Member, Maternal & Child Health Research Institute (MCHRI)
Doctor of Medicine, Dartmouth College (2015)
Bachelor of Science, Massachusetts Institute of Technology (2008)
Doctor of Philosophy, Dartmouth College (2013)
Post-doctoral Fellowship, Stanford University, Neuroscience
Residency, Stanford University, Psychiatry
Alan Schatzberg, Postdoctoral Faculty Sponsor
Ventral-Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility
SPRINGERNATURE. 2020: 312
View details for Web of Science ID 000596371000574
Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
There is a critical need to better understand the neural basis of antidepressant medication (ADM) response with respect to both symptom alleviation and quality of life (QoL) in major depressive disorder (MDD). Reward neurocircuitry has been implicated in QoL, the neural basis of MDD, and the mechanisms of ADM response. Yet, we do not know whether change in reward neurocircuitry as a function of ADM is associated with change in symptoms and QoL. To address this gap in knowledge, we analyzed data from 128 patients with MDD who participated in the iSPOT-D trial and were assessed with functional neuroimaging pre- and post-ADM treatment (randomized to sertraline, venlafaxine-XR, or escitalopram). 58 matched healthy controls were scanned at the same time points. We quantified functional connectivity (FC) of reward neurocircuitry using nucleus accumbens (NAc) seed regions of interest, and then characterized how changes in FC relate to symptom response (primary outcome) and QoL response (secondary outcome). Symptom responders showed an increase in NAc-dorsal anterior cingulate cortex (ACC) FC relative to non-responders (p<0.001) which was associated with improvement in physical QoL (p<0.0003), and a decrease in NAc-inferior parietal lobule FC relative to controls (p<0.001). QoL response was characterized by increases in FC between NAc-ventral ACC for environmental, NAc-thalamus for physical, and NAc-paracingulate gyrus for social domains (p<0.001). Symptom responders to sertraline were distinguished by a decrease in NAc-insula FC (p<0.001) and to venlafaxine-XR by an increase in NAc-inferior temporal gyrus FC (p<0.005). Findings suggest that change in reward neurocircuitry may underlie differential ADM response profiles with respect to symptoms and QoL in depression.
View details for DOI 10.1038/s41386-020-00905-3
View details for PubMedID 33230268
- ABERRANT REWARD FUNCTION AND STRUCTURE IS ASSOCIATED WITH SUICIDAL IDEATION AND BEHAVIOR IN YOUTH WITH DEPRESSION AND OBESITY ELSEVIER SCIENCE INC. 2020: S278
- NEURAL CORRELATES OF REWARD PROCESSING DISTINGUISH HEALTHY YOUTH AT FAMILIAL RISK FOR BIPOLAR DISORDER FROM YOUTH AT FAMILIAL RISK FOR MDD ELSEVIER SCIENCE INC. 2020: S170
Neural Correlates of Positive Emotion Processing That Distinguish Healthy Youth at Familial Risk for Bipolar Versus Major Depressive Disorder.
Journal of the American Academy of Child and Adolescent Psychiatry
OBJECTIVE: Familial risk for bipolar (BD) or major depressive (MDD) disorder may lead to differential emotion processing signatures, resulting in unique neural vulnerability.METHOD: Healthy offspring of a parent with BD (n=29, "BD-risk") or MDD (n=44, "MDD-risk") and youth without any personal or family psychopathology (n=28, "HC") ages 8-17 (13.64 ± 2.59) completed an implicit emotion perception functional magnetic resonance imaging task. Whole-brain voxel-wise and psychophysiological interaction analyses examined neural differences in activation and connectivity during emotion processing. Regression modeling tested for neural associations with behavioral strengths and difficulties and conversion to psychopathology at follow-up (3.71 ± 1.91 years).RESULTS: BD-risk youth showed significantly reduced bilateral putamen activation, and decreased connectivity between the left putamen and the left ventral anterior cingulate cortex (vACC) and the right posterior cingulate cortex (PCC) during positive-valence emotion processing compared to MDD-risk and HC (Z >2.3; p <.001). Decreased left putamen- right PCC connectivity correlated with subsequent peer problems in BD-risk (beta = -2.90; p <.05) and MDD-risk (beta = -3.64; p <.05). Decreased left (beta = -.09; p < .05) and right putamen activation (beta = -.07; p = .04) were associated with conversion to a mood or anxiety disorder in BD-risk. Decreased left putamen-right PCC connectivity was associated with a higher risk of conversion in BD-risk (HR = 8.28 , p < .01) and MDD-risk (HR = 2.31, p = .02).CONCLUSION: Reduced putamen activation and connectivity during positive emotion processing appear to distinguish BD-risk youth from MDD-risk and HC youth, and may represent a marker of vulnerability.
View details for DOI 10.1016/j.jaac.2020.07.890
View details for PubMedID 32738282
Cannabis and the Developing Adolescent Brain.
Current treatment options in psychiatry
2020; 7 (2): 144–61
Purpose of Review: This review summarizes (1) recent trends in delta-9-tetrahydrocannabionol [THC] and cannabidiol (CBD) content in cannabis products, (2) neurobiological correlates of cannabis use on the developing adolescent brain, (3) effects of cannabis on psychiatric symptoms and daily functioning in youth (i.e., academic performance, cognition, sleep and driving), (4) cannabis products used to relieve or treat medical issues in youth, and (5) available treatments for cannabis use disorder in adolescence.Recent findings: Despite marked increases in THC content and availability of cannabis, there has been a decline in perceived risk and an increase in use of THC extract products among youth in the United States. The primary psychiatric symptoms associated with cannabis use in youth are increased risk for addiction, depressive, and psychotic symptoms. Cannabis alters endocannabinoid system function which plays a central role in modulating the neurodevelopment of reward and stress systems. To date, few studies have examined neurobiological mechanisms underlying the psychiatric sequalae of cannabis exposure in youth. Adolescent cannabis exposure results in impaired cognition, sleep, and driving ability. There are very limited FDA-approved cannabinoid medications, none of them supporting their use for the treatment of psychiatric symptoms. Behavioral therapies are currently the mainstay of treating cannabis misuse, with no pharmacotherapies currently approved by the FDA for cannabis use disorder in youth.Summary: Here, we summarize the most up-to-date knowledge on the neurobiological psychiatric, and daily function effects of the most commonly used cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We then review FDA approved medical use of cannabinoid treatments as well as pharmacological and psychological treatments for cannabis use disorder in youth. Our current understanding of the effects of cannabis on the developing brain and treatments for cannabis misuse in youth remain limited. Future research aimed at examining the neurobiological effects of cannabis, with objective measures of exposure, over the course of pediatric development and in relation to psychiatric symptoms are needed.
View details for DOI 10.1007/s40501-020-00202-2
View details for PubMedID 32714742
Family Dynamics and Emotion Processing: Functional Connectivity Biomarkers of Risk and Resilience in Youth at Familial Risk for Mood Disorders
ELSEVIER SCIENCE INC. 2020: S288
View details for Web of Science ID 000535308200705
Functional Connectivity of Reward Circuitry is a Core Mechanistic Biomarker of Treatment Response and Quality of Life in Depression
ELSEVIER SCIENCE INC. 2020: S396–S397
View details for Web of Science ID 000535308201213
Variable Neurobehavioral Outcomes in Youth at Familial Risk for Mood Disorders
ELSEVIER SCIENCE INC. 2020: S68
View details for Web of Science ID 000535308200162
Functional neuroimaging biomarkers of resilience in major depressive disorder.
Current opinion in psychiatry
In this review, we provide an overview of definitions and determinants of resilience in the context of neuroimaging research in major depressive disorder (MDD). We summarize emerging literature on functional neuroimaging biomarkers of resilience in MDD and discuss their clinical relevance and implications for future research.Resilience in MDD is characterized by dissociable profiles of activation and functional connectivity within brain networks involved in cognitive control, emotion regulation, and reward processing. Increased activation of frontal cortical brain regions implicated in cognitive appraisal and emotion regulation is a common characteristic of resilient individuals at high risk for MDD and of individuals with MDD with a favorable illness course. Furthermore, significant associations between fronto-striato-limbic functional connectivity and both positively interpreted stressful life events in resilient high-risk individuals and a favorable response to first-line treatments in depressed individuals suggest that neuro-compensatory changes and experience-dependent plasticity underlie resilience in MDD.Emerging research has identified putative functional neuroimaging biomarkers of resilience in MDD. A continued focus on identifying neurobiological underpinnings of resilience, in the context of dynamic environmental and developmental influences on MDD, will advance our understanding of resilience in this disorder and improve approaches to prevention and treatment.
View details for DOI 10.1097/YCO.0000000000000662
View details for PubMedID 33027183
Insulin Resistance and Structural Change in the Anterior Cingulate Cortex in Youth With Depression and Obesity
NATURE PUBLISHING GROUP. 2019: 143–44
View details for Web of Science ID 000509665600281
Functional Connectivity Biomarkers of Emotion Regulation That Distinguish Risk for Bipolar Versus Unipolar Depression in Clinically Asymptomatic High-Risk Youth
NATURE PUBLISHING GROUP. 2019: 434–35
View details for Web of Science ID 000509665600788
- DISSOCIABLE NEURAL NETWORK MARKERS OF RISK AND RESILIENCE IN PEDIATRIC BIPOLAR DISORDER ELSEVIER SCIENCE INC. 2019: S362
- REWARD PROCESSING IN DEPRESSED AND OBESE CHILDREN ELSEVIER SCIENCE INC. 2019: S274
- EFFECTS OF MARIJUANA USE ON BRAIN CIRCUITRY AND DEPRESSIVE SYMPTOMS IN ADOLESCENTS WITH BIPOLAR DISORDER ELSEVIER SCIENCE INC. 2019: S299
- Emotion Network Predictors of Clinical Outcome in Youth at High Risk for Bipolar Disorder ELSEVIER SCIENCE INC. 2019: S2
- Reward-circuit biomarkers of risk and resilience in adolescent depression JOURNAL OF AFFECTIVE DISORDERS 2019; 246: 902–9
Reward-circuit biomarkers of risk and resilience in adolescent depression.
Journal of affective disorders
2019; 246: 902–9
Dysfunctional reward processing is a core feature of major depressive disorder. While there is growing knowledge of reward processing in adolescent depression, researchers have ignored neural mechanisms of resilience to depression. Here, we examine neural correlates of reward processing that characterize resilience and risk in adolescents at risk for depression, facilitating the development of effective intervention approaches that strengthen resilience to psychopathology in at-risk youth.50 adolescent females were followed through age 18: 32 at-risk adolescents who either did (remitted-depressed; n = 15) or did not (resilient; n = 17) experience a depressive episode, and 18 low-risk healthy controls. Participants completed clinical assessments at 18-month intervals and an fMRI reward-processing task in late adolescence. We conducted predictive modeling with a priori reward regions of interest (ROIs).At-risk resilient and remitted-depressed adolescents exhibited less striatal activation than did controls during anticipation of reward. Resilient adolescents exhibited greater activation than did remitted-depressed adolescents in the middle frontal gyrus during reward anticipation, and less activation in the superior frontal gyrus and cuneus during processing of reward outcome. Using predictive modeling, ventral anterior cingulate cortex and putamen activation during reward processing distinguished resilient from remitted-depressed adolescents with 83% accuracy.The relatively small sample size of only females and the fact that fMRI data were obtained at one time point in late adolescence are limitations.Distinct patterns of neural activation in reward circuitry appear to be markers of risk and resilience that may be targets for prevention and treatment approaches aimed at strengthening adaptive reward processing in at-risk adolescents.
View details for PubMedID 30795497
Neural Markers of Resilience in Adolescent Females at Familial Risk for Major Depressive Disorder
2018; 75 (5): 493–502
Adolescence is a neurodevelopmental period during which experience-dependent plasticity in brain circuitry may confer vulnerability to depression as well as resilience to disorder. Little is known, however, about the neural mechanisms that underlie resilience during this critical period of brain development.To examine neural functional connectivity correlates of resilience in adolescent females at high and low familial risk for depression who did and did not develop the disorder.A longitudinal study was conducted at Stanford University from October 1, 2003, to January 31, 2017. Sixty-five female adolescents participated in the study: 20 at high risk in whom depression did not develop (resilient), 20 at high risk in whom depression developed (converted), and 25 at low risk with no history of psychopathology (control).We compared functional connectivity between resilient and converted, and between resilient and control, adolescent females using voxelwise 2-sided t tests to examine neural markers of resilience to depression as the main outcomes of interest. Specifically, we assessed differences in connectivity of the limbic (amygdala seed), salience (anterior insula seed), and executive control (dorsolateral prefrontal cortex seed) networks, implicated in emotion regulation. We also examined the association between functional connectivity and life events.Of the 65 participants (mean [SD] age, 18.9 [2.5] years), adolescent females in the resilient group had greater connectivity between the amygdala and orbitofrontal cortex (z score = 0.23; P < .001) and between the dorsolateral prefrontal cortex and frontotemporal regions (z score = 0.24; P < .001) than did converted adolescent females. In adolescent females in the resilient group only, strength of amygdala-orbitofrontal cortex connectivity was correlated with positive life events (r18 = 0.48; P = .03). Resilient adolescent females had greater connectivity within frontal (z score = 0.07; P < .001) and limbic (z score = 0.21; P < .001) networks than did control individuals. Both high-risk groups had greater salience network connectivity: the converted group had greater intranetwork connectivity than did the resilient (z score = 0.13; P < .001) and control (z score = 0.10; P < .001) groups, and the adolescent females in the resilient group had greater salience network connectivity with the superior frontal gyrus than did the converted (z score = 0.24; P < .001) adolescent females.Resilient adolescent females have compensatory functional connectivity patterns in emotion regulatory networks that correlate with positive life events, suggesting that experience-dependent plasticity within these networks may confer resilience to depression. Further studies are warranted concerning connectivity-associated targets for promoting resilience in high-risk individuals.
View details for PubMedID 29562053
View details for PubMedCentralID PMC5875355
Understanding marijuana's effects on functional connectivity of the default mode network in patients with schizophrenia and co-occurring cannabis use disorder: A pilot investigation
2018; 194: 70–77
Nearly half of patients with schizophrenia (SCZ) have co-occurring cannabis use disorder (CUD), which has been associated with decreased treatment efficacy, increased risk of psychotic relapse, and poor global functioning. While reports on the effects of cannabis on cognitive performance in patients with SCZ have been mixed, study of brain networks related to executive function may clarify the relationship between cannabis use and cognition in these dual-diagnosis patients. In the present pilot study, patients with SCZ and CUD (n=12) and healthy controls (n=12) completed two functional magnetic resonance imaging (fMRI) resting scans. Prior to the second scan, patients smoked a 3.6% tetrahydrocannabinol (THC) cannabis cigarette or ingested a 15mg delta-9-tetrahydrocannabinol (THC) pill. We used resting-state functional connectivity to examine the default mode network (DMN) during both scans, as connectivity/activity within this network is negatively correlated with connectivity of the network involved in executive control and shows reduced activity during task performance in normal individuals. At baseline, relative to controls, patients exhibited DMN hyperconnectivity that correlated with positive symptom severity, and reduced anticorrelation between the DMN and the executive control network (ECN). Cannabinoid administration reduced DMN hyperconnectivity and increased DMN-ECN anticorrelation. Moreover, the magnitude of anticorrelation in the controls, and in the patients after cannabinoid administration, positively correlated with WM performance. The finding that DMN brain connectivity is plastic may have implications for future pharmacotherapeutic development, as treatment efficacy could be assessed through the ability of therapies to normalize underlying circuit-level dysfunction.
View details for PubMedID 28823723
Looking at the Brighter Side: Functional Connectivity Biomarkers of Resilience to Adolescent Depression in Emotion Regulation Networks
NATURE PUBLISHING GROUP. 2017: S501
View details for Web of Science ID 000416846303040
Functional Connectivity Markers of Resilience in Adolescents at Familial Risk for Depression
NATURE PUBLISHING GROUP. 2016: S470–S471
View details for Web of Science ID 000440366400025
The Clinical Applicability of Functional Connectivity in Depression: Pathways Toward More Targeted Intervention.
Biological psychiatry. Cognitive neuroscience and neuroimaging
2016; 1 (3): 262–70
Resting-state functional magnetic resonance imaging provides a noninvasive method to rapidly map large-scale brain networks affected in depression and other psychiatric disorders. Dysfunctional connectivity in large-scale brain networks has been consistently implicated in major depressive disorder (MDD). Although advances have been made in identifying neural circuitry implicated in MDD, this information has yet to be translated into improved diagnostic or treatment interventions. In the first section of this review, we discuss dysfunctional connectivity in affective salience, cognitive control, and default mode networks observed in MDD in association with characteristic symptoms of the disorder. In the second section, we address neurostimulation focusing on transcranial magnetic stimulation and evidence that this approach may directly modulate circuit abnormalities. Finally, we discuss possible avenues of future research to develop more precise diagnoses and targeted interventions within the heterogeneous diagnostic category of MDD as well as the methodological limitations to clinical implementation. We conclude by proposing, with cautious optimism, the future incorporation of neuroimaging into clinical practice as a tool to aid in more targeted diagnosis and treatment guided by circuit-level connectivity dysfunction in patients with depression.
View details for PubMedID 29560882
- Response to "Cortico-accumbens circuitry in schizophrenia: Merely a reward system?" by Rolland and Jardri (SCHRES-14-D-00731) SCHIZOPHRENIA RESEARCH 2015; 161 (2-3): 519-519
Impaired functional connectivity of brain reward circuitry in patients with schizophrenia and cannabis use disorder: Effects of cannabis and THC
2014; 158 (1-3): 176-182
Cannabis use disorder (CUD) occurs in up to 42% of patients with schizophrenia and substantially worsens disease progression. The basis of CUD in schizophrenia is unclear and available treatments are rarely successful at limiting cannabis use. We have proposed that a dysregulated brain reward circuit (BRC) may underpin cannabis use in these patients. In the present pilot study, we used whole-brain seed-to-voxel resting state functional connectivity (rs-fc) to examine the BRC of patients with schizophrenia and CUD, and to explore the effects of smoked cannabis and orally administered delta-9-tetrahydrocannabinol (THC) on the BRC. 12 patients with schizophrenia and CUD and 12 control subjects each completed two fMRI resting scans, with patients administered either a 3.6% THC cannabis cigarette (n=6) or a 15 mg THC capsule (n=6) prior to their second scan. Results revealed significantly reduced connectivity at baseline in patients relative to controls, with most pronounced hypoconnectivity found between the nucleus accumbens and prefrontal cortical BRC regions (i.e., anterior prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex). Both cannabis and THC administration increased connectivity between these regions, in direct correlation with increases in plasma THC levels. This study is the first to investigate interregional connectivity of the BRC and the effects of cannabis and THC on this circuit in patients with schizophrenia and CUD. The findings from this pilot study support the use of rs-fc as a means of measuring the integrity of the BRC and the effects of pharmacologic agents acting on this circuit in patients with schizophrenia and CUD.
View details for DOI 10.1016/j.schres.2014.04.033
View details for Web of Science ID 000341314800029
View details for PubMedID 25037524
View details for PubMedCentralID PMC4778557
Predicting inpatient complications from cerebral aneurysm clipping: the Nationwide Inpatient Sample 2005-2009
JOURNAL OF NEUROSURGERY
2014; 120 (3): 591-598
Precise delineation of individualized risks of morbidity and mortality is crucial in decision making in cerebrovascular neurosurgery. The authors attempted to create a predictive model of complications in patients undergoing cerebral aneurysm clipping (CAC).The authors performed a retrospective cohort study of patients who had undergone CAC in the period from 2005 to 2009 and were registered in the Nationwide Inpatient Sample (NIS) database. A model for outcome prediction based on preoperative individual patient characteristics was developed.Of the 7651 patients in the NIS who underwent CAC, 3682 (48.1%) had presented with unruptured aneurysms and 3969 (51.9%) with subarachnoid hemorrhage. The respective inpatient postoperative risks for death, unfavorable discharge, stroke, treated hydrocephalus, cardiac complications, deep vein thrombosis, pulmonary embolism, and acute renal failure were 0.7%, 15.3%, 5.3%, 1.5%, 1.3%, 0.6%, 2.0%, and 0.1% for those with unruptured aneurysms and 11.5%, 52.8%, 5.5%, 39.2%, 1.7%, 2.8%, 2.7%, and 0.8% for those with ruptured aneurysms. Multivariate analysis identified risk factors independently associated with the above outcomes. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated using the area under the receiver operating characteristic curve, and it was found to have good discrimination.The featured model can provide individualized estimates of the risks of postoperative complications based on preoperative conditions and can potentially be used as an adjunct in decision making in cerebrovascular neurosurgery.
View details for DOI 10.3171/2013.8.JNS13228
View details for Web of Science ID 000332048800002
View details for PubMedID 24032701
- Teaching the Bayesian child: Three-and-a-half-year-olds’ reasoning about ambiguous evidence Journal of Cognition and Development 2012; 13 (2): 266-280
- Teaching three-and-a-half-year-olds to reason about ambiguous evidence Psychology Press 2011