Semel Institute

Anderson, United States

Semel Institute

Anderson, United States
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Wang G.-Z.,Southwestern Medical Center | Belgard T.G.,Semel Institute | Belgard T.G.,University of Oxford | Mao D.,Advanced Imaging Research Center | And 9 more authors.
Neuron | Year: 2015

The relationship between functional brain activity and gene expression has not been fully explored in the human brain. Here, we identify significant correlations between gene expression in the brain and functional activity by comparing fractional amplitude of low-frequency fluctuations (fALFF) from two independent human fMRI resting-state datasets to regional cortical gene expression from a newly generated RNA-seq dataset and two additional gene expression datasets to obtain robust and reproducible correlations. We find significantly more genes correlated with fALFF than expected by chance and identify specific genes correlated with the imaging signals in multiple expression datasets in the default mode network. Together, these data support a population-level relationship between regional steady-state brain gene expression and resting-state brain activity. © 2015 Elsevier Inc.

Ganz P.A.,University of California at Los Angeles | Kwan L.,University of California at Los Angeles | Castellon S.A.,University of California at Los Angeles | Oppenheim A.,University of California at Los Angeles | And 6 more authors.
Journal of the National Cancer Institute | Year: 2013

BackgroundCognitive complaints are reported frequently after breast cancer treatments. Their association with neuropsychological (NP) test performance is not well-established.MethodsEarly-stage, posttreatment breast cancer patients were enrolled in a prospective, longitudinal, cohort study prior to starting endocrine therapy. Evaluation included an NP test battery and self-report questionnaires assessing symptoms, including cognitive complaints. Multivariable regression models assessed associations among cognitive complaints, mood, treatment exposures, and NP test performance.ResultsOne hundred eighty-nine breast cancer patients, aged 21-65 years, completed the evaluation; 23.3% endorsed higher memory complaints and 19.0% reported higher executive function complaints (>1 SD above the mean for healthy control sample). Regression modeling demonstrated a statistically significant association of higher memory complaints with combined chemotherapy and radiation treatments (P =. 01), poorer NP verbal memory performance (P =. 02), and higher depressive symptoms (P <. 001), controlling for age and IQ. For executive functioning complaints, multivariable modeling controlling for age, IQ, and other confounds demonstrated statistically significant associations with better NP visual memory performance (P =. 03) and higher depressive symptoms (P <. 001), whereas combined chemotherapy and radiation treatment (P =. 05) approached statistical significance.ConclusionsAbout one in five post-adjuvant treatment breast cancer patients had elevated memory and/or executive function complaints that were statistically significantly associated with domain-specific NP test performances and depressive symptoms; combined chemotherapy and radiation treatment was also statistically significantly associated with memory complaints. These results and other emerging studies suggest that subjective cognitive complaints in part reflect objective NP performance, although their etiology and biology appear to be multifactorial, motivating further transdisciplinary research. © 2013 The Author.

Andre V.M.,Semel Institute | Cepeda C.,Semel Institute | Fisher Y.E.,Semel Institute | Huynh M.,Semel Institute | And 5 more authors.
Journal of Neuroscience | Year: 2011

There is considerable evidence that alterations in striatal medium-sized spiny neurons (MSSNs) giving rise to the direct (D1 receptorexpressing) and indirect (D2 receptor-expressing) pathways differentially contribute to the phenotype of Huntington's disease (HD). To determine how each subpopulation of MSSN is functionally affected, we examined spontaneous excitatory postsynaptic currents (sEPSCs) and dopamine (DA) modulation in two HD mouse models, the YAC128 and the BACHD (a bacterial-artificial chromosome). These mice also expressed enhanced green fluorescent protein (EGFP) under the control of the promoter for eitherDAD1 or D2 receptors to identify neurons. In early symptomatic YAC128 and BACHD mice, glutamate transmission was increased in both D1 and D2 MSSNs, but in different ways. D1 cells displayed increased sEPSC frequencies and decreased paired-pulse ratios (PPRs) while D2 cells displayed larger evoked glutamate currents but no change in sEPSC frequencies or PPRs. D1 receptor modulation of sEPSCs was absent in D1-YAC128 cells at the early symptomatic stage but was restored by treating the slices with tetrabenazine. In contrast, in fully symptomatic YAC128 mice, glutamate transmission was decreased specifically inD1cells, and D1receptor modulation was normal in D1-YAC128 cells. Behaviorally, early symptomatic mice showed increased stereotypies that were decreased by tetrabenazine treatment. Together, these studies support differential imbalances in glutamate and DA transmission in direct and indirect pathway MSSNs. Stereotypic behavior at an early stage could be explained by increased glutamate activity and DA tone in direct pathway neurons, whereas hypokinesia at later stages could result from reduced input onto these neurons. Copyright © 2011 the authors.

Geschwind D.H.,Semel Institute | State M.W.,University of California at San Francisco
The Lancet Neurology | Year: 2015

Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment. © 2015 Elsevier Ltd.

Chung B.,RAND Corporation | Chung B.,University of California at Los Angeles | Jones L.,Healthy African American Families II | Dixon E.L.,Queenscare Health and Faith Partnership | And 3 more authors.
Journal of Health Care for the Poor and Underserved | Year: 2010

Quality improvement (QI) for depression in primary care can reduce disparities in outcomes. We describe how community-partnered participatory research was used to design Community Partners in Care, a randomized trial of community engagement to activate a multiple-agency network versus support for individual agencies to implement depression QI in underserved communities.

Greco T.,Semel Institute | Greco T.,University of California at Los Angeles | Hovda D.,Semel Institute | Hovda D.,University of California at Los Angeles | And 2 more authors.
Journal of Neurotrauma | Year: 2013

Adolescents are one of the highest groups at risk for sustaining both traumatic brain injury (TBI) and repeat TBI (RTBI). Consequences of endocrine dysfunction following TBI have been routinely explored in adults, but studies in adolescents are limited, and show an incidence rate of endocrine dysfunction in 16-61% in patients, 1-5 years after injury. Similar to in adults, the most commonly affected axis is growth hormone (GH) and insulin-like growth hormone 1 (IGF-1). Despite TBI being the primary cause of morbidity and mortality among the pediatric population, there are currently no experimental studies specifically addressing the occurrence of pituitary dysfunction in adolescents. The present study investigated whether a sham, single injury or four repeat injuries (24 h interval) delivered to adolescent rats resulted in disruption of the GH/IGF-1 axis. Circulating levels of basal GH and IGF-1 were measured at baseline, 24 h, 72 h, 1 week, and 1 month after injury, and vascular permeability of the pituitary gland was quantified via Evans Blue dye extravasation. Changes in weight and length of animals were measured as a potential consequence of GH and IGF-1 disruption. The results from the current study demonstrate that RTBI results in significant acute and chronic decreases in circulation of GH and IGF-1, reduction in weight gain and growth, and an increase in Evans Blue dye extravasation in the pituitary compared with sham and single injury animals. RTBI causes significant disruption of the GH/IGF-1 axis that may ultimately affect normal cognitive and physical development during adolescence. © 2013, Mary Ann Liebert, Inc.

Walwyn W.M.,Semel Institute | Miotto K.A.,University of California at Los Angeles | Evans C.J.,Semel Institute and Brain Research Institute
Drug and Alcohol Dependence | Year: 2010

There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies. © 2010.

Dolezal B.A.,University of California at Los Angeles | Chudzynski J.,Semel Institute | Dickerson D.,Semel Institute | Mooney L.,Semel Institute | And 3 more authors.
Medicine and Science in Sports and Exercise | Year: 2014

PURPOSE: Heart rate variability (HRV) reflects a healthy autonomic nervous system and is increased with physical training. Methamphetamine dependence (MD) causes autonomic dysfunction and diminished HRV. We compared recently abstinent methamphetamine-dependent participants with age-matched, drug-free controls (DF) and also investigated whether HRV can be improved with exercise training in the methamphetamine-dependent participants. METHODS: In 50 participants (MD = 28; DF = 22), resting heart rate (HR; R-R intervals) was recorded over 5 min while seated using a monitor affixed to a chest strap. Previously reported time domain (SDNN, RMSSD, pNN50) and frequency domain (LFnu, HFnu, LF/HF) parameters of HRV were calculated with customized software. MD were randomized to thrice-weekly exercise training (ME = 14) or equal attention without training (MC = 14) over 8 wk. Groups were compared using paired and unpaired t-tests. Statistical significance was set at P ≤ 0.05. RESULTS: Participant characteristics were matched between groups (mean ± SD): age = 33 ± 6 yr; body mass = 82.7 ± 12 kg, body mass index = 26.8 ± 4.1 kg·min. Compared with DF, the MD group had significantly higher resting HR (P < 0.05), LFnu, and LF/HF (P < 0.001) as well as lower SDNN, RMSSD, pNN50, and HFnu (all P < 0.001). At randomization, HRV indices were similar between ME and MC groups. However, after training, the ME group significantly (all P < 0.001) increased SDNN (+14.7 ± 2.0 ms, +34%), RMSSD (+19.6 ± 4.2 ms, +63%), pNN50 (+22.6% ± 2.7%, +173%), HFnu (+14.2 ± 1.9, +60%), and decreased HR (-5.2 ± 1.1 bpm, -7%), LFnu (-9.6 ± 1.5, -16%), and LF/HF (-0.7 ± 0.3, -19%). These measures did not change from baseline in the MC group. CONCLUSIONS: HRV, based on several conventional indices, was diminished in recently abstinent, methamphetamine-dependent individuals. Moreover, physical training yielded a marked increase in HRV, representing increased vagal modulation or improved autonomic balance. © 2014 by the American College of Sports Medicine.

Ford C.L.,University of California at Los Angeles | Wallace S.P.,University of California at Los Angeles | Newman P.A.,University of Toronto | Lee S.-J.,University of California at Los Angeles | And 2 more authors.
Gerontologist | Year: 2013

Purpose: One in 4 persons living with HIV/AIDS is an older adult (age 50 or older); unfortunately, older adults are disproportionately diagnosed in late stages of HIV disease. Psychological barriers, including belief in AIDS-related conspiracy theories (e.g., HIV was created to eliminate certain groups) and mistrust in the government, may influence whether adults undergo HIV testing. We examined relationships between these factors and recent HIV testing among at-risk, older adults. Design and Methods: This was a cross-sectional study among older adults enrolled in a large venue-based study. None had a previous diagnosis of HIV/AIDS; all were seeking care at venues with high HIV prevalence. We used multiple logistic regression to estimate the associations between self-reported belief in AIDS-related conspiracy theories, mistrust in the government, and HIV testing performed within the past 12 months. Results: Among the 226 participants, 30% reported belief in AIDS conspiracy theories, 72% reported government mistrust, and 45% reported not undergoing HIV testing within the past 12 months. Belief in conspiracy theories was positively associated with recent HIV testing (adjusted odds ratio [OR] = 1.94, 95% confidence interval [CI] = 1.05- 3.60), whereas mistrust in the government was negatively associated with testing (OR = 0.43, 95% CI = 0.26-0.73). Implications: Psychological barriers are prevalent among at-risk older adults seeking services at venues with high HIV prevalences and may influence HIV testing. Identifying particular sources of misinformation and mistrust would appear useful for appropriate targeting of HIV testing strategies. © The Author 2013. All rights reserved.

Greco T.,Semel Institute | Greco T.,University of California at Los Angeles | Hovda D.A.,Semel Institute | Hovda D.A.,University of California at Los Angeles | And 2 more authors.
Developmental Neurobiology | Year: 2015

Adolescents are at greatest risk for traumatic brain injury (TBI) and repeat TBI (RTBI). TBI-induced hypopituitarism has been documented in both adults and juveniles and despite the necessity of pituitary function for normal physical and brain development, it is still unrecognized and untreated in adolescents following TBI. TBI induced hormonal dysfunction during a critical developmental window has the potential to cause long-term cognitive and behavioral deficits and the topic currently remains unaddressed. The purpose of this study was to determine if four mild TBIs delivered to adolescent male rats disrupts testosterone production and adult behavioral outcomes. Plasma testosterone was quantified from 72 hrs preinjury to 3 months postinjury and pubertal onset, reproductive organ growth, erectile function and reproductive behaviors were assessed at 1 and 2 months postinjury. RTBI resulted in both acute and chronic decreases in testosterone production and delayed onset of puberty. Significant deficits were observed in reproductive organ growth, erectile function and reproductive behaviors in adult rats at both 1 and 2 months postinjury. These data suggest adolescent RTBI-induced hypopituitarism underlies abnormal behavioral changes observed during adulthood. The impact of undiagnosed hypopituitarism following RTBI in adolescence has significance not only for growth and puberty, but also for brain development and neurobehavioral function as adults. © 2014 Wiley Periodicals, Inc.

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