fMRI Studies of Pediatric Mood and Anxiety Disorders

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

This work is conducted under NCT00018057, NCT03283930, NCT06595953, NCT05652465, and NCT003388606. 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. 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. In work completed over the life of this protocol, we noted the presence of such deficits. 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. While key hypotheses have been confirmed, our studies are now moving forward to see how they might be used to inform advances in treatment. This focus has led to the creation of large-scale collaborations. 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 how 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. In fact, they represent one of the five greatest health problems facing children and adolescents of the world. 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 attention bias as it relates to both cognitive behavioral therapy and cognitive training. Similarly, work in pediatric depressive disorders is defining the boundaries of treatment resistance, differentiating adolescents most likely to benefit from currently available treatments from those likely to need newer one. As such, this protocol defines a promising pathway for generating treatments that may alter clinical practice. For work completed at the NIH, we target randomized controlled trials where data are acquired from brain imaging. We recently completed a trial in 121 patients, and this paper has been accepted for publication. Moreover, based on the strength of these results, we were able to design and launch a new randomized clinical trial (RCT) that attempts to improve on the recently completed trial. While both trials target attention bias, the completed trial utilized training of reaction time to alter attention. This produced less robust effects on attention as compared to procedures that train attention using training of eye gaze. In the past year, we launched the new trial using this new eye-gaze based procedure. Finally, we have also reported results on biological correlates of anxiety and their changes with treatment. This generated another publication reporting results from the new trial and a promising new biomarker. This differentiates possible biomarkers that respond to current treatments from those that do not change. 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 enrolled more than 75 subjects in our ongoing study targeting this theme. We have collected considerable brain imaging data on patients with symptoms of major depressive disorder, publishing important papers on this issue in high-impact journals. Finally, we have adjusted our plans for using transcranial magnetic stimulation for the treatment of MDD in adolescents who fail to respond to established therapies. Two factors led to this change. First, a very high proportion of patients seen at the NIH in our protocols for this project are responding well to psychotherapy. As a result, we are prioritizing future research with psychotherapy over research with transcranial magnetic stimulation. Second, we have begun to collaborate with researchers outside of the NIH, to generate results in larger samples of patients with treatment-resistant MDD. 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 two years focuses on multivariate statistical approaches to brain imaging in large data sets. One of the high-impact papers recently accepted for publication utilized these methods. These efforts involve considerable attempts to replicate findings generated in patients seen in the NIH intramural research program 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. We have worked with our collaborators to mine the valuable insights from these data, and this has generated multiple papers examining facets of mental disorders in children and adolescents from around the world. 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.