SCIENCE TIMES Transcranial Focused Ultrasound Modulates the Activity of Primary Somatosensory Cortex in Humans
E
arly attempts at stimulation of the central nervous system to modulate function date back to ancient Rome, but it was Sir Victor Horsley who is credited with first utilizing intraoperative electrical stimulation for cortical mapping. Although noninvasive methods of stimulation have been developed, these suffer from poor spatial resolution. Consequently, attempts at neuromodulation often impact the activity of not only the intended target but also surrounding brain. The effects of focused ultrasound (FUS) on neuronal activity have been studied since the 1920s, and in animals have been shown to modulate activity of peripheral nerves, the retina, spinal reflexes, hippocampus, and motor cortex. Unlike high intensity, continuous ultrasound (US), FUS can exert nondestructive mechanical pressure effects on cellular membranes and ion channels without producing cavitation and thermal injury. Animal studies have demonstrated the ability of FUS to reversibly suppress visual evoked potentials, modulate activity of the frontal eye fields, and disrupt seizure activity, all in the absence of cellular damage. In a recent report, investigators sought to establish the ability of transcranial focused ultrasound (tFUS) to modulate brain activity in the human primary somatosensory cortex.1 Legon et al employed a single-element tFUS transducer to transmit a 0.5 MHz pulsed wave for 500 ms. The acoustic power of the tFUS waveform used was well below the maximum recommended limit for diagnostic imaging applications. The authors first characterized the acoustic pressure field emitted from the tFUS transducer in an acoustic test-tank. Next, a magnetic resonance imaging-based 3-D simulation model of a human head was created to estimate acoustic field distribution in the brain during tFUS. Ultimately the authors assessed the neuromodulating influence and spatial resolution of tFUS targeted to Brodmann area 3b (anterior
N8 | VOLUME 74 | NUMBER 6 | JUNE 2014
bank of the postcentral gyrus facing the central sulcus) by examining effects on somatosensory evoked potentials (SEPs) and sensory detection thresholds via within-subjects, sham-controlled, blinded design study of 12 volunteers. Primary endpoints included amplitude of short-latency and late-onset evoked potentials by median nerve stimulation, as well as two-point and frequency discrimination tasks. The focal volume of the ellipsoid acoustic beam produced was 0.21cm3 at 50% maximum intensity line and demonstrated spatial resolution of 4.9mm laterally and 18mm axially when focused through the human skull. Electrophysiologic studies demonstrated that tFUS targeted to Brodmann area 3b significantly reduced the amplitude of short-latency and late-onset evoked cortical activity elicited by median-nerve SEPs. The effects of tFUS on SEP activity were abolished when targeted to brain regions 1 cm posterior or 1 cm anterior to the postcentral gyrus. Functional investigations revealed that tFUS targeted to somatosensory cortex significantly enhanced discrimination of pins at closer distances as well as frequency of air puffs, without affecting response bias or task attention. Additionally, the authors noted that volunteers did not report thermal or mechanical sensations due to tFUS transmission through the scalp. Similarly, there were no reports of perceptual differences between the sham and tFUS conditions. These data demonstrate that a pulsed acoustic beam created by a single-element 0.5-MHz tFUS transducer for 500 ms can be used to transiently and noninvasively modulate neuronal activity in the cortex of humans. tFUS may transiently shift the balance of neuronal activity in favor of local inhibition, perhaps through either dampening thalamocortical excitation or increasing interneuron inhibitory firing. One hypothesis for the paradoxical improvement in somatosensory discrimination provided by the authors is through filtering by local inhibition. In other words, the inhibition produced by tFUS may reduce spatial spread of cortical excitation resulting in restricted neuronal population activation and a more precise cortical representation of tactile stimuli. Although this study provided evidence that the influence of tFUS can be restricted to discrete modules of cortex, it did not elucidate which cellular structures tFUS most affects.
Further studies are needed to characterize whether neurophysiologic effects vary according to anatomic location and/or cytoarchitectonic division. One of the most enticing applications of tFUS is the possibility of noninvasive, functional brain mapping of both cortical and sub-cortical structures and circuits. Subablative sonication targeting the ventral intermediate region of the thalamus has already been used to provide functional target confirmation prior to lesioning with MR guided high-intensity FUS. However, the current study highlights the nondestructive capabilities of tFUS and inspires exploration of potential applications in both the research and clinical settings. David M. Panczykowski, MD Edward A. Monaco, III, MD, PhD Robert M. Friedlander, MD University of Pittsburgh Pittsburgh, Pennsylvania
REFERENCE 1. Legon W, Sato TF, Opitz A, et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in human. Nat Neurosci. 2014; 17(2):322-329.
Morning Joe or After-Dinner Espresso? Improved Memory Consolidation After Caffeine Administration
C
affeine has long been touted as a cognitive enhancer, promoting vigilance, improving reaction times, and facilitating passive learning.1 However, caffeine’s effect on memory is contentious at best, with inconsistent effects on short-term memory and few evaluations of long-term memory.1 Since the majority of studies have used paradigms to evaluate short-term memory, caffeine has often been administered before a task in order to observe its effect on memory retrieval. Yet retrieval is only 1 element of the memory process. In recent work published in Nature Neuroscience, Borota and colleagues further evaluated caffeine’s effects on memory.2 They
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
SCIENCE TIMES
Figure 1. Demonstration of how the specificity of a 0.5 MHz tFUS can be targeted to spatially discrete regions of human cortex. (A) TopDown and (B) coronal Cutaway view showing the acoustic intensity field of the tFUS beam projected from EEG site CP3 into a realistic FEM model of the brain derived from whole-head structural magnetic resonance images. (C) Coronal magnetic resonance imaging slices depicting the measured tFUS fields from EEG electrode site CP3. CS, central sulcus; M1, primary motor cortex; S1, somatosensory cortex. Reprinted by permission from Macmillan Publishers Ltd: Nature Neuroscience (Legon W, Sato TF, Opitz A, et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014;17(2):322-329.), copyright (2014).
posited that caffeine may improve long-term memory consolidation, and may therefore be more effective if taken after, rather than before, task training. To test this hypothesis, the team conducted a randomized, double-blind, placebo-controlled
NEUROSURGERY
trial at Johns Hopkins exploring memory consolidation in caffeine-naïve, healthy, young volunteers (average age ¼ 21). On day 1, participants performed an incidental encoding task involving visual images in an indoor-outdoor judgment paradigm. After the
task, participants received either placebo or 200 mg of caffeine, a dose roughly equivalent to 1 short, 8-ounce cup of Pike Place Starbucks coffee.3 Baseline, 1-hour, and 3-hour saliva samples were obtained to measure caffeine metabolite levels. On day 2, the
VOLUME 74 | NUMBER 6 | JUNE 2014 | N9
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
E
arly attempts at stimulation of the central nervous system to modulate function date back to ancient Rome, but it was Sir Victor Horsley who is credited with first utilizing intraoperative electrical stimulation for cortical mapping. Although noninvasive methods of stimulation have been developed, these suffer from poor spatial resolution. Consequently, attempts at neuromodulation often impact the activity of not only the intended target but also surrounding brain. The effects of focused ultrasound (FUS) on neuronal activity have been studied since the 1920s, and in animals have been shown to modulate activity of peripheral nerves, the retina, spinal reflexes, hippocampus, and motor cortex. Unlike high intensity, continuous ultrasound (US), FUS can exert nondestructive mechanical pressure effects on cellular membranes and ion channels without producing cavitation and thermal injury. Animal studies have demonstrated the ability of FUS to reversibly suppress visual evoked potentials, modulate activity of the frontal eye fields, and disrupt seizure activity, all in the absence of cellular damage. In a recent report, investigators sought to establish the ability of transcranial focused ultrasound (tFUS) to modulate brain activity in the human primary somatosensory cortex.1 Legon et al employed a single-element tFUS transducer to transmit a 0.5 MHz pulsed wave for 500 ms. The acoustic power of the tFUS waveform used was well below the maximum recommended limit for diagnostic imaging applications. The authors first characterized the acoustic pressure field emitted from the tFUS transducer in an acoustic test-tank. Next, a magnetic resonance imaging-based 3-D simulation model of a human head was created to estimate acoustic field distribution in the brain during tFUS. Ultimately the authors assessed the neuromodulating influence and spatial resolution of tFUS targeted to Brodmann area 3b (anterior
N8 | VOLUME 74 | NUMBER 6 | JUNE 2014
bank of the postcentral gyrus facing the central sulcus) by examining effects on somatosensory evoked potentials (SEPs) and sensory detection thresholds via within-subjects, sham-controlled, blinded design study of 12 volunteers. Primary endpoints included amplitude of short-latency and late-onset evoked potentials by median nerve stimulation, as well as two-point and frequency discrimination tasks. The focal volume of the ellipsoid acoustic beam produced was 0.21cm3 at 50% maximum intensity line and demonstrated spatial resolution of 4.9mm laterally and 18mm axially when focused through the human skull. Electrophysiologic studies demonstrated that tFUS targeted to Brodmann area 3b significantly reduced the amplitude of short-latency and late-onset evoked cortical activity elicited by median-nerve SEPs. The effects of tFUS on SEP activity were abolished when targeted to brain regions 1 cm posterior or 1 cm anterior to the postcentral gyrus. Functional investigations revealed that tFUS targeted to somatosensory cortex significantly enhanced discrimination of pins at closer distances as well as frequency of air puffs, without affecting response bias or task attention. Additionally, the authors noted that volunteers did not report thermal or mechanical sensations due to tFUS transmission through the scalp. Similarly, there were no reports of perceptual differences between the sham and tFUS conditions. These data demonstrate that a pulsed acoustic beam created by a single-element 0.5-MHz tFUS transducer for 500 ms can be used to transiently and noninvasively modulate neuronal activity in the cortex of humans. tFUS may transiently shift the balance of neuronal activity in favor of local inhibition, perhaps through either dampening thalamocortical excitation or increasing interneuron inhibitory firing. One hypothesis for the paradoxical improvement in somatosensory discrimination provided by the authors is through filtering by local inhibition. In other words, the inhibition produced by tFUS may reduce spatial spread of cortical excitation resulting in restricted neuronal population activation and a more precise cortical representation of tactile stimuli. Although this study provided evidence that the influence of tFUS can be restricted to discrete modules of cortex, it did not elucidate which cellular structures tFUS most affects.
Further studies are needed to characterize whether neurophysiologic effects vary according to anatomic location and/or cytoarchitectonic division. One of the most enticing applications of tFUS is the possibility of noninvasive, functional brain mapping of both cortical and sub-cortical structures and circuits. Subablative sonication targeting the ventral intermediate region of the thalamus has already been used to provide functional target confirmation prior to lesioning with MR guided high-intensity FUS. However, the current study highlights the nondestructive capabilities of tFUS and inspires exploration of potential applications in both the research and clinical settings. David M. Panczykowski, MD Edward A. Monaco, III, MD, PhD Robert M. Friedlander, MD University of Pittsburgh Pittsburgh, Pennsylvania
REFERENCE 1. Legon W, Sato TF, Opitz A, et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in human. Nat Neurosci. 2014; 17(2):322-329.
Morning Joe or After-Dinner Espresso? Improved Memory Consolidation After Caffeine Administration
C
affeine has long been touted as a cognitive enhancer, promoting vigilance, improving reaction times, and facilitating passive learning.1 However, caffeine’s effect on memory is contentious at best, with inconsistent effects on short-term memory and few evaluations of long-term memory.1 Since the majority of studies have used paradigms to evaluate short-term memory, caffeine has often been administered before a task in order to observe its effect on memory retrieval. Yet retrieval is only 1 element of the memory process. In recent work published in Nature Neuroscience, Borota and colleagues further evaluated caffeine’s effects on memory.2 They
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
SCIENCE TIMES
Figure 1. Demonstration of how the specificity of a 0.5 MHz tFUS can be targeted to spatially discrete regions of human cortex. (A) TopDown and (B) coronal Cutaway view showing the acoustic intensity field of the tFUS beam projected from EEG site CP3 into a realistic FEM model of the brain derived from whole-head structural magnetic resonance images. (C) Coronal magnetic resonance imaging slices depicting the measured tFUS fields from EEG electrode site CP3. CS, central sulcus; M1, primary motor cortex; S1, somatosensory cortex. Reprinted by permission from Macmillan Publishers Ltd: Nature Neuroscience (Legon W, Sato TF, Opitz A, et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014;17(2):322-329.), copyright (2014).
posited that caffeine may improve long-term memory consolidation, and may therefore be more effective if taken after, rather than before, task training. To test this hypothesis, the team conducted a randomized, double-blind, placebo-controlled
NEUROSURGERY
trial at Johns Hopkins exploring memory consolidation in caffeine-naïve, healthy, young volunteers (average age ¼ 21). On day 1, participants performed an incidental encoding task involving visual images in an indoor-outdoor judgment paradigm. After the
task, participants received either placebo or 200 mg of caffeine, a dose roughly equivalent to 1 short, 8-ounce cup of Pike Place Starbucks coffee.3 Baseline, 1-hour, and 3-hour saliva samples were obtained to measure caffeine metabolite levels. On day 2, the
VOLUME 74 | NUMBER 6 | JUNE 2014 | N9
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
