Mo Chen's research while affiliated with University of Minnesota Duluth and other places

Background Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network–targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: β = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: β = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Background: The pathophysiology of adductor laryngeal dystonia (AdLD) remains unknown; however, there is growing evidence that dystonia is associated with disruptions in the inhibitory regulation of sensorimotor cortical areas. Using functional MRI (fMRI) and transcranial magnetic stimulation (TMS) complementarily, we previously demonstrated an overly activated laryngeal motor cortex and revealed correlations between blood-oxygen-level dependent (BOLD) activation and intracortical inhibition in a phonation (dystonia-related) task in adductor laryngeal dystonia (AdLD). Objective: Here, we aimed to characterize the brain-based findings in the primary motor cortex (M1) during a dystonia-unrelated (finger tapping) task in AdLD and controls (CTL). Methods: We examined the between-group differences in task-dependent BOLD activation and intracortical inhibition, measured by the TMS-evoked cortical silent period (cSP), in the M1. The correlations between fMRI and TMS responses were assessed. Results: There is more broadly dispersed BOLD activation, not confined to the hand motor cortex, and reduced intracortical inhibition in AdLD compared to CTL. Further, there are more positive correlations between cSP and BOLD activation in a task unrelated to dystonic symptoms in AdLD compared with CTL. This is in contrast to our previous work that demonstrated fewer positive correlations in AdLD during a dystonic phonation task. Conclusions: In unaffected musculature activation, there is dispersed BOLD activation that is correlated with intracortical inhibition suggesting a possible compensatory strategy in the non-dystonic muscles.

Background Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patients' ability to implement tic controllability behaviors. Methods The CBIT + TMS trial is a two-phase, milestone-driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, non-invasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12–21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1 Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori “Go/No Go Criteria” guide the decision to proceed to phase 2 and the selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants. Discussion This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. The results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change. Trial registration ClinicalTrials.gov NCT04578912. Registered on October 8, 2020.

Background: Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patient ability to implement tic controllability behaviors. Methods: The CBIT+TMS trial is a two-phase, milestone driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, noninvasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12-21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori “Go/No Go Criteria” guide the decision to proceed to Phase 2 and selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants. Discussion: This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. Results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change. Trial registration: ClinicalTrials.gov Identifier: NCT04578912. Registered October 8, 2020. https://clinicaltrials.gov/ct2/show/NCT04578912

Fear overgeneralization is a potential pathogenic mechanism of anxiety-related disorders. A dominant model posits that overgeneralization occurs when the hippocampus fails to distinctly encode benign stimuli with insufficient similarity to previously encountered fear cues, triggering excessive retrieval of stored fear representations. This model has cross-species support but has not been causally tested in humans. A developing literature demonstrates that hippocampal network targeted transcranial magnetic stimulation (HNT-TMS) can strengthen hippocampal-dependent memory encoding. Building on this literature, we hypothesized that HNT-TMS would strengthen encoding of perceptually similar stimuli and thereby reduce retrieval errors (i.e., sharpen discrimination) in participants with post-traumatic stress symptoms. We predicted that this effect would emerge for fear stimuli as measured by the Farmer Task and neutral stimuli as measured by the Mnemonic Similarity Task. Continuous theta-burst stimulation (cTBS) was delivered to individualized left posterior-parietal targets derived via precision functional mapping, seed-based connectivity, and electric-field modeling methods. A vertex control target was also stimulated in a within-subject design (final N = 25). Multilevel models did not reveal significant interactions between stimulation target and fear or neutral stimulus discrimination. However, HNT-TMS strengthened fear discrimination in participants with lower sensitization, indexed by responsivity to a control stimulus perceptually unrelated to the CS+. Sensitization reflects indiscriminate fear responding unrelated to CS + similarity and is not expected to engage the hippocampal CS + matching function. Our findings therefore indicate that HNT-TMS may selectively sharpen fear discrimination when the hippocampal CS + matching function is more strongly engaged.