Adolescence is a dynamic maturational period associated with profound neuro-developmental changes related to social and emotional functioning.
Adolescence is a dynamic maturational period associated with profound neuro-developmental changes related to social and emotional functioning. In addition, there are significant changes in the social and emotional environment, including increasing autonomy from family and deepening integration with peer groups. As such, studying adolescence brings opportunities to address questions about how neurodevelopment and salient social and emotional experiences interact to shape learning—in particular, how teens learn to manage emotion and behavior in order to pursue personal goals (e.g. peer or romantic affiliations, academic or athletic achievement, etc). At REMEDY, we examine these developmental processes with a focus on how they may help to explain the escalation of problems with managing emotion and behavior in adolescence (e.g. suicide, depression, risky behavior, substance dependence), and the associated 200% rise in morbidity and mortality during this period. We are particularly interested in where and when there may be opportunities to use novel training and learning interventions to positively influence trajectories of social and emotional development.
To address these translational research questions, REMEDY Research projects move between multi-method experimental designs to isolate social and emotional dimensions of interest, to the use of targeted intervention strategies to alter these dimensions in vulnerable youth. We also aim to examine developmental variables (e.g. age, puberty) in longitudinal designs to determine whether there are unique windows of neuro-maturation when certain strategies can maximally impact both short and long term functioning. With a constant eye toward public health impact, we focus efforts on intervention strategies that are grounded in neuroscience and could be used in a community or health services setting.
In the following sections, we outline several areas of ongoing inquiry, including:
Adolescence is characterized by marked changes in emotion, motivation, and many aspects of behavior, which influence—and are influenced by—neural systems of reward. In particular, there is growing interest in a set of changes in reward processing during pubertal maturation, as reflected by heightened emotional, cognitive, and physiological reactivity to cues of reward, that contribute to increased appetitive motivation to explore novel, arousing and rewarding situations. On one hand, these changes confer risks. Greater reward-seeking tendencies can contribute to negative spirals of emotion and behavior including substance abuse and addiction, risky decision-making, and reckless behavior. Alterations in reward processing also may contribute to the increased risk for developing affective disorders in adolescence. On the other hand, these same shifts in reward processing can lead adolescents to healthy versions of exploration and learning, including opportunities for motivational learning that is directed towards increasingly abstract and distal rewards, such as navigating new romantic relationships, or pursuing academic, athletic or artistic goals. When, how and for whom might there be opportunities to leverage this inflection point to positively shape emotional and motivational development?
As a starting point, I have been focused on depressed adolescents for several reasons: 1) low positive affect and altered reward function are central to the pathophysiology of depression (McMakin et al., 2011; Olino et al., In press),** 2) changes in reward systems around puberty appear to contribute to escalating symptoms of depression in adolescence (Morgan, Olino, McMakin, Ryan, & Forbes, In press; Olino et al., 2014), and 3) the symptom dimension of anhedonia (inability to experience pleasure) predicts poor prognosis among treatment resistant depressed adolescents ( McMakin et al., 2012). Directly targeting positive affect and reward-related systems may simultaneously reduce symptoms and improve developmental trajectories of affective functioning. Although the neuro-developmental course of reward system sensitivity diverges in healthy relative to depressed youth during adolescence, there may be a brief window when a small developmental shift toward heightened sensitivity in reward systems could be coaxed by the right positive affective experience to spark positive growth ( McMakin & Dahl, 2013).
One viable target for shaping reward-related neural systems in depressed adolescents may include training youth to sustain positive affective states in response to rewarding experiences. This hypothesis is based on our prior work in which we demonstrated that a key deficit in the context of depressed mood lies not so much in the ability to experience pleasure, but rather in the ability to enhance and sustain pleasure following a rewarding experience ( McMakin, Santiago, & Shirk, 2009). We became interested in the idea of “savoring” as a regulatory strategy (a mirror process to rumination) that may partially underlie this deficit, and could be amenable to intervention. In a two-stage translational treatment development trial (NIMH F31), we first showed that it was feasible to train dysphoric individuals to savor (via a written disclosure paradigm) and that savoring improved symptoms and positive affect ( McMakin, Siegle, & Shirk, 2011). As part of a single-case study design we then translated this work to a manualized intervention strategy—Positive Affect Stimulation and Sustainment (PASS) module—and showed that it was feasible to train depressed teens to savor their positive experiences.
More recently, we have been placing this work within a framework of developmental affective neuroscience. First, we developed a working conceptual model suggesting that sustaining positive affect via “savoring” may be an essential affective learning strategy—re-experiencing rewards through mental replay and social sharing makes experiences more emotionally and motivationally salient. The result is the formation of more stable mental representations that can motivate future behavior toward things that were previously experienced as personally rewarding. Adolescence may be a key time for this approach given changes in reward sensitivity and motivational learning. Second, we developed a Savoring Task for use in neuroimaging. In a recent exploratory study using this task with adolescents with depression (ages 12-18; n=23), relative to healthy youth (n=25), we found support for reduced connectivity in key reward-related circuits (e.g. nucleus accumbens and medial prefrontal cortex) that we proposed as relevant to sustaining positive affect. A remaining question that we are addressing in the ongoing PASS project is whether we can normalize this aberrant functioning (using these a priori neural regions) through targeted intervention. To this end, we randomize youth with depression (ages 12-16) to 6 sessions of PASS or Cognitive Therapy (CT) strategies. The primary aim is not to show that PASS exceeds CT in reducing symptoms, but rather if there are targeted changes at the level of neural circuitry and behavior. We will examine targeted response in the Savoring Task, and we will also examine whether effects generalize to reward-processing tasks in which we have previously shown aberrant functioning in depressed adolescents (Olino et al., 2011; Olino, et al., 2014). Our goal is to carry this work through as a model for using developmental neuroscience to inform intervention strategies that can probe mechanisms of interest, and complement existing intervention approaches. Once refined, these strategies may be used to answer questions about windows of plasticity in affective systems during dynamic maturational periods. Also, they can serve as building blocks for personalizing interventions to dimensions of functioning and developmental stages (consistent with NIMH RDoC priorities).
The role of sleep in affective development is another area of growing interest to REMEDY for the following reasons: 1) sleep and affective functioning are tightly linked systems with bidirectional influences (Mathyssek, Olino, McMakin, Verhulst, & van Oort, submitted); 2) neural systems underpinning affective and sleep/wake arousal systems both undergo dramatic change and remodeling around the onset of puberty; 3 ) biological and socio-contextual changes (e.g. late night social media, early school start times) in sleep systems lead to chronic sleep loss for as many as 69% of teens in the US (with similar rates across many nations), which can impact socio-affective functioning at the level of brain and behavior in both short and long term ways ( McMakin et al., submitted), and 4) finally, our clinical experience indicates that many youth are quite curious about sleep, and can be readily engaged in intervention. Taken together, this suggests that targeting sleep in youth who are vulnerable to escalating problems with affective health in adolescence (i.e. anxious youth(Silk, Davis, McMakin, Dahl, & Forbes, 2012)) may represent a powerful—yet relatively unexplored—approach to early intervention and prevention (Rofey, McMakin, Shaw, & Dahl, 2013). (Access Dr. McMakin’s discussion of these issues in the first 10 minutes of the following interview: http://www.wpr.org/listen/306581.)
To this end, we recently completed a project, along with Ron Dahl and colleagues, focused on sleep in anxious youth during the transition to puberty (n=163; ages 9-14). This project was part of a center grant focused on neurobehavioral correlates of anxiety treatment response (Child Anxiety Treatment Study [CATS]; PI Neal Ryan). As such, we have access to a broad battery of neurobehavioral measures of socio-affective functioning (e.g. fMRI, event-related potential, ecological momentary assessment, parent-child interaction). We are currently testing features of a model that predicts improved sleep (assessed by actigraphy, diaries, interviews) will result in better socio-affective functioning, as well as more enduring clinical improvements in anxiety (several publications in preparation). A long-term goal of our ongoing longitudinal work is to explore whether improving sleep in early adolescence can help to prevent the development of depression and other adverse health outcomes, and if there is a window of pubertal development when this is most powerful. Notably, this project included the development of a sleep intervention (Sleeping TIGERS) for anxious teens that includes savoring strategies at bed-time to activate positive feelings and self soothing, while counteracting worry and vigilance. We are finding this approach to be highly feasible and clinically useful with this population. Preliminary data have been promising (symposia presentations: McMakin et al., 2013; McMakin et al., 2011), and we are now finalizing primary data analyses for this project to examine how sleep intervention impacts key indices of sleep and anxiety.
Our work with pre-sleep savoring raised deeper mechanistic questions at the interface of sleep and affective functioning. These questions are grounded in our conceptual model that describes savoring as a strategy that can promote emotional learning. Interestingly, a critical function of sleep involves learning. Through a process of neural plasticity, daytime memories are not simply stored, but are consolidated into more stable mental representations (i.e. schema or gist-based) that can motivate future behavior. As a key function of sleep is to selectively consolidate those experiences that are most salient (often emotional) and discard those that are not, this could be one pathway through which negative or positive aspects of emotional experiences shape neurodevelopment in adolescence. Moreover, there may be opportunities to tip this learning process to strengthen positive memories as a strategy to reduce negativity biases common in anxiety (e.g. via pre-sleep savoring, as opposed to ruminating, to re-activate positive emotions and memories to prime selective consolidation during sleep).
To begin to address this framework in an experimental design, REMEDY and colleagues (Ines Wilhelm, Ron Dahl, Reto Huber) were awarded funding (Jacobs Foundation) for pilot work. Our preliminary data suggest that learning during sleep may play a key role in the formation of negative biases in anxious adolescents, and that it may be possible to manipulate these processes during sleep. We are now pursuing additional funding for a much more detailed examination of these questions in a home-based, longitudinal design using mobile polysomnography/qEEG, with a sample size sufficiently large to examine how neural mechanisms of sleep mediate associations between affective responses during encoding (affective reactivity, sustained affective response) and post-sleep memory (and generalization of memory) in youth across a range of anxious symptoms. We also use savoring as an experimental therapeutic probe to examine how pre-sleep emotion and memory priming may impact downstream learning processes during sleep. The broad (and testable) implications of our preliminary data and proposed project are that 1) sleep may play a key role in shaping negative views of the self and world in anxious youth at the start of adolescence, 2) these processes may impact developmental trajectories of affective health (e.g. depression) during the high risk period of adolescence, and 3) developmentally-informed prevention and intervention strategies may carry potential to shape learning during sleep to prevent escalation of affective problems in vulnerable youth.
Data and insights from these complementary projects will continue to refine our conceptual models, and inform our future work. In addition to the described work, we are also involved in two seed projects. The first is an R21 from NHLBI (Culture Beliefs and Practices Impacting Teenage Sleep; PI Fuligni) designed to build the capacity and infrastructure to create a research team and develop a transdisciplinary toolbox of methods to conduct basic behavioral research on the role of cultural beliefs and practices in teenage sleep. Led by Andrew Fuligni, this project is being conducted in collaboration with Adriana Galván, Thomas Weisner, and Kim M. Tsai (neuroscientist) of UCLA, Ronald E. Dahl (pediatrician) of the University of California, Berkeley, and Dana McMakin (psychologist and director of REMEDY). We are very enthusiastic about the current and future opportunities associated with this project. The second project is an R34 (PI: Brent) that incorporates savoring and sleep strategies into a novel treatment to prevent suicidal behavior in hospitalized youth during their transition to outpatient care (Brent, McMakin, Kennard, Goldstein, Mayes, Douaihy, 2013). This project is exciting because moving between experimental manipulations and real-world practice helps REMEDY to maintain translational relevance. Finally, we are eager to collaborate with new colleagues and to be inspired by areas of converging interest. Although we are interested in a range of topics and methods, REMEDY Research will be guided by the question that unites our group: Can experiences—and particularly those provided by training and learning interventions—shape neurodevelopment in adolescence to impact both short and long-term behavior and health?
**References throughout this statement emphasize the work of REMEDY Research group to highlight our program of research. However, there are many areas where a number of important papers have been published—We are happy to provide references to other relevant (and very interesting) papers. Please feel free to contact us with this purpose.
Learn more about our publications.
Drs. McMakin and Silk discuss research on teen depression in the Pittsburgh Post Gazette.
Dr. McMakin discusses sleep and health in adolescence on Wisconsin Public Radio, the Joy Cardin Show.
REMEDY research publication examining anhedonia in depressed teens is highlighted in Brown Univerity’s Child and Adolescent Psychopharmocology Update
REMEDY Research focused on sleep in children and adolescents is featured in the Wall Street Journal
Our research facility is located at the main campus of the University of Pittsburgh.
REMEDY is located in the Department of Psychiatry at the University of Pittsburgh, School of Medicine (main campus in Oakland). We are principally housed within Loeffler Building on the corner of Meyran Avenue and Forbes Avenue. Loeffler Building was designed specifically for research focused on clinical and developmental affective neuroscience research, allowing for an efficient and comfortable research set-up for children and families. Additional laboratory space includes an imaging facility in Presbyterian Hospital, and a sleep laboratory (including 5 bedrooms, and additional rooms for clinical interviewing and testing) in the Neuroscience Clinical Translational Research Center (N-CTRC), which is housed within Western Psychiatric Institute and Clinic. We are affiliated with the Developmental Affective Science Collective http://www.dascpitt.org/
REMEDY shares 3 clinical interviewing or behavioral observation rooms and 2 conference rooms with other Loeffler research groups. A large waiting room includes comfortable seating, as well as child friendly books and activities for families and siblings of participants. The clinical interviewing and observational rooms are equipped with audiovisual recording (mounted digital recorders), and laptops for administration of structured clinical interviews and questionnaires. Adjacent control rooms include computers for delivery of behavioral experiments via E-Prime. All computers utilize the WPIC Office of Academic Computing (OAC) network. The OAC is shared and funded by participating research projects in WPIC. Using the networking infrastructure of UPMC and the University, we share multiple MS-2000 and MS-2003 server platforms. As well, we use one Red Hat Enterprise Linux Server. All servers and workstations utilize archiving via DLT, SDLT, 4mm, 8mm, DVD and/or CD. All servers support, in varying degrees the following utilities: FTP, file server, SQL/Access server database and digital analysis and archiving. The OAC is an integrated part of the campus network with global Internet access behind a secure firewall.
fMRI assessments are conducted at the MR Center. The MR Center is located at Presbyterian Hospital (in Oakland), and is a state-of-the-art facility with space for imaging systems, support laboratories, technical support staff, image processing, and offices. The building housing the scanners is located in walking distance to REMEDY Research group principal location in Loeffler Building, and we have a longstanding relationship with the center and staff. The MR Center houses two 3T Siemens Trio full-body parallel imaging systems equipped with an ultra fast gradient system (Max. amplitude: 40 mT/m, slew rate 400 T/m/s, rise time: 100 us). The instrumentation is designed to handle the high data rates and storage required by fMRI. Computers for stimulus presentation, equipment for acquisition of physiological data, an infrared participant monitoring system, and a computer laboratory for data analysis are all available at the MR Center. The MR Center has maintenance agreements with Siemens that guarantee service whenever daily stability scans fail to meet established quality assurance procedures. Before fMRI assessments participants practice in our motion-training simulator to acclimate to the fMRI environment. The Child Anxiety Treatment Study center grant developed special procedures for helping children to feel comfortable and minimize motion while participating in neuroimaging research.
Our lab-based sleep studies take place in the Neuroscience Clinical and Translational Research Center (N-CTRC). N-CTRC is a clinical research center in the Department of Psychiatry at the University of Pittsburgh, located on the 13th floor of Western Psychiatric Institute and Clinic (WPIC). The N-CTRC is one component of the University of Pittsburgh Clinical and Translational Science Institute (CTSI; RR024153). Sleep physiological studies take place in the N-CTRC, which contains 7,253 sq. ft. of space. This space is divided into five bedrooms and two time isolation apartments, each with its own bathroom, audio/visual monitoring capabilities, TVs, and PCs. Two portable VCR/DVD players are also available. In addition, there is a separate technical/control room, a nurse’s station, treatment room, subject preparation room, and lounge. Three of the bedrooms are equipped with ports which allow for IV administration of medications and blood sampling. All patient rooms are equipped to monitor EEG sleep, EKG, respiration, oxyhemoglobin saturation, periodic limb movements, heart rate and heart rate variability, core body temperature, skin temperature, and mood and performance. This laboratory also has a GE MAC5500 EKG machine, a Pupillometer and Eye-Tracker, and the capability to perform studies requiring radionuclide injection for positron emission tomography (PET). Physiological data processing is conducted in adjacent office space including an electronics laboratory, a computing operations laboratory, a computer server room and adjacent offices. The computer operations laboratory contains 3 HP-UX model 715 UNIX workstations and 7 X-terminal remote UNIX workstations, 4 DVD burner stations for data archiving, and space for media and document storage. The adjacent computer server room consists of 210 square feet and houses all of the servers for the research computing network. Finally, for processing and analyzing EEG sleep and related data: seven Grass model 15 amplifiers, ten Hewlett Packard XW 4200 workstations loaded with Stellate Systems’ Harmonie/Luna software modules; one HP model d530 desktop computer for oximetry data processing and reporting; four Compaq Model 450 computers and four printers for mood, performance and temperature data collection; three HP 9000 workstations; and seven HP X-terminals for data processing and analysis.