The Critical Importance of the Adolescent Stage of Brain Development Beatriz Luna, PhD Staunton Professor of Psychiatry and Pediatrics Laboratory of Neurocognitive Development University of Pittsburgh Medical Center Disclosure There are no conflicts of interests to report New Yorker Adolescence 1 Adolescence • Stage of development when sexual maturation associated with pubertal hormonal changes • Hormones affect brain maturation • Hormones affect behavior • Socialization, mating, independence Age of Onset of Psychiatric Disorders Paus et al., 2008 • Major psychopathology emerges and intensifies during adolescence • Reward and cognitive systems are compromised in psychopathology • Reward and cognitive systems mature through adolescence Sex Differences Females Males •Mood, anxiety, and eating •Risk taking: accidental disorders deaths, suicide, substance abuse, and violent offenses •Earlier brain maturation. •Males have protracted development. frontal GM •Greater negative affect to •Greater physiological stress reactivity to stress. •Greater engagement of insula •Males show less functional (interoception) to stress reactivity to angry faces in amygdala. Ordaz & Luna 2012 2 Adolescence: Vulnerabilities • There is a peak in sensation seeking – Sensation seeking can lead to risk-taking undermining survival • Despite peak physical health there is a twofold increase in mortality (Dahl 2004) • Substance abuse, unprotected sex, extreme sports, suicide Adolescence: Vulnerabilities • There is a peak in sensation seeking that can lead to risk-taking undermining survival • Despite peak physical health there is a twofold increase in mortality (Dahl 2004) -Substance abuse, unprotected sex, extreme sports, suicide • Present across societies and species – Biologival Adaptive Stage SAMHSA Adolescence: Adaptive Development • Sensation seeking is present across species and cultures • It is an adaptive manner to obtain skills needed to survive as an independent adult • Sensation seeking is necessary for optimally sculpting the brain to fit its environment 3 Adolescence and Young Adulthood 2015 • 18-25 years of age Neurodevelopment Silbereis et al., 2016 4 Brain Maturation Functional Specificity • Synaptic pruning (Huttenlocher et al,1990) enhances local computations supporting complex processing • Myelination (Yakovlev and Functional Integration Lecours,1968, Benes 1999) speeds neuronal transmission allowing for the integration of distant brain regions and top down modulation of behavior 2 Adolescence Prefrontal Executive Limbic Motivational Processes Emotional Processes Abstract reasoning, Reward processing, impulse control, planning emotion regulation 5 Dual Systems B. Maturational Imbalance Model A. Dual Systems Model C. Driven Dual Systems Model (Casey et al., 2008) (Steinberg, 2008) (Luna & Wright, 2015) Strength Strength Strength Age Age Age Cognitive Control System Affective System Shulman et al., 2016 (Steinberg and Chein) Outline • Executive systems – PFC – HPC • Sz • Affective Systems – Reward – DA • depression • Connectivity: – DTI, DSI • Sz – Rest Brain Imaging Approaches Mehta & Parasuraman, 2013. 6 Neuroimaging Approaches MRI MEG PET DA fMRI rsfMRI Oscillations DWI MRSI EXECUTIVE SYSTEM Executive Function Cognitive Control • Goal directed purposeful behavior • Endogenously & voluntarily driven • Engages working memory, inhibitory control, and cognitive flexibility • Prefrontal cortex plays a critical role due to its widely distributed connectivity and unique neural computations 7 Adolescence Prefrontal Executive Processes Abstract reasoning, impulse control, planning Magnetic Resonance Imaging Normal off- RF Pulse spin 0.0003% of wikidoc protons aligned per Tesla of B0 Structural no function Structural MRI T1 images – FAT T2 images – FAT and WATER http://casemed.case.edu/clerkships/neurology/Web %20Neurorad/MRI%20Basics.htm 8 http://www.martinos.org/neurorecovery/technology.htm Gray Matter Thins Child Adolescence Adult Giedd lab Neocortical GM thins with development in association areas including but not exclusive to PFC Brain Processes Neuron Synaptic Pruning Synapse Axon Neurotransmitter Dendrite 9 Synaptic Pruning (Shore & Rima 1997) Synaptogenesis occurs in the first years of life followed by pruning of unused synapses and strengthening of used ones Adolescence 10 Brain Structure: PFC pruning Synaptic Pruning Huttenlocher et al., 1990 0 6m 1 7 10y 16y Adul Synaptic Density y Visiony Language Reasoningt Occ Temp FrontalHuttenlocher, 1990 Petanjek et al., 2011 Mechanisms of Brain Maturation • Glial cells play a critical role in synaptic pruning and maturation – Microglia (cytokine) (complement) • synaptic pruning & maturation (ASD, SZ) Schafer and Stevens 2015 Abnormal Pruning • Persistent pruning is associated with schizophrenia – Impaired mechanisms of closing critical period plasticity (perineuronal nets, complement cascade system) – Believed to underlie reductions in cortical thickness – Genetics indicate that genes involved in synaptic pruning are present in schizophrenia (Sekar et al., 2016) 11 Cognitive Development • The ability to stop an automatic response – Impulsivity • The ability to retain information on line in working memory – Making planned goal driven responses fMRI Capillary Bed - - + + - + + - - baseline - + + - + + + - - + + + - + - ++ + + activation + - + + + + + + + + - + + + Blood Oxygen Level Dependent (BOLD) response Timecourse of BOLD Response to Task vs. Fixation Fixation Saccade + 12 Hemodynamic Response Function • The BOLD response is slow with approximately a 6 sec delay from neuronal Stimulus (“Neural”) HRF Predicted Data firing • Temporal Resolution is at = the level of seconds • Spatial resolution is at the level of millimeters • Tasks last 3-10mins • BLOCK more power because averaging across trials • ER repeat task many times to obtain sufficient trials (40-60) Inhibitory Control: Antisaccade Task Don’t look Preparation + Response Inhibition Sarah Ordaz, PhD N=139 - 8-28yo (356, 1-6 visits) Instructor, Stanford University Errors Age • dACC function was associated with performance, and mediated the association between age and inhibitory control 13 Working Memory: Memory Guided Saccade Task Encoding Maintenance + + Retrieval Daniel Simmonds, PhD Working Memory Medical Student Simmonds et al., In Press DLPFC Visual Assoc Cortex 30 al al (beta) 20 10 0 10 15 20 25 BOLD sign PFC functioning 5 15 25 Age 14 Schizophrenia: Working Memory DLPFC DLPFC/ACC ACC (Jalbrzikowski et al., 2017) DLPFC is compromised in psychosis including that may undermine ACC performance monitoring. Mean Performance Variability in Performance Latency Accuracy tency SD of MGS SD ofMGS La SD of MGS Accuracy SD ofMGS • In addition to mean performance (accuracy and RT) improving with age, variability in responses decreases with age 15 Development through Variability in Brain Function David Montez, PhD Encode Maintain Retrieve (Montez et al., 2017) Brain State Var X Behavior Var WM Brain State Var X Age Encoding Maintenance Retrieval n.s. p<.001e-6 p<.001e-7 PFC functioning 5 15 25 Age 16 Hippocampus HPC-PFC Model of Adolescence Finn Calabro PhD Research Instructor Vishnu Murty PhD Assistant Prof Murty, Calabro, & Luna NBR 2016 • During adolescence PFC/HPC integration supports memory/experience driven guidance of executive function and is enhanced by mesolimbic function 17 Hippocampal-Prefrontal Functional Connectivity Finn Calabro PhD Research Instructor Methods (Calabro et al., under review) A Prosaccades Antisaccades + + + > 0 36 157.5 205.5 327 366 • Off-period connectivity 15s from task (Fair et al, 2007) • Subjects (n=143, ages 8-32, 78 female) were tested longitudinally, with up to 10 yearly visits (455 total scans, mean 3.2 scans/subject) PFC and HPC ROIs vmPFC vlPFC dlPFC Ant/Post HPC VTA • ROIs for PFC and anterior and posterior HPC were partitioned based on anatomical atlases: PFC (Mackey and Petrides, 2014), HPC (Harvard-Oxford), and VTA using a probabilistic atlas of (Murty et al., 2014). 18 Development of HPC Connectivity to: vmPFC, vlPFC, and dlPFC Anterior HPC Posterior HPC * * ns ns • Age related changes in HPC connectivity were only evident with vmPFC Replication of HPC Connectivity to: vmPFC, vlPFC, and dlPFC on PNC Anterior HPC Posterior HPC * * ns ns • Results were replicated cross-sectionally on 807 10-22yo subjects from the Philadelphia Neurodevelopmental Cohort (PNC) resting state fMRI dataset HPC-vmPFC vlPFC dlPFC and Cognition • CANTAB tasks (Luciana, 2003): • Delayed Match to Sample (DMS) • Spatial Span (SSP) • Stockings of Cambridge (SOC) • Memory guided saccade (MGS) task 19 HPC-vmPFC vlPFC dlPFC and Cognition aHPC pHPC * * 12 SOC 10 Spatial Planning 8 Task 6 SOC Performance 4 14 20 26 32 Age • HPC-vmPFC connectivity predicts performance on Stockings of Cambridge (executive functions: WM, future planning) task after controlling for age DA role (VTA/PFC) in HPC/PFC connectivity • VTA/vmPFC functional connectivity mediated increases with age in anterior and posterior HPC/vmPFC functional connectivity Conclusions • DA changes in adolescence increase HPC- vmPFC connectivity facilitating the integration of context and encoding supporting developmental improvements in executive function 20 PFC and HPC development/DA 5 15 25 Age AFFECTIVE SYSTEM 21 Sensation seeking • Drive to take risks (physical, legal) to obtain "varied, novel, complex and intense” experiences (Zuckerman, 2007) • Sensation Seeking Scale – Degree of sensory stimulation to reach optimal level of arousal – Thrill and adventure seeking (extreme