Topographic and widespread auditory modulation of the somatosensory cortex: potential for bimodal sound and body stimulation for pain treatment.

Objective. There has been growing interest in understanding multisensory integration in the cortex through activation of multiple sensory and motor pathways to treat brain disorders, such as tinnitus or essential tremors. For tinnitus, previous studies show that combined sound and body stimulation can modulate the auditory pathway and lead to significant improvements in tinnitus symptoms. Considering that tinnitus is a type of chronic auditory pain, bimodal stimulation could potentially alter activity in the somatosensory pathway relevant for treating chronic pain. As an initial step towards that goal, we mapped and characterized neuromodulation effects in the somatosensory cortex (SC) in response to sound and/or electrical stimulation of the body.Approach.We first mapped the topographic organization of activity across the SC of ketamine-anesthetized guinea pigs through electrical stimulation of different body locations using subcutaneous needle electrodes or with broadband acoustic stimulation. We then characterized how neural activity in different parts of the SC could be facilitated or suppressed with bimodal stimulation.Main results. The topography in the SC of guinea pigs in response to electrical stimulation of the body aligns consistently to that shown in previous rodent studies. Interestingly, auditory broadband noise stimulation primarily excited SC areas that typically respond to stimulation of lower body locations. Although there was only a small subset of SC locations that were excited by acoustic stimulation alone, all SC recording sites could be altered (facilitated or suppressed) with bimodal stimulation. Furthermore, specific regions of the SC could be modulated by stimulating an appropriate body region combined with broadband noise.Significance. These findings show that bimodal stimulation can excite or modulate firing across a widespread yet targeted population of SC neurons. This approach may provide a non-invasive method for altering or disrupting abnormal firing patterns within certain parts of the SC for chronic pain treatment.

Ultrasound does not activate but can inhibit in vivo mammalian nerves across a wide range of parameters.

Ultrasound (US) has been shown to stimulate brain circuits, however, the ability to excite peripheral nerves with US remains controversial. To the best of our knowledge, there is still no in vivo neural recording study that has applied US stimulation to a nerve isolated from surrounding tissue to confirm direct activation effects. Here, we show that US cannot excite an isolated mammalian sciatic nerve in an in vivo preparation, even at high pressures (relative to levels recommended in the FDA guidance for diagnostic ultrasound) and for a wide range of parameters, including different pulse patterns and center frequencies. US can, however, reliably inhibit nerve activity whereby greater suppression is correlated with increases in nerve temperature. By prohibiting the nerve temperature from increasing during US application, we did not observe suppressive effects. Overall, these findings demonstrate that US can reliably inhibit nerve activity through a thermal mechanism that has potential for various health disorders, though future studies are needed to evaluate the long-term safety of therapeutic ultrasound applications.

Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway.

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.

Investigating a new neuromodulation treatment for brain disorders using synchronized activation of multimodal pathways.

Neuromodulation is an increasingly accepted treatment for neurological and psychiatric disorders but is limited by its invasiveness or its inability to target deep brain structures using noninvasive techniques. We propose a new concept called Multimodal Synchronization Therapy (mSync) for achieving targeted activation of the brain via noninvasive and precisely timed activation of auditory, visual, somatosensory, motor, cognitive, and limbic pathways. In this initial study in guinea pigs, we investigated mSync using combined activation of just the auditory and somatosensory pathways, which induced differential and timing dependent plasticity in neural firing within deep brain and cortical regions of the auditory system. Furthermore, by varying the location of somatosensory stimulation across the body, we increased or decreased spiking activity across different neurons. These encouraging results demonstrate the feasibility of systematically modulating the brain using mSync. Considering that hearing disorders such as tinnitus and hyperacusis have been linked to abnormal and hyperactive firing patterns within the auditory system, these results open up the possibility for using mSync to decrease this pathological activity by varying stimulation parameters. Incorporating multiple types of pathways beyond just auditory and somatosensory inputs and using other activation patterns may enable treatment of various brain disorders.

A new concept for noninvasive tinnitus treatment utilizing multimodal pathways.

Current noninvasive treatments for tinnitus have shown mixed results. There have been encouraging developments in using invasive brain or vagal nerve stimulation to modulate neural populations driving the tinnitus percept. However, these invasive treatments can only be used in a small patient population with severe conditions. In this preliminary study, we present a new treatment option we call Multimodal Synchronization Therapy (MST), which attempts to achieve synchronized and localized brain activation without invasive neural stimulation. MST combines multiple sensory, motor, limbic, and cognitive inputs to elicit activation of multimodal neurons to potentially modulate specific neurons driving the tinnitus percept. We present preliminary data in a guinea pig model showing activation of somatosensory and auditory pathways to alter neural activity within the inferior colliculus, a multimodal integration region that has shown pathological changes in animals and patients with tinnitus. Electrical stimulation of different body locations induced excitatory responses in the inferior colliculus, eliciting responses in up to 41% of all recording sites for a given somatic site. Paired somatic and acoustic stimulation resulted in enhanced or suppressed acoustic-driven neural activity in the inferior colliculus that varied depending on stimulation and recording location. Similar modulation effects were observed in the auditory cortex, which may relate to changes in auditory perception. Further studies need to incorporate multiple multimodal pathways and must also confirm that MST can suppress the abnormal neural patterns that directly drive the tinnitus percept.