Understanding the Value and Limitations of MRI Neuroimaging in Psychiatry

White matter makes up a large portion of the brain and is critical in providing structural connectivity across brain regions, and the myelin sheath surrounding axons modulates the fine-tuning of the timing of information transfer across communicating brain regions. Using diffusion-weighted MRI, various white matter alterations have been reported across different disorders. Tung et al. (7) assessed the extent to which white matter parameters in a large cohort of individuals with ADHD (N=279, with 121 unaffected siblings) and autism spectrum disorder (ASD) (N=175, with 72 unaffected siblings) deviated from white matter in typically developing subjects (N=626). The authors were motivated to understand the similarities and differences in white matter alterations between ADHD and ASD because these illnesses share some symptomatic features, can have overlapping presentations, and are neurodevelopmental in origin. While some differences were found between the disorders, relative to the comparison subjects, alterations in the estimated developmental trajectory of various white matter tracts were shared across both patient groups. Involved tracts broadly included the corpus callosum, some cortical-cortical tracts, and some cortical-subcortical tracts. The authors also found that unaffected siblings of patients with ADHD and ASD had white matter profiles that were related to their affected sib. Additionally, within the patient groups, there was more individual variation in the white matter parameters of the altered tracts, termed an increase in “idiosyncrasy.” The authors interpreted this finding as being possibly related to the wide range of heterogeneity of symptoms seen in ADHD and ASD. Also, along these lines, the authors found that different cognitive and psychopathological features correlated with alterations in specific white matter tracts. Taken together, these alterations in white matter tracts, shared across ADHD and ASD patients, are consistent with numerous other neuroimaging findings that appear to be transdiagnostic in nature and not illness specific.

Norman et al. (8) aimed to understand the longitudinal, within-individual relationship between resting-state functional coupling MRI measures and ADHD symptoms in children and adolescents treated with stimulants. Based on previous studies related to ADHD, the focus of this work was on the cingulo-opercular, striatal-thalamic, and default-mode networks. Study subjects (110 with ADHD and 142 typically developing comparison youths) were followed longitudinally in relation to their naturalistic treatment with stimulants and were scanned up to five times with resting-state MRI. The findings revealed that worse responses to treatment were associated with an age-related atypical increase in connectivity in the cingulo-opercular network. Better responses to treatment were associated with appropriate age-related cingulo-opercular connectivity. The frontal operculum, insula, dorsal anterior cingulate cortex, and posterior medial prefrontal cortex are components of the cingulo-opercular network, and it was previously shown in children with ADHD that acute stimulant administration was associated with the normalization of the function of this network. In general, this finding is consistent with other studies in other psychiatric illnesses and suggests that individuals with more intact functioning of hypothetically involved circuits are more likely to be responsive to treatments. In an editorial provided by Dr. Samuele Cortese, from the University of Southampton in the U.K., the findings from this study are reviewed and contextualized in relation to biomarker development and the steps necessary to validate algorithms for personalized medicine approaches (9). He concludes that the findings from the Norman et al. study are an important but very early step in this process.

In an attempt to better understand how developmental trajectories of altered social communication relate to ASD, Riglin and colleagues present a paper that reports on longitudinal data from a large set of unselected individuals (N=8,094) assessed from ages 7 to 25 (10). By using the Social and Communication Disorders Checklist (SCDC), the authors identified three different developmental trajectories over this time period. Eighty-eight percent of participants were characterized to be in the low SCDC score trajectory group, whereas 5% were in the declining SCDC score group, and 6.5% were in the late-emerging group. To assess ASD, childhood diagnoses were used and “risk” for ASD diagnosis in adulthood was assessed with the Autism Spectrum Quotient, completed by the young adult and a parent. Childhood diagnoses of ASD were very low in the low SCDC and late-emerging trajectory groups (<5%) and were around 9% in the declining-trajectory SCDC group. When using the parent rating for ASD risk that was assessed during early adulthood, high risk for adult ASD was very low for the low-trajectory group, around 50% for the late-emerging group, and less than 20% for the declining-trajectory group. The finding that ASD symptoms decreased with age in the declining-trajectory group, the group with the highest levels of childhood autism diagnoses, is consistent with previous reports. In relation to the late-emerging trajectory group, the authors interpret the data to support the existence of a developmental trajectory for ASD that is characterized by the late emergence of symptoms and disability. In their editorial on this paper, Dr. Catherine Lord, from UCLA, and Dr. Somer Bishop, from UCSF, review the findings and highlight the design and value of the study in tracking social deficits across development (11). They also challenge a variety of assumptions made in the paper, including the notion that ASD, as an illness, is on the extreme end of a continuum of “autistic traits.” Further, Lord and Bishop emphasize the importance of not equating deficits in social behavior with ASD, as social deficits are nonspecifically related to a variety of developmental problems.

It has been suggested that various psychiatric disorders are associated with alterations in interoceptive processes, and the paper by Nord et al. in this issue presents findings from a neuroimaging meta-analysis characterizing the transdiagnostic neural correlates of interoception (12). Interoceptive processes are critical for survival, as they support the maintenance of homeostasis, in part by providing individuals with information about their internal physiological state. In this regard, the insular cortex has been identified to be critically involved in awareness and in particular in the interoceptive processing of bodily states. The insula can be subdivided into anterior, mid, and posterior portions, with the anterior insula more related to cognitive, emotional, and affective processing, the posterior insula more related to somatosensory processing, and the mid-insula providing connectivity between the anterior and posterior portions. By comparing fMRI data from 626 patients with a range of psychiatric diagnoses to 610 control subjects, the authors found altered interoception-related left dorsal mid-insula activation to be common across the patient groups (diagnoses included schizophrenia, bipolar disorder, depression, anxiety disorders, posttraumatic stress disorder, eating disorders, and substance use disorders). The authors further demonstrated that the identified mid-insula region did not overlap with regions that are associated with affective processing or regions that are associated with interventions for affective disorders. In their editorial, Drs. Martin Paulus and Sahib Khalsa, from the Laureate Institute for Brain Research, discuss the implications of this finding, highlighting the connectivity of this relatively underappreciated mid-insular cortex region to the midcingulate cortex, a region involved in cognitive control and decision making (13). They also discuss “interoception prediction errors” and their own work in relation to how they understand the development of interoception-related psychopathology.

Sylvester and colleagues use fMRI in sleeping neonates to examine the neural systems that are associated with infants’ responses to the presentation of unexpected auditory stimuli (14). Such a paradigm probes the early and fundamental automatic responses to novelty, which later in life are highly relevant to the assessment of, responding to, and coping with potential threat. Furthermore, increased responsivity to unexpected stimuli early in life has been associated with the development of pathological anxiety, and studies in adults have characterized the neural correlates related to the presentation of unexpected stimuli. In imaging 41 infants from a normative sample (average age, 28 days), the researchers characterized the infants’ responses to deviant sounds, identifying regions of activation that are similar to those observed in adults. Some of these regions included the thalamus, dorsal anterior cingulate cortex (ACC), anterior insular cortex, and dorsal medial frontal cortex. Additionally, the researchers examined the extent to which individual differences in levels of maternal trait anxiety were related to their infant’s pattern of brain activation. Results demonstrated numerous brain regions in the neonates in which brain activation was significantly correlated with maternal trait anxiety, including the anterior insula, dorsal ACC, subgenual ACC, and ventrolateral prefrontal cortex. Notably, altered activation of these regions has also been associated with anxiety disorders. The authors point out that high levels of maternal anxiety confer significant risk for offspring to develop anxiety disorders and suggest that the early-life neural findings uncovered by their work may represent the earliest brain manifestations of this risk.

The papers presented in this issue of the Journal highlight the use of MRI as a tool to understand psychopathology. The findings from these papers reveal structural and functional brain alterations that are associated with illnesses such as ADHD, ASD, and anxiety disorders. The findings include the observation that similar white matter alterations are shared across ADHD and ASD and that functional connectivity of the cingulo-opercular network is associated with treatment response in ADHD patients. Other papers in this issue characterize neural circuits that are associated with processes that are related to the diverse presentations of psychopathology. These include identifying altered interoception-related activation of the mid-insula as being common across psychiatric diagnoses and identifying, in neonates, brain regions that are activated by the presentation of unexpected stimuli that are correlated with maternal anxiety. Despite these potentially important findings, which lend new insights into brain alterations associated with psychopathology, the extent to which they are related to etiology or pathophysiology remains to be determined. By their nature, the findings cannot address questions of causality. After years of neuroimaging research, it is apparent that there are considerable limitations to current imaging methods that challenge the earlier enthusiasm about the use of MRI in psychiatry. At the same time, it is important to recognize the very significant contributions from neuroimaging studies that have allowed for an in-depth understanding of brain-behavior relationships in humans. These studies, like those presented in this issue, provide new ideas about adaptive and maladaptive cognitive, emotional, and behavioral processes that are relevant to psychiatric illnesses. Neuroimaging measures and other measures of brain activity such as EEG are already being explored in the development of personalized treatment approaches. In pursuit of this goal, it will be critical to take advantage of machine learning methods in relation to large-scale neuroimaging, genomic, and demographic data that can be used to develop algorithms that are reliable at the individual patient level.