Oxygen-15 Labeled Water Positron Emission Tomography During External Trigeminal Nerve Stimulation.

Background: Neuromodulation through external trigeminal nerve stimulation (eTNS) is an emerging noninvasive wearable treatment for neuropsychiatric disorders including attention deficit disorder, epilepsy, and major depression. eTNS is now US Food and Drug Administration approved for attention deficit disorder and investigational for the treatment of epilepsy, major depression, and other neuropsychiatric disorders. Rodent studies indicate eTNS activates key brainstem nuclei, in addition to the amygdala and hippocampus. However, the effect of eTNS on cortical blood flow and metabolism is not known. A better understanding of which brain areas are activated or deactivated by eTNS would provide a scientific basis for current applications and could provide a roadmap to identify new disease targets and interventions.

Objectives: This study aimed to investigate the effect of eTNS on brain blood flow using oxygen-15 labeled water positron emission tomography ([¹⁵O]H₂O PET) to advance the understanding of the networks, pathways, and mechanisms of action of eTNS in humans.

Material and methods: Institutional review board approval and informed consent were obtained. Five subjects underwent eTNS using electrodes positioned 2.5 cm from the nasal midline to stimulate the paired supraorbital branches of the trigeminal nerve. [¹⁵O]H₂O brain PET scans were performed using a Siemens-CTI HR+ EXACT system at the University of California Los Angeles Laboratory of Neuroimaging. Three scans were performed with trigeminal stimulation ON (scans 1, 3, and 6), and three scans were performed with trigeminal stimulation OFF (scans 2, 4, and 5). Data were analyzed comparing stimulus ON with stimulus OFF scans. Adjustments for multiple comparisons were performed using the family-wise error correction.

Results: eTNS of the supraorbital branches of the trigeminal nerve produced significant activations (increased cerebral blood flow) in bilateral anterior cingulate gyri; bilateral parieto-temporal cortex; left inferior frontal gyrus; and right medial and middle frontal gyri. The most significant deactivations (decreased blood flow) occurred in the left parahippocampal gyrus, right sensorimotor cortex, right superior parietal area, bilateral temporo-occipital cortex, and bilateral visual cortex.

Conclusions: eTNS of bilateral supraorbital nerves (V₁ division) generates significant activations during [¹⁵O]H₂O PET imaging in regions associated with major depression and attention deficit disorder. Deactivations of cortical regions including the parahippocampal gyrus, sensorimotor cortex, and others provide a rationale for some of the antiseizure effects of trigeminal nerve stimulation. The results of this study advance our understanding of mechanisms of action of trigeminal nerve stimulation in neuropsychiatric disorders and epilepsy.