ABSTRACT
Background: Anxiety affects 4.4-million children in the United States with an onset between childhood and adolescence, a period marked by neural changes that impact emotions and memory. Negative overgeneralization - or responding similarly to innocuous events that share features with past aversive experiences - is common in anxiety but remains mechanistically underspecified. The nucleus reuniens (RE) has been considered a crucial candidate in the modulation of memory specificity. Our study investigated its activation and functional connectivity with the medial prefrontal cortex (mPFC) and hippocampus (HPC) as neurobiological mechanisms of negative overgeneralization in anxious youth. Methods: As part of a secondary data analysis, we examined data from 34 participants between 9-14 years (mean age ± SD, 11.4 ± 2.0 years, 16 females) with varying degrees of anxiety severity. During the Study session participants rated images as negative, neutral, and positive. After 12-hours, participants returned for a Test session, where they performed a memory recognition test with repeated (targets) and similar (lures) images. Labeling negative relative to neutral lures as "old" (false alarms) was our operational definition of negative overgeneralization. Results: Negative relative to neutral false alarmed stimuli displayed elevated RE activation (at Study and Test) and increased functional connectivity with the CA1 (at Test only). Elevated anxiety severity was associated with reductions in the RE-mPFC functional coupling for neutral relative to negative stimuli. Exploratory analyses revealed similar patterns in activation and functional connectivity with positive stimuli. Conclusions: Our findings demonstrate the importance of the RE in the overgeneralization of memories in anxious youth.
ABSTRACT
The midline thalamus is critical for flexible cognition, memory, and stress regulation in humans and its dysfunction is associated with several neurological and psychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. Despite the pervasive role of the midline thalamus in cognition and disease, there is a limited understanding of its function in humans, likely due to the absence of a rigorous noninvasive neuroimaging methodology to identify its location. Here, we introduce a new method for identifying the midline thalamus in vivo using probabilistic tractography and k-means clustering with diffusion weighted imaging data. This approach clusters thalamic voxels based on data-driven cortical and subcortical connectivity profiles and then segments the midline thalamus according to anatomical connectivity tracer studies in rodents and macaques. Results from two different diffusion weighted imaging sets, including adult data (22-35 years) from the Human Connectome Project (n = 127) and adolescent data (9-14 years) collected at Florida International University (n = 34) showed that this approach reliably classifies midline thalamic clusters. As expected, these clusters were most evident along the dorsal/ventral extent of the third ventricle and were primarily connected to the agranular medial prefrontal cortex (e.g., anterior cingulate cortex), nucleus accumbens, and medial temporal lobe regions. The midline thalamus was then bisected based on a human brain atlas into a dorsal midline thalamic cluster (paraventricular and paratenial nuclei) and a ventral midline thalamic cluster (rhomboid and reuniens nuclei). This anatomical connectivity-based identification of the midline thalamus offers the opportunity for necessary investigation of this region in vivo in the human brain and how it relates to cognitive functions in humans, and to psychiatric and neurological disorders.
