Perturbation of the Treatment of Resistant Depression Connectome by Fast-Acting Therapies

Study Overview

The goal of this project is to identify connectome-specific correlates and predictors of successful treatment outcome in patients with severe depression followed prospectively while receiving one of three rapidly acting therapeutic interventions. These interventions include electroconvulsive therapy (ECT), serial ketamine infusion and total sleep deprivation (TSD). Via neurostimulation, pharmacological or behavioral perturbation, each elicits relatively robust antidepressant effects and has a distinct mode of access to the central nervous system. A related goal is to characterize variations in neural connectivity associated with individual clinical, behavioral or physiological factors that distinguish patients with severe depression from demographically similar non-depressed controls. Since response to standard antidepressant therapies is moderate, variable, and protracted, understanding how brain networks change with rapid clinical improvement could provide a key opportunity to devise more immediate, personalized and effective treatment and prevention strategies for refractory depression.

Project Timespan: Sept. 2, 2016 - May 31, 2020




Investigators

Randall Espinoza

Randall Espinoza, MD - UCLA Principal Investigator

Co-PI

Katherine Narr

Katherine Narr, Ph.D. - UCLA Principal Investigator

Contact: Email

Danny Wang

Danny Wang, Ph.D - USC Principal Investigator

Sub-contract PI

Study Protocol Overview

Data Being Collected 

  • Standard HCP demographics
  • Imaging: Structural, functional (resting state and task), diffusion and perfusion MRI data collected on Siemens 3T Prisma system located at UCLA is acquired using sequences identical to those developed for the HCP-Aging Project. Functional imaging tasks probe emotional processing and cognitive control. 
  • Clinical Assessments (Baseline): Structured Clinical Interview for DSM-5, Research Version (SCID-5-RV); Antidepressant Treatment History Form (ATHF); Prescribed Medication History Questionnaire; ChronoType Questionnaire; PhenX Toolkit Substance Abuse and Addiction Questionnaires; Fagestrom Test for Nicotine Dependence; Daily Stress Inventory; Stress and Adversity Inventory (STRAIN); Parental Bonding and Early Life Events Questionnaire; Behavioral Inhibition and Activation System Questionnaires (BIS/BAS), Migraine Screener; World Health Organization Disability Assessment Schedule (WHODAS); National Network of Depression Centers Comorbidity Questionnaire; Combined Trait Rumination Questionnaire.
  • Clinical Assessments (Repeated): Hamilton Depression Rating Scale, 17 item (HAMD-17); Inventory of Depressive Symptomatology – Clinician Rated (IDS-C); Computerized Adaptive Tests for Depression, Anxiety, Mania/Hypomania, and Suicide (CAT-MH); Young Mania Rating Scale (YMRS); Quick Inventory of Depressive Symptomatology – Self-Rated (QIDS-SR); Depression Anxiety Stress Scales (DASS); Combined State Rumination Questionnaire; Snaith-Hamilton Pleasure Scale (SHAPS); Apathy Evaluation Scale (AES); Pittsburg Sleep Quality Index; Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Test. 
  • Behavioral Assessments: NIH Toolbox and University of Pennsylvania Computerized Neuropsychological (PennCNP) Tests; Autobiographical Memory Test, Effort Expenditure for Rewards Task.
  • Repeated Physiological Measures: Plasma for gene expression analyses and storage of DNA for future genotyping.


Cohort Description

Subjects include 200 patients with severe depression clinically eligible to receive ECT (n=60), serial ketamine (n=60) or TSD (n=80) and 140 controls, combining control data collected locally (n=40) with data from the HCP resource (n=100). Each patient will receive MRI, behavioral/cognitive testing and a blood draw before and after completing one of the interventions.


Data Release

  • The first data release includes 20 unique subjects.
  • The second data release includes 110 unique subjects, 90 with repeat data.
  • The third data release includes 110 unique subjects, 90 with repeat data.
  • Gene expression raw and analyzed data will be deposited in the Gene Expression Omnibus (GEO) database ( http://www.ncbi.nlm.nih.gov/geo) at the end of the project.


Keywords

Major Depression, Mood Disorders, White Matter, Functional Connectivity, Structural Connectivity, Neuroplasticity, Antidepressant

Publications

  • Modulation of intrinsic brain activity by electroconvulsive therapy in major depression.

    Amber M Leaver, Randall Espinoza, Tara Pirnia, Shantanu H Joshi, Roger P Woods, Katherine L Narr
    Show Summary

    One of the most effective interventions for intractable major depressive episodes is electroconvulsive therapy (ECT). Because ECT is also relatively fast-acting, longitudinal study of its neurobiological effects offers critical insight into the mechanisms underlying depression and antidepressant response. Here we assessed modulation of intrinsic brain activity in corticolimbic networks associated with ECT and clinical response.

  • Structural connectivity and response to ketamine therapy in major depression: A preliminary study.

    Megha M Vasavada, Amber M Leaver, Randall T Espinoza, Shantanu H Joshi, Stephanie N Njau, Roger P Woods, Katherine L Narr
    Show Summary

    Ketamine elicits an acute antidepressant effect in patients with major depressive disorder (MDD). Here, we used diffusion imaging to explore whether regional differences in white matter microstructure prior to treatment may predict clinical response 24h following ketamine infusion in 10 MDD patients.

  • Desynchronization and Plasticity of Striato-frontal Connectivity in Major Depressive Disorder.

    Amber M Leaver, Randall Espinoza, Shantanu H Joshi, Megha Vasavada, Stephanie Njau, Roger P Woods, Katherine L Narr
    Show Summary

    Major depressive disorder (MDD) is associated with dysfunctional corticolimbic networks, making functional connectivity studies integral for understanding the mechanisms underlying MDD pathophysiology and treatment. Resting-state functional connectivity (RSFC) studies analyze patterns of temporally coherent intrinsic brain activity in "resting-state networks" (RSNs). The default-mode network (DMN) has been of particular interest to depression research; however, a single RSN is unlikely to capture MDD pathophysiology in its entirety, and the DMN itself can be characterized by multiple RSNs. This, coupled with conflicting previous results, underscores the need for further research. Here, we measured RSFC in MDD by targeting RSNs overlapping with corticolimbic regions and further determined whether altered patterns of RSFC were restored with electroconvulsive therapy (ECT). MDD patients exhibited hyperconnectivity between ventral striatum (VS) and the ventral default-mode network (vDMN), while simultaneously demonstrating hypoconnectivity with the anterior DMN (aDMN). ECT influenced this pattern: VS-vDMN hyperconnectivity was significantly reduced while VS-aDMN hypoconnectivity only modestly improved. RSFC between the salience RSN and dorsomedial prefrontal cortex was also reduced in MDD, but was not affected by ECT. Taken together, our results support a model of ventral/dorsal imbalance in MDD and further suggest that the VS is a key structure contributing to this desynchronization.

  • Electroconvulsive therapy mediates neuroplasticity of white matter microstructure in major depression.

    H Lyden, R T Espinoza, T Pirnia, K Clark, S H Joshi, A M Leaver, R P Woods, K L Narr
    Translational psychiatry, Apr 10, 2014 PMID: 24713861
    Show Summary

    Whether plasticity of white matter (WM) microstructure relates to therapeutic response in major depressive disorder (MDD) remains uncertain. We examined diffusion tensor imaging (DTI) correlates of WM structural connectivity in patients receiving electroconvulsive therapy (ECT), a rapidly acting treatment for severe MDD. Tract-Based Spatial Statistics (TBSS) applied to DTI data (61 directions, 2.5 mm(3) voxel size) targeted voxel-level changes in fractional anisotropy (FA), and radial (RD), axial (AD) and mean diffusivity (MD) in major WM pathways in MDD patients (n=20, mean age: 41.15 years, 10.32 s.d.) scanned before ECT, after their second ECT and at transition to maintenance therapy. Comparisons made at baseline with demographically similar controls (n=28, mean age: 39.42 years, 12.20 s.d.) established effects of diagnosis. Controls were imaged twice to estimate scanning-related variance. Patients showed significant increases of FA in dorsal fronto-limbic circuits encompassing the anterior cingulum, forceps minor and left superior longitudinal fasciculus between baseline and transition to maintenance therapy (P<0.05, corrected). Decreases in RD and MD were observed in overlapping regions and the anterior thalamic radiation (P<0.05, corrected). Changes in DTI metrics associated with therapeutic response in tracts showing significant ECT effects differed between patients and controls. All measures remained stable across time in controls. Altered WM microstructure in pathways connecting frontal and limbic areas occur in MDD, are modulated by ECT and relate to therapeutic response. Increased FA together with decreased MD and RD, which trend towards normative values with treatment, suggest increased fiber integrity in dorsal fronto-limbic pathways involved in mood regulation.

Data Use Terms

When users request access to the NIMH Data Archive (NDA), they sign the NDA Data Use Certification (DUC) under which the data is shared. This DUC is usually submitted to the NDA electronically, but this printable version can also be submitted to NDAhelp@mail.nih.gov.

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