fMRI Studies of Pediatric Mood and Anxiety Disorders

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

This work is conducted under protocol 01-M-0192, 18-M-0037, and 000776, as well as NCT00018057. We are using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) to examine neurocognitive correlates of pediatric mood and anxiety disorders. We also are comparing findings in these syndromes with findings in adult mood and anxiety disorders. While studies conducted at the NIH as part of this protocol focus most narrowly and deeply on pediatric mood and anxiety disorders, studies conducted with collaborators focus most deeply on adult mood and anxiety disorders. Collaborative work therefore allows us to examine the similarities and differences between pediatric and adult mood and anxiety disorders. The current protocol has generated key insights on novel treatments, which are now being studied in the context of brain-imaging research. The protocol also focuses deeply on the manner in which effective treatment changes neural correlates, so that research on novel therapeutics might target such neural correlates. The work performed under this protocol and with the many associated collaborators holds the potential to dramatically impact public health, for various reasons. Mood and anxiety disorders deeply undermine the well-being of children and adolescents. Nevertheless, relatively little work has been conducted on the underlying pathophysiology of these conditions, using methods that allow direct extensions to work in basic neuroscience. Brain imaging research using fMRI and MEG is vital for work in this area. Such research assesses brain function in children using methods that are directly comparable to the techniques used to study brain function in animal models. There is a pressing need to use new understandings from neuroscience to generate new ideas about treatment. Work in this protocol holds the hope of generating new insights in ways that will lead to novel treatment discovery. For example, replicable perturbations, identified through the confluence of findings in animal models and children, might be targeted by novel treatments. In the current protocol, such work has focused on extinction as it relates to cognitive behavioral therapy, and on attention bias as it relates to both cognitive behavioral therapy and cognitive training. As such, this protocol defines a promising pathway for generating treatments that may alter clinical practice. In the past five years, we have published multiple papers that demonstrate such promise by targeting aspects of attention and plasticity in fear responses, extending research completed in prior years. Four randomized controlled trials were published in this area through work with collaborators and following on from highly similar randomized controlled trials published in prior years. For work completed at the NIH, we target randomized controlled trials where data are acquired from brain imaging. We have enrolled 121 patients from a trial that will finish when the 121st patient finishes treatment. Enrollment did stall with the COVID-19 pandemic, but we saw an increase during the past year, to the point where we have enrolled the final subject in the trial. Moreover, we have also developed an alternative form of attention bias modification that we have successfully piloted in the past year. Once the analysis from our main randomized control trial finishes, we will evaluate the possibility of improving our current approach through the alternative form of treatment piloted in the past year. We hope to also launch this new trial in the coming year. Finally, we have been actively analyzing our data on neurobiology, which we will relate to clinical response in the coming year. As such, this protocol demonstrates the potential importance of embedding a clinical trial within a brain imaging study. Beyond our work on anxiety, extinction, and attention bias, other treatment research in the current protocol focuses on major depressive disorder (MDD). Thus, we have initiated new studies that evaluate the efficacy of psychotherapy for the treatment of depression. We have enrolled 10 subjects in our ongoing study targeting this theme. We have collected considerable brain imaging data on patients with symptoms of major depressive disorder, publishing an important paper on this issue in a high-impact journal. Finally, we received approval from the Food and Drug Administration (FDA) to initiate a trial of transcranial magnetic stimulation for the treatment of MDD in adolescents who fail to respond to established therapies. The central focus of the protocol is on individual differences in neural circuitry function, as they relate to individual differences in behavior and clinical response to treatment. Replicated findings from this project clearly implicate many such deficits in anxiety and MDD. Particularly exciting work from the past year focuses on multivariate statistical approaches to brain imaging in large data sets. These efforts involve considerable attempts to replicate findings generated in patients seen on campus with findings generated in extramural research. In recent years, this involves a leadership role in collaborative studies across the world performed by the NIMH team. We have assembled brain imaging data from more than 10,000 individuals with mood disorder or with anxiety disorders, which allows us to compare data collected at the NIMH with data collected at other sites. As in past years, we continue to show that neural circuitry specifically related to anxiety or depression can be differentiated from the neural circuitry that anxiety shares with other forms of psychopathology. Prior neuropsychological studies in children as well as in adults note that mood and anxiety disorders are associated with deficits in attention modulation and emotional memory. We have found consistent evidence of such deficits in the current protocol. This work relies on fMRI attention modulation and emotional memory paradigms, where we find different patterns of engagement of cortico-limbic brain regions in psychiatrically healthy and anxious, impaired participants. These studies are ongoing in more than 1000 participants. For these participants, each received neurocognitive examinations, and a subset received fMRI examinations. Each also received standardized assessments of response to treatment. This has allowed our group to use our data as part of international collaborations, where our group is playing an increasingly large role. As part of our studies in healthy individuals, we also successfully developed each of the fMRI protocols that will be used in the current project. We have a particularly strong interest in studying reliability of brain function, as assessed with fMRI. In recent years, we have been able to develop paradigms with acceptable levels of reliability. Many of our initial hypotheses have been confirmed, and our studies are now moving forward to examine issues of specificity and to consider how our findings might be used to inform advances in treatment. This focus has led to the creation of large-scale collaborations.