|Wireless Communication in the Brain
II. Evidence from Ultrasound Stimulation
Neuronal excitation by ultrasound has been demonstrated nearly ninety years ago [E.N. Harvey, Am. J. Physiol., 91 (1929), pp. 284–290], but only recently have researchers begun active investigations in this area (Tyler et al., 2008; Tufail et al., 2010; Mueller et al., 2014; Lee et al., 2015; Ye et al., 2016; Li et al., 2016; Kamimura et al., 2016; Lee et al., 2017). Its underlying mechanism remains unclear (Rezayat and Toostani, 2016). This paper will show that the "Microtubule Model for Excitability" (Paper 2) originally proposed for wireless communication in the brain (Paper 1) can readily explain the ultrasound stimulation. Furthermore, the same mechanism may also apply to "traumatic brain injury" which is the topic of Paper 13.
According to the "BDNF Cascade Hypothesis", the deficiency of brain-derived neurotrophic factor (BDNF) plays a pivotal role in Alzheimer's disease (AD) and other neurodegenerative disorders. Paper 11 has presented several approaches to increasing BDNF level. The ultrasound stimulation may provide an additional method.
The Mechanism of Ultrasound Stimulation
The Microtubule Model for Excitability suggests that the external force, either electromagnetic (EM) or mechanical force, may cause microtubules to dissociate from the membrane at the axon initial segment (AIS), thereby enhancing excitability. The ultrasound produces mechanical pressure waves and thus could also act on microtubules to modulate excitability. At AIS, microtubules are organized as "fascicles", each is a bundle of several individual microtubules that are parallel with each another. Since microtubules are highly negatively charged, their association with the membrane has inhibitory effects on neuronal firing, equivalent to membrane hyperpolarization. Dissociation of microtubules from the membrane has the same effects as depolarization. While static forces could knock off microtubules from the AIS membrane, oscillating forces are usually more efficient especially if the oscillating frequency is in resonance with the intrinsic vibrational mode of the microtubule. The EM frequency employed by brain communication is estimated to be around 10 MHz (Paper 1), which is comparable to the ultrasound frequencies (1 - 5 MHz) used in some studies (Ye et al., 2016; Li et al., 2016; Kamimura et al., 2016).
In Paper 1, only the transverse mode of microtubule vibration was considered. Figure 1 shows microtubule vibration in the longitudinal direction, which may lead to partial detachment (bending) from the AIS membrane. Microtubule bending (buckling) has been demonstrated experimentally (Figures 2 and 3). Its peak displacement could be as large as 1 μm (= 1000 nm), which should have significant influence on neuronal excitability (Paper 1). Therefore, both transverse and longitudinal vibrations may enhance excitability by causing the microtubule fascicle to completely or partially detach from the membrane, but the transverse vibration seems more effective.
Not all AIS structures are equal. The microtubules capable of sensing EM waves and regulating excitability are expected to exist only in the neurons participating in long range synchronization and other types of wireless communication. They are located in hippocampus (theta rhythm), primary motor cortex (beta rhythm), locus coeruleus (slow oscillations), and sensorimotor cortex (mu rhythm) (Paper 5). These areas are also the major targets of low intensity focused ultrasound stimulation (LIFUS) (Tyler et al., 2008; Tufail et al., 2010; Kamimura et al., 2016; Lee et al., 2017). Therefore, LIFUS may act on the same AIS microtubules to modulate excitability.
BDNF Enhancement by Ultrasound Stimulation
BDNF plays a key role in hippocampal plasticity. It is normally stored in the vesicles of presynaptic terminal, and released in an activity dependent manner (Park et al., 2014). The released BDNF may trigger the BDNF-TrkB signaling pathway, resulting in the production of plasticity-related proteins, including BDNF itself (Paper 4). Hence, ultrasound can excite hippocampal neurons to produce more BDNF, as has been demonstrated experimentally (Tufail et al., 2010; Lin et al., 2015; Huang et al., 2017).
Author: Frank Lee