A longitudinal study examining three RDoC constructs in adolescents with non-suicidal self-injury
Kathryn Cullen, MD (Department of Psychiatry)
Bonnie Klimes-Dougan, PhD (Department of Psychology), Kelvin Lim, MD (Department of Psychiatry), Karina Quevedo, PhD (Department of Psychiatry), Katie Thomas, PhD (Institute of Child Development)
Non-Suicidal Self Injury (NSSI) is a common clinical problem that cuts across many different psychiatric diagnoses, leads to severe negative outcomes, and has limited treatment options. Advancement of new interventions for NSSI is hindered by a lack of knowledge about its neural mechanisms. NSSI usually emerges during adolescence, a time period notable for significant developmental changes in brain and behavior. Characterizing the developmental trajectories of key aberrant neural systems would enhance our understanding of the pathophysiology of NSSI. The current study will be instrumental in guiding foundational knowledge necessary for creating targeted early interventions for adolescents with NSSI that are designed to promote healthy neurodevelopment.
A phase I, multicenter, open-label, single-dose, dose ranging study to assess the safety and tolerability of SB-318, a rAAV2/6-based gene transfer in subjects with mucopolysaccharidosis I (MPS I)
Chester B. Whitley PhD, MD (Department of Pediatrics)
Julie Eisengart, PhD (Department of Pediatrics), Bradley S. Miller PhD, MD (Department of Pediatrics)
Current therapies for MPS I include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). HSCT can prevent or reverse most clinical features, and is recommended for those with the severe form of the disease (Hurler syndrome [MPS IH]). However, the reported mortality rate after HSCT is 15%, and the survival rate with successful engraftment is 56%. Patients with the attenuated forms of the disease (Hurler-Scheie syndrome [MPS IHS], Scheie syndrome [MPS IS]) are treated with ERT using laronidase (recombinant human α-L-iduronidase; Aldurazyme). Laronidase has been shown to improve pulmonary function, hepatosplenomegaly, and exercise capacity. However limitations of ERT include the need for life-long treatment; development of neutralizing antibodies; inability to cross the blood brain barrier; continued cardiac, orthopedic, and ocular complications; and the inconvenience of weekly intravenous (IV) infusions.
The current proposed study uses ZFN gene-specific targeted insertion of a/6 hIDUA transgene into the liver albumin genome locus to provide long-term production of hIDUA in patients with the attenuated forms of MPS I.The objective and rationale for the proposed SB-318 investigational therapy is to remove or decrease the need for enzyme replacement therapy by in vivo genome editing.
A phase II multi-center, randomized, doubleblind, 24-week, 3-ARM, parallel group, placebo-controlled study to investigate the efficacy and safety of RO5285119 in children and adolescents Age 5-17 with autism spectrum disorder (ASD)
Suma Jacob, MD, PhD (Department of Psychiatry)
Bradley Miller, MD, PhD (Department of Pediatrics), Rebekah Hudock, PhD (Department of Pediatrics)
To date, few studies have investigated the effect of pharmacological treatments on the social and communication deficits in ASD and no agent has received marketing approval for treating these core symptoms. Currently in the US, the only two approved medications for ASD are the atypical antipsychotics risperidone and aripiprazole, which only target irritability associated with ASD, but not core symptoms. In summary, there is no pharmacological treatment available for the social and communication deficits in individuals with ASD and as a consequence there is a high unmet medical need for effective pharmacological therapies in the treatment of core symptoms in ASD. The V1a receptor has been shown to modulate key social behaviors in both human and animal studies. Chronic administration of RO5285119 has been shown to normalize the social behavior and cognitive impairments induced in rats by prenatal valproate (VPA) exposure, an animal model that reflects some of the behavioral changes seen in ASD patients. Also, in the CNTNAP2 KO genetic mouse model of autism, V1a antagonism has been shown to rescue social impairment and repetitive behavior. In conclusion, a V1a antagonist may provide a novel and first approach to treat the core social and communication deficits in ASD.
Autobiographical Memory and Social Problem Solving in Children and Adolescents
Kathleen Thomas, PhD (Institute of Child Development)
Evren Guler, PhD (Augsburg University)
The ability to remember our personal past (autobiographical memory) is fundamental to our sense of self, our personality, as well as daily functioning in the world. Autobiographical memory is thought to serve multiple functions, one of which is planning for future behaviors and directing future goals. For instance, the ability to solve a current problem will likely be enhanced if one can recall a specific past event that is relevant to the current situation. Several studies have shown that autobiographical memory specificity predicts social problem solving in adults. To date, no studies have addressed whether individual differences in autobiographical memory recall relate to variation in problem-solving in childhood and adolescence. Given that both autobiographical memory specificity and problem solving improve with age, it is important to examine whether these two constructs are related in children and adolescents ages 8-17 years.
Emotion regulation in the transition to adolescence
Shreya Lakhan-Pal, Graduate Student (Institute of Child Development)
Kathleen Thomas, PhD (Institute of Child Development)
The capacity to regulate one’s emotions is a critical skill that develops into adulthood. Adolescence is a period of emotional vulnerability and hypersensitivity, and is marked by a rise in the onset of affective disorders like depression and anxiety. Problems with emotion regulation (ER) are implicated in most forms of psychopathology and in decreased socioemotional health, suggesting that successful ER may be a key protective factor during adolescence. Despite its significance in psychopathology and emotional development, little is known about changes in ER in this time.
While social regulation plays an important role throughout the lifespan, evidence suggests that it becomes less effective during adolescence. Social structures and expectations are in dramatic flux, and emotions are more volatile. During stressful situations, neither parent nor friend presence effectively regulates stress hormones or emotion-related neural activity,and neural networks for self-regulation are still developing. Thus, it seems likely that there is a period of emotional vulnerability when social regulation wanes while self-regulation is still maturing. In the proposed study, I aim to address this gap by jointly examining social and self-regulation efficacy during the transition to adolescence, and by determining how the two are associated with caregiver emotional styles.
Microstructural and functional MRI signatures of brain alterations in patients with mucopolysaccharidosis
Igor Nestrasil, MD, PhD (Department of Pediatrics)
Julie Eisengart, Phd, LP (Department of Pediatrics)
We intend to employ a non-invasive technique using brain magnetic resonance imaging (MRI) along with analysis of microstructural and functional MRI signatures of these regions to measure and determine the alterations and their impact on clinical variability in mucopolysaccharidosis (MPS) patients. The study aims to identify the neuronal and functional signatures in MPS patients who have been scanned longitudinally. To accomplish this aim, we have established MRI parameters for detection of abnormalities in myelin content, microstructural integrity, and functional connectivity in the brain of MPS patients. The study also aims to determine the role of myelin abnormalities in cognitive deterioration in MPS subjects by relating comprehensive neurocognitive assessments to their respective MRI outcomes.
Mindful breathing and neuromodulation for depression in young people
Kathryn Cullen, MD (Department of Psychiatry)
Bonnie Klimes-Dougan, PhD (Department of Psychology), Kelvin Lim, MD (Department of Psychiatry)
Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that can modulate neural activity. If paired with Mindful breating training (MBT), tDCS may be able to enhance learning and neural changes associated with MBT. This study will test the efficacy of a novel treatment comprised of MBT and tDCS in adolescent depression. We propose that for patients with depression, where the core feature is persistent negative mood, a training task that engages the DLPFC’s role in regulating emotion may optimally reduce symptoms of depression. Mindful breathing training may be a suitable task to down-regulate negative affect and prime the fronto-limbic circuit. Further, this work will advance our understanding the synergistic effects of combining MBT with tDCS to target the connections between the DLPFC with the default mode network (DMN) and limbic regions. If successful, this study will aid in the development of novel treatments for adolescent depression and improve the ability of neuromodulation to treat depression.
Neurobehavioral mechanisms in tic suppression
Christine Conelea, PhD (Department of Psychiatry)
Kathryn Cullen, MD (Department of Psychiatry), Kelvin Lim, MD (Department of Psychiatry)
The overall research objective of this project is to examine neurobehavioral mechanisms underlying tic suppression using an innovative methodology that integrates repetitive transcranial magnetic stimulation (rTMS) with an established behavioral tic suppression paradigm. TMS is a non-invasive procedure that temporarily increases or decreases cortical activity, which allows researchers to make inferences about the neurobiological underpinnings of a disorder. TMS has been used to examine the pathophysiology of tics by targeting the motor cortex node of the CSTC, which is involved in voluntary suppression of movement (primary motor cortex, M1) and involuntary urges to move (supplementary motor cortex, SMA). This work has primarily compared M1 and SMA functioning across discrete diagnostic categories (e.g., Tourette Syndrome (TS) vs. controls; TS vs. TS+ADHD) but has yet to focus on the relationship between motor cortex functioning and tics themselves. Direct examination of tics and urges after rTMS can be accomplished using an established behavioral paradigm developed to study the effects of context on tic suppression. The proposed study will examine the effect of 1hz active versus sham rTMS over SMA on tic frequency, suppressability, and urges in youth with chronic tics. Research linking this behavioral tic suppression paradigm with targeted examination of SMA activation will help clarify the neurobehavioral mechanisms underlying tic suppression.
Neurodevelopmental effects of fetal alcohol exposure (CIFASD)
Jeff Wozniak, Ph.D., L.P. (Department of Psychiatry)
Bryon Mueller, Ph.D. (Psychiatry), Christopher Boys, Ph.D. (Department of Pediatrics), Kelvin Lim, M.D. (Department of Psychiatry)
The long-term aims of this research are to understand the neurobiological abnormalities that underlie cognitive and behavioral deficits in children with prenatal alcohol exposure. Prior research has clearly demonstrated that children with Fetal Alcohol Syndrome (FAS) have characteristic abnormalities in both the structure and function of their brains. Individuals with FAS have lower intellectual functioning, attention deficits, problems with memory/learning, and difficulties with organization/planning. Much less is known about brain structure and function in children who have a less severe diagnosis within the category of Fetal Alcohol Spectrum Disorder (FASD). This is the diagnostic term applied to those who have been exposed to alcohol prenatally and show some cognitive deficits but do not show all of the classic physical features of FAS (such as delayed growth and unusual facial features). We will use Magnetic Resonance Imaging (MRI) and neurocognitive tests to assess brain abnormalities in children with FASD compared to control participants.
Neuromodulation augmented cognitive remediation to improve executive dysfunction in fetal alcohol spectrum disorder
Jeffrey R. Wozniak, Ph.D., L.P. (Department of Psychiatry)
Christopher J. Boys, Ph.D. (Department of Pediatrics), Kelvin Lim, MD (Department of Psychiatry)
Prenatal alcohol exposure (PAE) has profound detrimental effects on brain development and, as a result, has permanent consequences for cognition, learning, and behavior. Individuals with Fetal Alcohol Spectrum Disorders (FASD) commonly have a range of neurocognitive impairments that directly lead to practical problems with learning, attention, working memory, task planning/execution, and decision making, among other areas of functioning. Despite the profound public health burden posed by FASD, there have been very few treatment studies of any sort in this population. Our group conducted the first randomized controlled trials of the nutrient choline as a neurodevelopmental intervention in 2-5 year old children with FASD, in which we demonstrated effects on sequential memory. For older children, a very different neurodevelopmental target is needed, and for this we have narrowed our focus to “plasticity” (the brain’s ability to adapt). We propose to conduct a novel pilot study to examine the effects of cognitive remediation training augmented with tDCS in children and adolescents with FASD. Functional magnetic resonance imaging will be collected to provide preliminary data of brain circuitry changes created by this intervention.