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A thermal mechanism underlies tFUS neuromodulation

Open AccessPublished:November 15, 2019DOI:https://doi.org/10.1016/j.brs.2019.10.018
      We read with great interest the commentary titled, “Reversible Neuroinhibition Does Not Require a Thermal Mechanism” in response to our article “Reversible Neuroinhibition by Focused Ultrasound is mediated by a Thermal Mechanism.” [
      • Darrow D.P.
      • O’Brien P.
      • Richner T.J.
      • Netoff T.I.
      • Ebbini E.S.
      Reversible neuroinhibition by focused ultrasound is mediated by a thermal mechanism.
      ] We are grateful that the authors highlight an important and complex point of ongoing discussion in the literature about the underlying mechanism(s) of FUS-mediated neuromodulation.
      There are some differences of interpretation that we are happy to address in a response. We measure significant suppression at temperature changes caused by US at around 1–2° Celsius. This is consistent with our interpretation of other’s work that temperature changes were relatively small. [
      • Korb A.S.
      • Shellock F.G.
      • Cohen M.S.
      • Bystritsky A.
      Low-intensity focused ultrasound pulsation device used during magnetic resonance imaging: evaluation of magnetic resonance imaging-related heating at 3 Tesla/128 MHz.
      ] Spivak et al. therefore interpret these results as not supporting the thermal hypothesis. Our claim is that even temperature changes at these magnitudes can cause significant suppression of neural activity as a signature of thermal activity.
      A major difference in our work is the chosen frequency of ultrasound. We use a 3.2 MHz carrier frequency due to its ability to provide high spatial resolution. Below are our results supporting that ultrasound-mediated thermal effect plays a significant role in neuromodulation:
      • 1)
        The evidence for a thermal mechanism does not rest on the absolute value of the temperature measured in brain tissue, regardless of the modality. Brain tissue temperature is a product of heat transfer, thermal source, thermal conductivity, and brain perfusion. Measuring temperature change is a sufficient but not necessary method of evaluating a thermal mechanism. For example, in our manuscript, the time course of the peak-to-peak suppression versus the change in temperature suggests that the maximum effect occurs earlier than the peak temperature change.
      • 2)
        We also described time constants of the neuroinhibition effects that were consistent with the time constants of thermal effects, on the order of 10s of seconds to minutes. These extraordinarily long time constants relative to sensory evoked responses (∼50 ms) are unusual for nonthermal effects. Similarly, Yoo et al. found a group average of 7 minutes before visual-evoked potentials returned to baseline from 9 seconds of sonication (an effect nearly 50 times longer than the intervention). [
        • Yoo S.-S.
        • Bystritsky A.
        • Lee J.-H.
        • Zhang Y.
        • Fischer K.
        • Min B.-K.
        • et al.
        Focused ultrasound modulates region-specific brain activity.
        ] Yoo et al. even suggest thermal effects as a potential mechanism but dismiss this as unlikely because of a lack of measured temperature change. In our best effort to compare sonication parameters between these studies, they equate an ISPPA of 3.3 W/cm2 with an ISPTA of 1.6 W/cm2. We report changes in temperature of less than 0.3C at an ISPTA of 4.4 W/cm2. As a result, 1.6 W/cm2 should produce less than 0.3C change, which falls under the stated sensitivity of their MR thermometry of 0.3±0.06C. Despite the sensitivity of MR thermometry, it is not clear that a 0.3C change is not an important factor that suggests a high rate of thermal generation given the short sonication time.
      • 3)
        We also found that the suppressive effect of ultrasound was related predominantly to the intensity of sonication. Typically, in order to minimize the thermal effect of ultrasound, short pulses at lower duty cycles are used to maximize peak pressures. We found that at a constant intensity, the duty cycle did not appreciably change the effect of the ultrasound when varied from 3% to 70%. As a result, the effect of the ultrasound was not affected by the peak pressures, which were necessarily adjusted to hold the intensity constant.
      • 4)
        Using a laser through fiberoptic delivery, we were able to replicate the temperature change seen during higher sonication amplitudes, which likely produces an even more spatially-restricted focus. The suppression of SSEPs and the associated time constants were found to closely match that of sonication. While it is possible that there are two separate effects (one for light and one for sound), we believe the parsimonious explanation is that the common thermal component is responsible for neuroinhibition.
      There were other significant differences between our work and Yoo et al. The most significant difference is that while Yoo et al. performed a craniectomy to obtain an unimpeded acoustic window, our study was performed transcranially using a higher carrier frequency of 3.2 MHz. Secondly, we used a fine-needle thermistor to measure changes at the acoustic focus, in contrast to MR thermometry employed by Yoo et al.
      Yoo et al. reported a 0.7C change when an ISPPA of 23 W/cm2 was used during a prolonged sonication (27s). We also report a steady-stage temperature change of approximately 0.7° at a similar intensity (ISPTA = 11 W/cm2) after more than 30s of sonication.
      In Sharabi et al., despite claiming a nonthermal mechanism for sonication, there was no mention of measuring or validating any thermal change. Interestingly, while Yoo et al. did report temperature changes from an ISPPA of 23 W/cm2, Sharabi et al. [
      • Sharabi S.
      • Daniels D.
      • Last D.
      • Guez D.
      • Zivli Z.
      • Castel D.
      • et al.
      Non-thermal focused ultrasound induced reversible reduction of essential tremor in a rat model.
      ] used an even higher intensity of 27.2 W/cm2 with no measurement of thermal change to support the claim that it was not thermal.
      In summary, there has been a lot of controversy in the field about the mechanism of ultrasound neuromodulation. Many groups have posited that the effect is not thermal based on the fact that the observed temperature changes caused by ultrasound are small. We believe that our paper has provided some of the best thermal measurements and several lines of evidence by changing the ultrasound waveform, heating through a different modality, and supported by the findings that the time course and dosage dependence only correlates to the temperature changes suggesting that a thermal mechanism is likely to be the primary mechanism. We do not rule out that there may be other effects caused by ultrasound, but temperature seems to be the dominant mechanism. If ultrasound only acts through a thermal mechanism, it in no way diminishes the importance of ultrasound as a non-invasive tool for neuromodulation.

      Declaration of competing interest

      A provisional patent application (U.S. 62/738,420) has been filed concerning the technology presented in this work.

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