity and PPV (>91%). Good to excellent sensitivity was dependent upon use of a 32-day gap allowance, particularly as duration of concurrent antipsychotic use increased. The proposed claims-based measure (90-day concurrent use of >/=2 or more antipsychotics, allowing for a 32-day gap) had excellent specificity (99.1%, 95%CI: 98.2-99.6) and PPV (90.9%, 95%CI: 83.1-95.7) with good sensitivity (79.4%, 95%CI: 70.4-86.6). The overall level of concordance between claims and medical record-based categorization of antipsychotic polypharmacy was high (96.4%, n = 301/312 clients, Cohen's K = 84.7, 95%CI: 75.9-93.5). Discrepant cases were reviewed, and implications are discussed. Conclusions Administrative claims data can be used to construct valid measures of antipsychotic polypharmacy

Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypoactivity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (>P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

The present study was conducted to better understand the influence of the child-perpetrator relationship on responses to child sexual and physical trauma for a relatively large, ethnically diverse sample of children and youth presenting for clinical evaluation and treatment at child mental health centers across the United States. This referred sample includes 2,133 youth with sexual or physical trauma as their primary treatment focus. Analyses were conducted to ascertain whether outcomes were dependent on the perpetrator's status as a caregiver vs. non-caregiver. Outcome measures included psychiatric symptom and behavior problem rating scales. For sexual trauma, victimization by a non-caregiver was associated with higher posttraumatic stress, internalizing and externalizing behavior problems, depression, and dissociation compared to youth victimized by a caregiver. For physical trauma, victimization by a non-caregiver was also associated with higher posttraumatic symptoms and internalizing behavior problems. The total number of trauma types experienced and age of physical or sexual trauma onset also predicted several outcomes for both groups, although in disparate ways. These findings are consistent with other recent studies demonstrating that perpetration of abuse by caregivers results in fewer symptoms and problems than abuse perpetrated by a non-caregiving relative. Thus, clinicians should not make a priori assumptions that children and adolescents who are traumatized by a parent/caregiver would have more severe symptoms than youth who are traumatized by a non-caregiver. Further exploration of the role of the perpetrator and other trauma characteristics associated with the perpetrator role is needed to advance our understanding of these findings and their implications for clinical practice.