"Transcranial focused ultrasound (tFUS) is an emerging method for non-invasive neuromodulation akin to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). tFUS offers several advantages over electromagnetic methods including high spatial resolution and the ability to reach deep brain targets. Here we describe two experiments assessing whether tFUS could modulate mood in healthy human volunteers by targeting the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation.
"In a randomized, placebo-controlled, double-blind study, participants received 30 s of 500 kHz tFUS or a placebo control. Visual Analog Mood Scales (VAMS) assessed mood four times within an hour (baseline and three times after tFUS). Participants who received tFUS reported an overall increase in Global Affect (GA), an aggregate score from the VAMS scale, indicating a positive shift in mood.
"Experiment 2 examined resting-state functional (FC) connectivity using functional magnetic resonance imaging (fMRI) following 2 min of 500 kHz tFUS at the rIFG. As in Experiment 1, tFUS enhanced self-reported mood states and also decreased FC in resting state networks related to emotion and mood regulation. These results suggest that tFUS can be used to modulate mood and emotional regulation networks in the prefrontal cortex.
Introduction
"Transcranial focused ultrasound (tFUS) is an emerging tool for non-invasive neuromodulation that transmits low-intensity ultrasound through the skull to temporarily and safely modulate regional brain activity (Tyler, 2011).
Ultrasound neuromodulation offers advantages over transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), such as better spatial resolution and the ability to reach deep targets in the brain (Fini and Tyler, 2017). tFUS reversibly modulates neuronal activity in rats (Tufail et al., 2010; Kim et al., 2014), sheep (Lee et al., 2016c), pigs (Dallapiazza et al., 2017), and monkeys (Downs et al., 2016). In humans, tFUS has temporarily altered activity in somatosensory (Lee et al., 2016a), visual (Lee et al., 2016b), and thalamic brain regions (Legon et al., 2018). Researchers are interested in clinical applications of tFUS, including the treatment of psychiatric and neurological disease (Bystritsky and Korb, 2015; Monti et al., 2016).
"The current experiments investigated whether tFUS could modulate mood in healthy participants by sonicating a region in the prefrontal cortex implicated in emotional regulation, thereby uncovering a target for future therapeutic interventions (Experiment 1). The second experiment used resting-state functional magnetic resonance imaging (fMRI) to investigate FC changes after sonication of the prefrontal cortex to demonstrate that tFUS modulates brain function in networks related to emotional processing and mood.
"The prefrontal cortex plays a vital role in emotion and mood regulation (Phan et al., 2002; Coan and Allen, 2004; Ochsner and Gross, 2005; Price and Drevets, 2012). Hemispheric asymmetries in prefrontal activity are thought to contribute to emotional processing (Coan and Allen, 2004; Davidson, 2004; Craig, 2005), and dysfunctions in these networks are related to mood disorders like depression (Stewart et al., 2014) and bipolar disorder (Kerestes et al., 2012).
"Higher levels of left frontal activity are correlated with more approach motivation (Phillips et al., 2008) and positive mood (Fitzgerald et al., 2008), whereas higher levels of right frontal activity are associated with more withdrawal motivation, negative mood (Hauptman et al., 2008), and increased risk for anxiety and depression (Rempel-Clower, 2007). Currently, TMS and tDCS interventions target lateralized frontal cortex to enhance emotional control in healthy participants or to treat negative mood states in depression (George et al., 2000) and bipolar disorder (Michael and Erfurth, 2004).
"In addition to TMS and tDCS, tFUS shows promise as a neuromodulation technique for altering mood states. In a pilot experiment testing the effects of ultrasound neuromodulation on patients, Hameroff et al. (2013) used a clinical ultrasound device at eight megahertz and found that 15 s of sonication of the prefrontal cortex enhanced mood in chronic pain patients, which lasted up to 40 min. Although this experiment suggests that ultrasound neuromodulation could be useful as a therapeutic tool to modulate mood states, the results must be interpreted with caution due to methodological limitations. First, the researchers delivered ultrasound to the prefrontal cortex contralateral to the side that patients reported the most significant pain.
"In other words, the location where the ultrasound transducer was placed was not uniform across patients. Second, Hameroff and colleagues used an unfocused ultrasound beam applied to the temporal window of the skull, likely sonicating frontal, temporal, and prefrontal cortices. The lack of control of stimulation location makes it impossible to determine whether the unfocused ultrasound affected mood directly, by stimulating a substrate of mood, or indirectly, by modulating other networks, such as those involved in pain perception (i.e., reducing pain perception may lead to more positive mood states). tFUS can untangle these issues by directly targeting brain regions involved in mood and emotional regulation.
"One major advantage of tFUS relative to the other neuromodulation techniques like TMS and tDCS is that tFUS has a higher spatial resolution relative to the others. In tFUS applications, the ultrasound beam can be focused at virtually any depth through the human skull to target distinct cortical areas with millimeter resolution (Kubanek, 2018). Lee et al. (2015) showed that tFUS targeting the primary somatosensory cortex produced sonication-specific tactile sensations and somatosensory evoked potentials. Another study further demonstrated the high spatial specificity of tFUS by targeting the primary or secondary sensory cortices with a dual-transducer apparatus, which elicited tactile sensations correlated with the targeted cortical area (Lee et al., 2016a).
"Sonication of a sub-region of the thalamus with tFUS modulates somatosensory evoked potentials in healthy volunteers, exhibiting the deep focal ability and superior spatial resolution of tFUS (Legon et al., 2018). These experiments suggest that tFUS offers a unique modality for non-invasive modulation of region-specific brain function, and could be a useful method for exploring the effects of ultrasound neuromodulation on emotional regulation centers in the prefrontal cortex.
"The goal of the current study was to use tFUS to modulate mood by targeting the right ventrolateral prefrontal cortex (rVLPFC), one of the major areas in the prefrontal cortex for emotional control and mood regulation (Sang and Hamann, 2007), and in particular the regulation and suppression of negative emotions (Ochsner and Gross, 2005; Goldin et al., 2008; Wager et al., 2008). Increased activity of rVLPFC is associated with less negative emotional experience when participants view aversive stimuli (Wager et al., 2008), and symptoms of depression inversely correlate with rVLPFC activity (Drevets et al., 2008).
"Several experiments show that modulation of the rVLPFC can alter the subjective experience of emotions. For instance, the application of anodal tDCS over the rVLPFC reduces negative feelings in social isolation video games (Riva et al., 2012, 2015a,b) and reduces emotional reactions to negative video clips, even when participants are not explicitly told to suppress negative emotion (Vergallito et al., 2018).
"Thus, the rVLPFC can serve as a target to enhance control over the emotional experience, which may lead to more positive mood states. Given the focal specificity of tFUS, we chose to target a specific region in rVLPFC, the right inferior frontal gyrus (rIFG; BA 35). The rIFG is a central hub for inhibition and cognitive control (Aron et al., 2014) and has been demonstrated to promote control over emotional processing (Chiu et al., 2008). We predicted that tFUS to the rIFG, using pulse parameters previously shown by Hameroff et al. (2013) to modulate mood in chronic pain patients, would enhance mood in healthy volunteers (Experiment 1).
"Experiment 2 used resting-state fMRI FC analysis to determine whether tFUS to the rIFG temporarily altered networks associated with mood and emotional regulation. These results would support the notion that the rVLPFC (specifically the rIFG) is involved in processing mood states and would serve as the foundation for future research investigating therapeutic applications of tFUS for mood-related disorders.
Conclusion
"Transcranial focused ultrasound at 500 kHz targeting the rIFG for 30 s (Experiment 1) and 2 min (Experiment 2) increased self-reported mood in healthy participants as compared to baseline mood. Corresponding connectivity changes in networks relevant for emotion/mood regulation occurred 20 min after sonication in Experiment 2, demonstrating that tFUS could modulate functionally specific brain networks relevant for mood regulation. These results are in line with recent experiments suggesting that tFUS can modulate network connectivity (Folloni et al., 2019; Verhagen et al., 2019).
"These results are the first to demonstrate that tFUS can affect mood and cortical networks important for mood regulation, with effects that appear on the order of 20 min following tFUS delivery. Our results show that tFUS aimed at rIFG with a single element transducer can modulate prefrontal cortical activity and improve mood. The present findings suggest that tFUS could be a useful tool in the treatment of clinical disorders characterized by negative mood states, like depression and anxiety disorders and future studies are warranted.
Please read the entire publication and references: https://www.frontiersin.org/articles/10.3389/fnhum.2020.00052/full [Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans by Joseph L. Sanguinetti1,2,3*, Stuart Hameroff1,2,4, Ezra E. Smith1,5, Tomokazu Sato6†, Chris M. W. Daft7, William J. Tyler8 and John J. B. Allen1 Front. Hum. Neurosci., 28 February 2020 | https://doi.org/10.3389/fnhum.2020.00052]
