The research team led by Miriam Klein-Flügge, PhD, associate professor of psychiatry and experimental psychology at the University of Oxford, has been investigating the potential use of transcranial ultrasound stimulation (TUS) for the treatment of depression and other psychiatric disorders. TUS uses low intensity focused ultrasound for neuromodulation purposes. The group recently conducted a mechanistic study to confirm whether the basolateral amygdala (BLA) of the brain was responsible for resolving emotional ambiguity, a state in which a person cannot identify emotions that are subtle and uncertain.
In phase one, the researchers created and validated a computer-based emotional ambiguity learning task. In the task, healthy participants (n=29) were shown happy, angry, or neutral faces and asked to decide whether to approach (push left button) or avoid (push right button) each face. If the participant chose approach, the face would grow larger; if avoid was chosen, the face would shrink smaller. The participant was then given feedback on whether their response was accurate (with a goal of learning from that feedback). After collecting data over multiple sessions, the team validated the task as a measure of emotional biases and feedback learning. Baseline MRIs were also performed on each participant during phase one.
The next step was to apply TUS to determine whether it would affect the emotional ambiguity processes. Correct transducer placement was registered to the previously acquired MRI. Participants were tested at three separate visits with one of the following noninvasive interventions: TUS to the amygdala, TUS to the mid-insula as control region, or a sham procedure. After each TUS session, the participant underwent further MRI scanning, with each full session lasting 1.5 to 2 hours.
Investigators applied the TUS bilaterally to each brain region with the Brainbox NeuroFUS Pro system using a 212 kHz Sonic Concepts NeuroFUS Pro transducer. The treatment was continuously tracked by the Brainsight neuronavigation system. The TUS was sequentially delivered for a duration of 80 seconds to each hemisphere at a 5-Hz pulse repetition frequency, 20-ms pulse width, 200-ms pulse repetition interval, and 10% duty cycle. After undergoing TUS, participants were moved into a 7T MRI scanner for the collection of task fMRI, resting-state fMRI, and magnetic resonance spectroscopy data.
The study revealed that applying bilateral TUS to the BLA:
Was a safe, precise, and efficient way to perturb neural activityAffected various measures of neural activity, including decreasing resting-state connectivity between the BLA and its mono-/di-synaptically connected regionsChanged metabolites with a decreased excitation/inhibition balance in the glutamate/gamma-aminobutyric acid ratio (no change in glutamate/increase in gamma-aminobutyric acid)Altered participant responses to emotionally ambiguous stimuli (increased tendency to approach neutral faces)Changed participant response speed to emotionally ambiguous stimuli (increased reaction time to happy and neutral faces)
“This study revealed that the BLA plays a role in detecting and resolving emotional ambiguity,” said Dr. Klein-Flügge. “Given the amygdala is a key brain region with abnormal metabolism in mood disorders, the ability to modulate its activity noninvasively and see effects on emotional processing is an exciting step for us and the field. Future investigations on mood disorder patients are likely to be informed by these results.”
The authors also noted that the bilaterality of the stimulation protocol was likely significant to the emotional processing and behavior findings.
This project was funded by the Wellcome Trust with investigators also acknowledging various individual funding sources.