Reducing default mode network connectivity with mindfulness-based fMRI neurofeedback: a pilot study among adolescents with affective disorder history

Molecular Psychiatry ARTICLE www.nature.com/mp OPEN Reducing default mode network connectivity with mindfulnessbased fMRI neurofeedback: a pilot study among adolescents with affective disorder history ✉ Jiahe Zhang 1 , Jovicarole Raya1, Francesca Morfini1, Zoi Urban1, David Pagliaccio Randy P. Auerbach 2,3,5,7, Clemens C. C. Bauer1,6,7 and Susan Whitfield-Gabrieli1,4,6,7 2,3 , Anastasia Yendiki4, 1234567890();,: © The Author(s) 2023 Adolescents experience alarmingly high rates of major depressive disorder (MDD), however, gold-standard treatments are only effective for ~50% of youth. Accordingly, there is a critical need to develop novel interventions, particularly ones that target neural mechanisms believed to potentiate depressive symptoms. Directly addressing this gap, we developed mindfulness-based fMRI neurofeedback (mbNF) for adolescents that aims to reduce default mode network (DMN) hyperconnectivity, which has been implicated in the onset and maintenance of MDD. In this proof-of-concept study, adolescents (n = 9) with a lifetime history of depression and/or anxiety were administered clinical interviews and self-report questionnaires, and each participant’s DMN and central executive network (CEN) were personalized using a resting state fMRI localizer. After the localizer scan, adolescents completed a brief mindfulness training followed by a mbNF session in the scanner wherein they were instructed to volitionally reduce DMN relative to CEN activation by practicing mindfulness meditation. Several promising findings emerged. First, mbNF successfully engaged the target brain state during neurofeedback; participants spent more time in the target state with DMN activation lower than CEN activation. Second, in each of the nine adolescents, mbNF led to significantly reduced within-DMN connectivity, which correlated with post-mbNF increases in state mindfulness. Last, a reduction of within-DMN connectivity mediated the association between better mbNF performance and increased state mindfulness. These findings demonstrate that personalized mbNF can effectively and non-invasively modulate the intrinsic networks associated with the emergence and persistence of depressive symptoms during adolescence. Molecular Psychiatry; https://doi.org/10.1038/s41380-023-02032-z INTRODUCTION In the United States, major depressive disorder (MDD) results in ~ $200 billion of lost productivity and health care expenses annually [1], and rates among adolescents are alarmingly high [2]. Goldstandard treatments for depression are only effective for ~50% of youth [3], underscoring the critical need to develop novel treatments to improve clinical outcomes. At the neural systems level, MDD is characterized by elevated resting state connectivity within the default mode network (DMN), which includes core midline hubs in the subgenual anterior cingulate cortex (sgACC), medial prefrontal cortex (MPFC), and posterior cingulate cortex (PCC) [4, 5]. Although the sgACC is not typically considered a DMN node in ICA-based analyses (likely due to its low signal-to-noise ratio compared to other major DMN nodes at 3 Tesla), seed-based connectivity analyses have consistently placed the sgACC within canonical DMN topography (e.g., [6, 7]). DMN hyperconnectivity, especially sgACC hyperconnectivity, is associated with symptom severity in depressed individuals [8, 9] and characterizes children with elevated familial risk for depression [10]. The DMN is thought to facilitate patterns of depressogenic, self-referential processing and a heightened focus on distressing emotional states [4, 11–13]. In MDD, it is theorized that dysregulation of the DMN by top-down control networks, such as the central executive network (CEN) [14, 15], also contributes to heightened self-focus. Accordingly, hyperconnectivity within the DMN has been linked to rumination (i.e., the tendency to perseverate about one’s symptoms), a common trait that contributes to depression onset, maintenance, and recurrence [16–18] as well as cognitive therapy non-response and relapse [17, 19]. As DMN connectivity is a promising biomarker of MDD [9, 20], new interventions targeting DMN have been explored. For example, transcranial magnetic stimulation (TMS) targeting the dorsolateral prefrontal cortex (i.e., a CEN node that is anticorrelated with DMN) normalizes DMN connectivity and improves depressive symptoms in adults [21]. Interestingly, mindfulness 1 Department of Psychology, Northeastern University, Boston, MA 02115, USA. 2Department of Psychiatry, Columbia University, New York, NY 10032, USA. 3New York State Psychiatric Institute, New York, NY 10032, USA. 4Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. 5Division of Clinical Developmental Neuroscience, Sackler Institute, New York, NY 10032, USA. 6Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 7These authors contributed equally: Randy P. Auerbach, Clemens C. C. Bauer, Susan Whitfield-Gabrieli. ✉email: Received: 16 August 2022 Revised: 2 March 2023 Accepted: 10 March 2023 J. Zhang et al. 2 Table 1. Sociodemographic and clinical information (n = 9). Category Sociodemographic Age (mean/SD) 18.8 (0.7) Sex: female (n/%) 6 (66.7%) Pubertal status: stage (mean/SD) 4.28 (0.6) Handedness: right (n/%) 9 (100.0%) Race: White (n/%) 8 (88.9%) IQ (mean/SD) 115.1 (15.3) Current symptoms (mean/SD) Depression symptoms (MFQ) 17.4 (13.7) General anxiety symptoms (RCADS) 3.7 (2.7) Social anxiety symptoms (RCADS) 13.1 (6.5) Current psychiatric disorders (n/%) Comorbid depression and anxiety disorders 2 (22.2%) Anxiety disorders (without depression) 1 (11.1%) Any comorbidity (beyond primary depression and/or anxiety) 3 (33.3%) ADHD 2 (22.2%) Bulimia 0 (0%) OCD or related disorders 1 (11.1%) Oppositional defiant disorder 0 (0%) Lifetime psychiatric disorders (n/%) Comorbid depression and anxiety disorder 5 (55.5%) Anxiety disorders 9 (100.0%) Any comorbidity (beyond primary depression and/or anxiety) 5 (55.5%) ADHD 4 (44.4%) Bulimia 1 (11.1%) OCD or related disorders 3 (33.3%) Oppositional defiant disorder 1 (11.1%) Current medication (n/%) Any psychiatric medication 6 (66.7%) Antidepressant medication 6 (66.7%) ADHD medication 3 (33.3%) Anxiety disorders = generalized anxiety disorder (ncurrent = 1, nlifetime = 3), social phobia (ncurrent = 2, nlifetime = 6), separation anxiety (ncurrent = 0, nlifetime = 1), and specific phobia (ncurrent = 0, nlifetime = 1); OCD or related disorders = OCD (ncurrent = 1, nlifetime = 1), excoriation (ncurrent = 0, nlifetime = 1), trichotillomania (ncurrent = 0, nlifetime = 1). ADHD attention-deficit/hyperactivity disorder, MFQ Mood and Feelings Questionnaire, OCD obsessive-compulsive disorder, RCADS Revised Child Anxiety and Depression Scale. me (...truncated)