Invasive and noninvasive causal evidence of amygdala engagement by DLPFC stimulation

2407 

Abstract Submission 

Xianqing Liu^1,2, Joel Bruss^3,4, Brandt Uitermarkt^3,4, Nicholas Trapp¹, Hiroyuki Oya⁵, Aaron Boes^3,4, Jing Jiang^1,2

¹University of Iowa Hospitals and Clinics, Department of Psychiatry, Iowa City, IA, ²University of Iowa Hospitals and Clinics, Stead Family Department of Pediatrics, Iowa City, IA, ³University of Iowa Hospitals and Clinics, Neuroimaging & Noninvasive Brain Stimulation Laboratory, Iowa City, IA, ⁴University of Iowa Hospitals and Clinics, Department of Neurology, Iowa City, IA, ⁵University of Iowa Hospitals and Clinics, Department of Neurosurgery, Iowa City, IA

Xianqing Liu  
University of Iowa Hospitals and Clinics, Department of Psychiatry|University of Iowa Hospitals and Clinics, Stead Family Department of Pediatrics
Iowa City, IA|Iowa City, IA

Joel Bruss  
University of Iowa Hospitals and Clinics, Neuroimaging & Noninvasive Brain Stimulation Laboratory|University of Iowa Hospitals and Clinics, Department of Neurology
Iowa City, IA|Iowa City, IA

Brandt Uitermarkt  
University of Iowa Hospitals and Clinics, Neuroimaging & Noninvasive Brain Stimulation Laboratory|University of Iowa Hospitals and Clinics, Department of Neurology
Iowa City, IA|Iowa City, IA

Nicholas Trapp  
University of Iowa Hospitals and Clinics, Department of Psychiatry
Iowa City, IA

Hiroyuki Oya  
University of Iowa Hospitals and Clinics, Department of Neurosurgery
Iowa City, IA

Aaron Boes  
University of Iowa Hospitals and Clinics, Neuroimaging & Noninvasive Brain Stimulation Laboratory|University of Iowa Hospitals and Clinics, Department of Neurology
Iowa City, IA|Iowa City, IA

Jing Jiang  
University of Iowa Hospitals and Clinics, Department of Psychiatry|University of Iowa Hospitals and Clinics, Stead Family Department of Pediatrics
Iowa City, IA|Iowa City, IA

While invasive modulation of amygdala activity has shown promise in treating certain refractory psychiatric cases, its widespread use among millions of treatment-resistant patients is impractical and entails inherent neurosurgery-related risks. Our recent studies indicate transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) provides a potential noninvasive alternative (Eshel et al., 2020; Jiang, 2023). However, given the amygdala's deep location in the medial temporal lobe, there is a critical need for definitive causal evidence to determine whether and how DLPFC stimulation engages the amygdala. Therefore, the present study aims to get converging causal evidence of amygdala engagement to DLPFC stimulation from multimodal invasive and noninvasive imaging methods.

We performed 4 studies utilizing an unparalleled combination of invasive and noninvasive stimulation and recording methods in humans. We began with Study 1 in which we delivered single-pulse intracranial electrical stimulation (iES) to the left DLPFC while concurrently recording responses in the amygdala (n=11 electrodes) with intracranial EEG (iEEG) used in epilepsy patients being evaluated for surgery. The effect of iES to a control region, i.e., the left ventrolateral prefrontal cortex (VLPFC), in the amygdala was also assessed. To move towards clinical translatability, we performed another two noninvasive stimulation studies by delivering TMS to the left DLPFC while recording responses in the amygdala with iEEG in epilepsy patients (n=30 electrodes, Study 2) and with functional MRI (fMRI) in healthy individuals (N=85 subjects, Study 3). The effects of TMS to control regions, e.g., parietal cortex, in the amygdala were also assessed. Finally, we evaluated the potential role of DLPFC-amygdala connectivity assessed with resting state functional connectivity MRI in predicting amygdala responses induced by DLPFC stimulation in same participants from Study 2 and 3 (Study 4).

In Study 1, we found single-pulse iES to the DLPFC evokes significant potential change in the amygdala in two separate time windows (119~165ms and 349~430ms) as compared to baseline (t = 2.61~3.36, corrected p < 0.05). In contrast, single-pulse iES to the VLPFC did not evoke similar amygdala response. In Study 2, we observed that single-pulse active TMS to the DLPFC also evokes significant potential difference in three time windows (52~91ms, 194~244ms, and 326~347ms) in amygdala as compared to sham TMS condition (|t| = 2.68~5.01, corrected p < 0.05). However, TMS to the parietal cortex did not evoke similar amygdala response. In Study 3, DLPFC TMS evokes strongest BOLD responses in the amygdala as assessed with concurrent functional MRI (fMRI) in healthy individuals among TMS to 11 TMS sites (Cohen's d = 0.39, Power = 0.92). Finally, in Study 4, we identified significant correlations between DLPFC-amygdala functional connectivity and amplitude in second time window where TMS vs Sham evoked potentials differ (194~244ms; r = 0.54, p =0.011) and TMS-evoked BOLD responses (r = 0.25, p = 0.035) in the amygdala.

Together, our results provide converging and compelling causal evidence of amygdala engagement to DLPFC stimulation. The correlation between DLPFC-amygdala RSFC and DLPFC TMS-induced response in the amygdala suggests a possible functional connectivity-based strategy to target the amygdala, offering a circuit-based insight into the feasibility of noninvasive neuromodulatory therapies aiming at modulating the amygdala for psychiatric disorders.

Direct Electrical/Optogenetic Stimulation

Non-invasive Magnetic/TMS ²

Psychiatric (eg. Depression, Anxiety, Schizophrenia)

Multi-Modal Imaging ¹

FUNCTIONAL MRI

Psychiatric Disorders

Transcranial Magnetic Stimulation (TMS)

Other - Intracranial electrical stimulation (iES); resting state functional connectivity; amygdala; dlPFC; multi-modal imaging; neuromodulation