Faculty Bibliography

Congenital insensitivity to pain with anhidrosis (CIPA, also known as hereditary sensory and autonomic neuropathy type IV) is a rare autosomal recessive disorder caused by mutations in the gene encoding for neurotrophic tyrosine kinase receptor type 1, a receptor for nerve growth factor (NTRK1-NGF). We recently described that patients with CIPA have very low or undetectable circulating norepinephrine levels. Since these mutations severely deplete the development of noradrenergic neurons in the periphery, they presumably also affect those in the central nervous system. Patients with CIPA have low IQ and behavioral problems including hyperactivity and reckless impulsivity, likely the result of a central deficiency in norepinephrine. We explored whether treatment with droxidopa, a synthetic norepinephrine precursor, which crosses the blood brain barrier, could improve behavioral features in a patient with CIPA. Our patient was a 29-year-old woman with a classic phenotype and molecular confirmation of a mutation in the NTRK1 gene (c360- 2A >C pathogenic variant). She had symptoms of attention deficit and hyperactivity and scored highly on the adult ADHD self-report scales (Scores Part A: 4/6 and Part B: 9/12). She had high scores in the attentional (17 and 4), motor (21 and 10), and planning (21 and 17) domains of Barratt impulsiveness scale. NICHQ Vanderbilt assessment scale also indicated attention deficits and hyperactivity. After two months treatment with droxidopa (at 400 mg/day), attention and hyperactivity scales scores decreased to the normal range (Scores Part A: 3/6 and Part B: 4/12). Impulsiveness scores assessed by Barratt impulsiveness scales also improved (attentional scores 15 and 11, motor scores 19 and 9 and planning scores 20 and 9). This case report suggests that behavioral deficits might be reversed in patients with CIPA by norepinephrine replenishment therapy. Clinical studies to evaluate the usefulness of droxidopa to treat behavioral problems in CIPA patients are warranted

Uncertainty, which is ubiquitous in decision-making, can be fractionated into known probabilities (risk) and unknown probabilities (ambiguity). Although research has illustrated that individuals more often avoid decisions associated with ambiguity compared to risk, it remains unclear why ambiguity is perceived as more aversive. Here we examine the role of arousal in shaping the representation of value and subsequent choice under risky and ambiguous decisions. To investigate the relationship between arousal and decisions of uncertainty, we measure skin conductance response-a quantifiable measure reflecting sympathetic nervous system arousal-during choices to gamble under risk and ambiguity. To quantify the discrete influences of risk and ambiguity sensitivity and the subjective value of each option under consideration, we model fluctuating uncertainty, as well as the amount of money that can be gained by taking the gamble. Results reveal that although arousal tracks the subjective value of a lottery regardless of uncertainty type, arousal differentially contributes to the computation of value-that is, choice-depending on whether the uncertainty is risky or ambiguous: Enhanced arousal adaptively decreases risk-taking only when the lottery is highly risky but increases risk-taking when the probability of winning is ambiguous (even after controlling for subjective value). Together, this suggests that the role of arousal during decisions of uncertainty is modulatory and highly dependent on the context in which the decision is framed. (PsycINFO Database Record

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.Molecular Psychiatry advance online publication, 24 November 2015; doi:10.1038/mp.2015.172.

Objectives: Organizational Skills Training (OST), is a 10-week psychosocial intervention found effective in improving organizational, time management, and planning (OTMP) skills in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Little is known about the feasibility of identifying brain markers for treatment response. Using resting state fMRI (R-fMRI), we aimed to examine neuronal correlates of post-treatment change as a first step toward larger controlled studies of objective predictors of treatment response. Methods: We examined pre- and post-OST R-fMRI data of 15 children (12 males; mean age: 9+/-1 year) with ADHD and significant impairments in OTMP skills indexed by total scores on Children's Organizational Skills Scales-Parent (COSS-P) or Teacher (COSS-T). Our primary outcome measure was the change in COSS-P scores. As secondary summary outcome measure, we used prepost Z-score differences averaged across COSS-T, Homework Problems Checklist, Academic Progress Report and Academic Performance Rating scales. We selected a priori the intrinsic functional connectivity (iFC) of the dorsal anterior cingulate cortex (dACC), based on its role on cognitive control. Multivariate distance matrix regression (MDMR) analysis additionally allowed for whole-brain explorations. Follow-up iFC analyses were conducted on regions with significant within-subject post-OST differences by MDMR analysis. Results: COSS-P decreased significantly (t=7.1, p< 0.0001). In a cluster involving striatum bilaterally, dACC iFC decreased post-OST; these decreases were positively correlated with COSS-P improvements (r=.34, NS) and to improvements in the summary outcome (r=.63; p<0.03). MDMR analyses revealed iFC changes in the right medial and lateral precentral cortex. Followup seed-based iFC analyses of this region showed significant decreases in cortico-striatal iFC post-OST. Conclusions: Results support the feasibility of identifying changes in brain iFC after OST. Two distinct analysis converged on decreased corticosubcortical iFC post-treatment which related to change in clinical measures. As decreases in striato-cortical iFC characterize typical development, results suggest regionally-specific enhanced maturational effects of OST

Objectives: The goals of this study are to describe long-term clinical and functional outcomes in the New York Study of hyperactive children who were followed prospectively for 33 years and identify possible predictors that influence these outcomes. Methods: White hyperactive boys (N = 207 probands) were recruited in childhood and followed in adolescence (mean age 18 years), early adulthood (mean age 25 years), and mid-adulthood (mean age 41 years). In late adolescence, 178 comparison participants were recruited. At the final followup in mid-adulthood, a total of 135 probands and 136 comparison participants (65.2 and 76.4 percent of original cohort, respectively) were assessed. Outcome measures included occupational, economic, and educational attainment and marital history, occupational and social functioning, ongoing and lifetime psychiatric disorders, hospitalizations, obesity, risk-taking behaviors, and criminal behaviors. Results: Compared with peers without ADHD, probands showed greater persistence of ADHD, along with greater prevalence of CD/antisocial personality disorder (APD) and SUD in late adolescence. These dysfunctions continued into early adulthood, even when ADHD remitted for the majority of the sample group, and were associated with deficits in educational and occupational attainment, leading to a relative economic disadvantage. Furthermore, the disproportionally high rate of CD/APD and SUD in probands versus comparison participants translated to significantly higher rates of criminality, risk-taking behavior, and risk-related medical outcomes in adulthood. Probands also showed elevated obesity rates in relation to comparison participants but no differences in mood or anxiety disorders. Conclusions: There is heterogeneity in the clinical and functional outcomes of children with ADHD. This study's findings show that childhood ADHD does not preclude adequate functioning in various life domains. However, it does predispose to maladjustment in adolescence and adulthood in a subset of these children, particularly those who develop CD/APD, an important predictor of long-term outcome

The prodrug droxidopa increases blood pressure (BP) in patients with neurogenic orthostatic hypotension. The BP profile of droxidopa in neurogenic orthostatic hypotension patients (n = 18) was investigated using ambulatory BP monitoring. Following dose optimization and a washout period, 24-hour "off-drug" data were collected. "On-drug" assessment was conducted after 4-5 weeks of droxidopa treatment (mean dose, 444 mg, three times daily). Ambulatory monitoring off drug revealed that 90% of patients already had abnormalities in the circadian BP profile and did not meet criteria for normal nocturnal BP dipping. On treatment, both overall mean 24-hour systolic and diastolic BPs were higher compared to off drug (137/81 mm Hg vs. 129/76 mm Hg; P = .017/.002). Mean daytime systolic BP was significantly higher with droxidopa (8.4 +/- 3.1 mm Hg; P = .014). Although nocturnal BP was not significantly higher on droxidopa versus off treatment (P = .122), increases in nocturnal (supine) BP >/=10 mm Hg were observed in four cases (22%). Severe supine systolic hypertensive readings at night (>200 mm Hg) were captured in one case and only while on treatment. These data demonstrate that ambulatory BP monitoring is useful to evaluate the circadian BP profile after initiating treatment with a pressor agent.

Deposition of radiofrequency (RF) energy can be quantified via electric field or temperature change measurements. Magnetic resonance imaging has been used as a tool to measure three dimensional small temperature changes associated with RF radiation exposure. When duration of RF exposure is long, conversion from temperature change to specific absorption rate (SAR) is nontrivial due to prominent heat-diffusion and conduction effects. In this work, we demonstrated a method for calculation of SAR via an inversion of the heat equation including heat-diffusion and conduction effects. This method utilizes high-resolution three dimensional magnetic resonance temperature images and measured thermal properties of the phantom to achieve accurate calculation of SAR. Accuracy of the proposed method was analyzed with respect to operating frequency of a dipole antenna and parameters used in heat equation inversion. Bioelectromagnetics. 2016;9999:1-11. (c) 2016 Wiley Periodicals, Inc.

Systematic genetic access to GABAergic cell types will facilitate studying the function and development of inhibitory circuitry. However, single gene-driven recombinase lines mark relatively broad and heterogeneous cell populations. Although intersectional approaches improve precision, it remains unclear whether they can capture cell types defined by multiple features. Here we demonstrate that combinatorial genetic and viral approaches target restricted GABAergic subpopulations and cell types characterized by distinct laminar location, morphology, axonal projection, and electrophysiological properties. Intersectional embryonic transcription factor drivers allow finer fate mapping of progenitor pools that give rise to distinct GABAergic populations, including laminar cohorts. Conversion of progenitor fate restriction signals to constitutive recombinase expression enables viral targeting of cell types based on their lineage and birth time. Properly designed intersection, subtraction, conversion, and multi-color reporters enhance the precision and versatility of drivers and viral vectors. These strategies and tools will facilitate studying GABAergic neurons throughout the mouse brain.

Sharp-wave ripples (SPW-Rs) in the hippocampus are implied in memory consolidation, as shown by observational and interventional experiments. However, the mechanism of their generation remains unclear. Using two-dimensional silicon probe arrays, we investigated the propagation of SPW-Rs across the hippocampal CA1, CA2, and CA3 subregions. Synchronous activation of CA2 ensembles preceded SPW-R-related population activity in CA3 and CA1 regions. Deep CA2 neurons gradually increased their activity prior to ripples and were suppressed during the population bursts of CA3-CA1 neurons (ramping cells). Activity of superficial CA2 cells preceded the activity surge in CA3-CA1 (phasic cells). The trigger role of the CA2 region in SPW-R was more pronounced during waking than sleeping. These results point to the CA2 region as an initiation zone for SPW-Rs.