Faculty Bibliography

OBJECTIVES:Past research suggests that youth with sex chromosome aneuploidies (SCAs) present with verbal fluency deficits. However, most studies have focused on sex chromosome trisomies. Far less is known about sex chromosome tetrasomies and pentasomies. Thus, the current research sought to characterize verbal fluency performance among youth with sex chromosome trisomies, tetrasomies, and pentasomies by contrasting how performance varies as a function of extra X number and X versus Y status. METHODS:Participants included 79 youth with SCAs and 42 typically developing controls matched on age, maternal education, and racial/ethnic background. Participants completed the phonemic and semantic conditions of a verbal fluency task and an abbreviated intelligence test. RESULTS:Both supernumerary X and Y chromosomes were associated with verbal fluency deficits relative to controls. These impairments increased as a function of the number of extra X chromosomes, and the pattern of impairments on phonemic and semantic fluency differed for those with a supernumerary X versus Y chromosome. Whereas one supernumerary Y chromosome was associated with similar performance across fluency conditions, one supernumerary X chromosome was associated with relatively stronger semantic than phonemic fluency skills. CONCLUSIONS:Verbal fluency skills in youth with supernumerary X and Y chromosomes are impaired relative to controls. However, the degree of impairment varies across groups and task condition. Further research into the cognitive underpinnings of verbal fluency in youth with SCAs may provide insights into their verbal fluency deficits and help guide future treatments. (JINS, 2018, 24, 917-927).

Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in the children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus-key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

OBJECTIVE: Children with NF1 display multiple structural and functional changes in the central nervous system, such as white matter alterations, and a unique profile of neuropsy-chological cognitive abnormalities. Assessment of resting state networks (RSNs) can reveal differences in the functional architecture of the developing brain in response to neurofibromin deficiency resulting from NF1 mutation. Here, we focused on resting-state functional connectivity between the subcortical striatum and cortical networks differentiated as primary (e.g., visual, somatomotor) versus association (e.g., ventral attention, default). MATERIAL-METHODS: Eighteen children with NF1 who had resting-state fMRI scans were group-matched (age, gender and head movement) with 18 typically developing children (TDC) from the ABIDE repository. Coherent slow fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional connectivity of cortical-subcortical structures. Assessment of RSNs was done using a previously established automated clustering algorithm. RESULTS: NF1 children demonstrated abnormal organization of association networks, particularly, deficient long-distance functional connectivity. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered, with NF1 children demonstrating diminished functional connectivity between striatum and the ventral attention network, as well as the posterior cingulate area, which is associated with the default network. By contrast, somatomotor functional connectivity with the striatum was increased. Functional connectivity of the visual network with the striatum did not differ in the NF1 group. CONCLUSION: These findings suggest that, much like in animal studies, the striatum plays a major role in NF1 cognitive pathogenesis. In addition, the "immature" pattern of deficient long distance functional connectivity suggests that NF1-associated myelin abnormalities may also play a significant role in the disrupted formation of RSNs

Statistical learning-extracting regularities in the environment-may underlie complex social behavior. 124 children, 56 with autism and 68 typically developing, ages 2-8 years, completed a novel visual statistical learning task on an iPad. Averaged together, children with autism demonstrated less learning on the task compared to typically developing children. However, multivariate classification analyses characterized individual behavior patterns, and demonstrated a subset of children with autism had similar learning patterns to typically developing children and that subset of children had less severe autism symptoms. Therefore, statistically averaging data resulted in missing critical heterogeneity. Variability in statistical learning may help to understand differences in autism symptoms across individuals and could be used to tailor and inform treatment decisions.

Chronic pain (CP) and opioid use disorder (OUD) remain challenging complex public health concerns. This is an updated review on the relationship between CP and OUD and the use of stepped care models for assessment and management of this vulnerable population. A literature search was conducted from 2008 to the present in PubMed, Embase, and PsycInfo using the terms pain or chronic pain and opioid-related disorders, opiate, methadone, buprenorphine, naltrexone, opioid abuse, opioid misuse, opioid dependen*, heroin addict, heroin abuse, heroin misuse, heroin dependen*, or analgesic opioids, and stepped care, integrated services, multidisciplinary treatment, or reinforcement-based treatment. Evidenced-based data exists on the feasibility, implementation, and efficacy of stepped care models in primary care settings for the management of CP and opioid use. Although these studies did not enroll participants with OUD, they included a sub-set of patients at risk for the development of OUD. There remains a dearth of treatment options for those with comorbid CP and OUD. Future research is needed to explore the aetiology and impact of CP and OUD, and greater emphasis is needed to improve access to comprehensive pain and substance use programmes for high-risk individuals.

PIM (postictal mania) or PIP (postictal psychosis) usually comes on after a single episode or a seizure cluster of generalized tonic-clonic or complex partial secondarily generalized seizures. Patients maintain a lucid interval of clear consciousness which precedes a psychotic episode. The symptoms may include insomnia, hallucinations, delusions, elated expansive mood, euphoria, and distractibility. We present a case of a 62-year-old male with PIP or mania preceding an episode of seizure. In the light of this case report, we illustrate the importance of being vigilant about the psychotic symptoms in a patient with epilepsy in order to minimize the morbidity.

We report on a search for weakly interacting massive particles (WIMPs) using 278.8 days of data collected with the XENON1T experiment at LNGS. XENON1T utilizes a liquid xenon time projection chamber with a fiducial mass of (1.30±0.01)  ton, resulting in a 1.0 ton yr exposure. The energy region of interest, [1.4,10.6]  keV_{ee} ([4.9,40.9] keV_{nr}), exhibits an ultralow electron recoil background rate of [82_{-3}^{+5}(syst)±3(stat)]  events/(ton yr keV_{ee}). No significant excess over background is found, and a profile likelihood analysis parametrized in spatial and energy dimensions excludes new parameter space for the WIMP-nucleon spin-independent elastic scatter cross section for WIMP masses above 6  GeV/c^{2}, with a minimum of 4.1×10^{-47}  cm^{2} at 30  GeV/c^{2} and a 90% confidence level.

Valproic acid, first manufactured as an anticonvulsant, is commonly used to treat both neurological and psychiatric conditions. A rare and deadly side effect of this medication is hyperammonemia, presenting as lethargy, confusion, seizure, and, ultimately, coma. In rare circumstances, hyperammonemia can be recurrent and devastating, especially in patients with an underlying N-acetyl glutamate synthase (NAGS) deficiency, as the valproic acid can enhance this enzyme deficiency and inhibit the conversion of ammonia into urea in the liver. For these subtypes of patients, the United States Food and Drug Administration (US FDA) has recently approved carglumic acid, a medication that can act as a scavenger by effectively increasing the levels of NAGS, ultimately enhancing the conversion of ammonia to urea. In our case report, we have mentioned a patient with treatment-resistant bipolar disorder, who presented with elevated ammonia levels secondary to valproic acid treatment. Valproic acid was the only drug that was effective in his case, so we initiated therapy to reduce his elevated ammonia levels. After a thorough evaluation, we found the patient had a genetic NAGS deficiency. Carglumic acid was initiated and proved efficacious in our patient.