The Association between Performance Monitoring, Anterior Cingulate Volume and Obsessive-Compulsive Disorder in Early Development

What's the science?

Obsessive-compulsive disorder (OCD) has been associated with heightened performance monitoring. Although monitoring one's performance on tasks can be beneficial, too much performance monitoring may affect daily function. The anterior cingulate cortex is a brain region known to be involved in performance monitoring. It is unknown whether elevated performance monitoring in early childhood predicts later development of OCD, and whether this is associated with structural changes in anterior cingulate cortex. Identifying early markers of OCD has important implications for public health. This week in JAMA Psychiatry Gilbert and colleagues investigate the association between performance monitoring, OCD risk and anterior cingulate volume in a longitudinal cohort of preschool-aged children.

How did they do it?

292 preschool-aged children who were part of a longitudinal depression study completed an observational task where they received negative evaluation (i.e. performance based). The child’s performance monitoring behavior was rated by blinded observers. Performance monitoring was scored as the average of a number of measures representative of performance monitoring, including frustration, deliberateness and care while drawing circles and observed self-criticism and intensity. The participants were then followed up annually for 12 years with clinical assessments and received 1-3 MRI scans throughout the follow-up. 133 completed the final behavioral follow-up and 152 completed MRI scans. The development of OCD was recorded over the 12-year period (using the DSM-V criteria). The authors used logistic regression to test whether performance monitoring was associated with increased risk of OCD. They also measured anterior cingulate cortex volume using MRI and used multi-level modeling (this method can model changes over time) to test whether performance monitoring was associated with anterior cingulate volume over time.

What did they find?

35 children in total developed OCD over the course of the follow-up. High performance monitoring of pre-school aged children (at initial assessment) was associated with a greater risk (2 times higher) of developing OCD later on after controlling for medication, clinical and demographic variables. This association was specific to OCD, meaning there was no association with performance monitoring and the development of other psychiatric disorders. High performance monitoring at baseline was also associated with reduced right dorsal anterior cingulate volume over time. Baseline anxiety was also associated with reduced right anterior cingulate volume. A follow-up exploratory analysis showed that high performance monitoring was also associated with larger left thalamus volume.

                                      Brain, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What's the impact?

This is the first study to demonstrate that performance monitoring in preschool-aged children is associated with later development of OCD. Further, heightened performance monitoring is also associated with reductions in anterior cingulate volume as children age. This study could help in the identification of children at high risk of developing OCD and furthers our understanding of the brain mechanisms involved.

Gilbert et al. Associations of Observed Performance Monitoring During Preschool With Obsessive-Compulsive Disorder and Anterior Cingulate Cortex Volume Over 12 Years. JAMA Psychiatry 2018.  Access the original scientific publication here.

A New Autoantibody involved in Neuropathic Pain

What's the science?

Neuropathic pain can be caused by conditions such as nerve injury, nerve demyelination, spinal cord injury, or stroke, and refers to pain due to injury or disease of the sensory system, according to the International Association for the Study of Pain (IASP). In particular, patients with multiple sclerosis can experience pain which may be due to inflammation of the spinal cord (myelitis). This inflammation may cause an immune response, and a potential mechanism of neuropathic pain could be due to autoantibodies, antibodies within the body’s own immune system which may somehow affect the nerves. This week in Annals of Neurology, Fujii and colleagues assessed autoantibodies in neuropathic pain patients to understand what role they might play in neuropathic pain.

How did they do it?

110 patients with a condition causing probable or definite neuropathic pain (IASP criteria for neuropathic pain) and 50 controls participated. Controls were comprised of 20 healthy individuals, 20 people with a neurodegenerative disease and 10 people with a collagen-vascular disease. Sera was extracted from blood from each individual. Immunofluorescence assays were performed, using sera from human study participants and tissue that had been removed from adult male mice (the dorsal root ganglia, the spinal cord, and skin). Human IgG antibodies bound to the tissue were detected using anti-human IgG antibodies. In the dorsal root ganglia (nerve root near the spinal cord) double immunostaining for both human IgG antibodies and neuronal markers was performed. Participants were classified as seropositive (IgG antibody binding to mouse tissues) or seronegative (no immunoreactivity). Each participant’s IgG subtype was also identified. Western blotting was performed to identify proteins/antigens that the autoantibody was bound to.

What did they find?

There was no immunoreactivity to the dorsal root ganglion neurons amongst controls, but serum IgG binding was positive in 11 neuropathic pain patients (seropositive patients). IgG subclass IgG2 was dominant in these seropositive patients. Using dual immunostaining, the authors identified that IgG antibody binding occurred most frequently at unmyelinated C fiber neurons (most commonly non-peptidergic). C fiber neurons are known to be involved in pain. When the authors performed dual staining for antibodies and two receptors known to be involved in pain (TRPV1 and P2X3), they found that antibodies were partially (TRPV1) or mostly (P2X3) co-localized with the receptors. The stain for IgG antibodies also co-localized with axon terminals in the spinal cord in lamina (layer) I and II (where C fiber neurons are known to terminate). The authors then characterized the autoantigen (that the autoantibody binds to) immunochemically using mass spectrometry, and found that it was likely to be plexin D1 (in mice). To characterize plexin D1 in humans, the authors performed immunostaining in tissue from two deceased human donors and observed co-localization of unmyelinated afferents and plexin D1 in the dorsal horn of the spinal cord. This finding suggests that the autoantibody was specific to neurons important for pain.

The 11 patients with auto-antibodies for small unmyelinated dorsal root ganglion neurons tended to be younger and female, and had burning or tingling pain with sensory impairment. Sera from patients with anti-D1 plexin antibodies was then applied to dorsal root ganglion neurons in mice, and cellular and nuclear swelling and increased permeability of the membrane was observed, suggesting cytotoxicity.

What's the impact?

This is the first study to identify human autoantibodies that bind to neurons known to be involved in pain in neuropathic pain patients. Autoantibodies were found to be specific to the plexin D1 protein, which plays various roles in the immune and nervous systems. This study could have important implications for the study of neuropathic pain and its response to immunotherapy.

Fujii et al. A novel autoantibody against plexin D1 in patients with neuropathic pain. Annals of Neurology. 2018.  Access the original scientific publication here.

Accents and Confidence Modulate Brain Activity during Speech Perception

Post by: Shireen Parimoo

What's the science?

In-group favoritism refers to people’s tendency to hold more positive views about members of their own social group compared to members of an out-group. Accents act as indicators of social belonging, and a speaker’s voice also conveys information about their trustworthiness; they are more likely to be believed when their tone is confident rather than doubtful. We don’t know how voice-based perception of a speaker is processed in the brain and how level of confidence may influence the perception of an out-group speaker. This week in NeuroImage, Jiang and colleagues investigated patterns of brain activity in participants listening to in-group and out-group speakers with different accents and varying degrees of confidence.

How did they do it?

Twenty-six young adults listened to and rated the believability of English statements spoken in their native accent (Canadian-English; in-group), in a regional accent (Québécois-French; out-group/regional), and in a foreign accent (Australian; out-group/foreign). The statements also varied in whether they sounded confident, neutral, or doubtful. Participants rated how intelligible each accent sounded to them and how much they liked each accent. Neural activity was recorded using functional magnetic resonance imaging (fMRI) to understand whether in-group and out-group accents differentially activated the brain while participants judged believability. The authors used psycho-physiological interaction (PPI) analysis to determine if activity in regions involved in confidence judgments, such as the right superior temporal gyrus and the inferior frontal gyrus, was correlated with activity in other brain regions while participants made believability judgments. Finally, they examined whether these functional connections in the brain were modulated by the speaker’s accent.

What did they find?

Overall, participants were more likely to believe statements spoken in their native accent than those spoken in a regional or foreign accent. Listening to speakers with out-group accents activated temporal regions of the brain (e.g. superior temporal gyrus), whereas listening to in-group accents activated frontal regions (e.g. superior frontal gyrus). Participants also rated neutral and confidently spoken statements as more believable than doubtful statements; statement confidence was related to increased activity in the superior temporal gyrus, while statements made in a doubtful voice were associated with greater activation of temporal areas. Although confident statements were rated as equally believable across all accents, brain activity was greater in the caudate, cuneus, and fusiform regions when confident statements were heard in out-group accents. This could be because judging the believability of out-group speakers requires more in-depth processing of the vocal and acoustic characteristics of speech. PPI analysis revealed that listening to out-group accents resulted in increased connectivity between regions involved in decoding confidence – such as the superior temporal gyrus – and regions involved in inferring meaning of sentences, such as the inferior frontal gyrus. Statement believability was associated with greater connectivity between the superior temporal gyrus and the middle temporal gyrus and between the superior temporal gyrus and the lingual gyrus/middle occipital gyrus when listening to out-group speakers. These findings suggest that neural activity associated with processing voice characteristics and associated biases towards out-group speakers can be modified by the level of confidence of the speaker.

                                     Brain, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What's the impact?

The study demonstrates how distinct neural mechanisms are involved in carrying out the same decision-making process in speech perception depending on the speaker’s accent and degree of confidence. These results provide a deeper understanding of how different regions of the brain are involved in categorizing speakers based on group membership, and the effect this has on social inference from speech.

Jiang et al. Neural architecture underlying person perception from in-group and out-group voices. NeuroImage. 2018.  Access the original scientific publication here.