scholarly journals Offline impact of transcranial focused ultrasound on cortical activation in primates

2018 ◽  
Author(s):  
Lennart Verhagen ◽  
Cécile Gallea ◽  
Davide Folloni ◽  
Charlotte Constans ◽  
Daria EA Jensen ◽  
...  
Keyword(s):  
Focused Ultrasound ◽  
Brain Regions ◽  
Cortical Activation ◽  
Transcranial Ultrasound ◽  
Full Potential ◽  
Non Invasive ◽  
Specific Effects ◽  
Brain Circuits ◽  
Induced Signal ◽  
Stimulation Technique

AbstractTo understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound (TUS) is a promising non-invasive brain stimulation technique. To date, investigations have focused on short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting ‘offline’ changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 seconds of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS’ impact can be demonstrated by showing such patterns change for stimulated areas. We report regionally specific TUS effects for two medial frontal brain regions – supplementary motor area and frontal polar cortex. Independently of these site-specific effects, TUS also induced signal changes in the meningeal compartment. TUS effects were temporary and not associated with microstructural changes.

scholarly journals Offline impact of transcranial focused ultrasound on cortical activation in primates

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Lennart Verhagen ◽  
Cécile Gallea ◽  
Davide Folloni ◽  
Charlotte Constans ◽  
Daria EA Jensen ◽  
...  
Keyword(s):  
Focused Ultrasound ◽  
Brain Regions ◽  
Cortical Activation ◽  
Transcranial Ultrasound ◽  
Full Potential ◽  
Non Invasive ◽  
Specific Effects ◽  
Ultrasound Stimulation ◽  
Induced Signal ◽  
Stimulation Technique

To understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique. To date, investigations report short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting ‘offline’ changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 s of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS caused stimulated areas to interact more selectively with the rest of the brain. In a within-subject design, we observe regionally specific TUS effects for two medial frontal brain regions – supplementary motor area and frontal polar cortex. Independently of these site-specific effects, TUS also induced signal changes in the meningeal compartment. TUS effects were temporary and not associated with microstructural changes.

scholarly journals Transcranial ultrasound selectively biases decision-making in primates

2018 ◽  
Author(s):  
Jan Kubanek ◽  
Julian Brown ◽  
Patrick Ye ◽  
Kim Butts Pauly ◽  
Tirin Moore ◽  
...  
Keyword(s):  
Choice Behavior ◽  
Focused Ultrasound ◽  
Target Selection ◽  
Brain Regions ◽  
Transcranial Ultrasound ◽  
Specific Effects ◽  
Visual Hemifield ◽  
Left Target ◽  
The Right ◽  
Spatial Specificity

AbstractTranscranial focused ultrasound has the promise to evolve into a transformative noninvasive way to modulate activity of neuronal circuits deep in the brain. The approach may enable systematic and causal mapping of how individual brain circuits are involved in specific behaviors and behavioral disorders. Previous studies demonstrated neuromodulatory potential, but the effect polarity, size, and spatial specificity have been difficult to assess. Here, we engaged non-human primates (macaca mulatta) in an established task that provides a well defined framework to characterize the neuromodulatory effects. In this task, subjects decide whether to look at a right or a left target, guided by one the targets appearing first. Previous studies showed that excitation/inhibition of oculomotor circuits leads to contralateral/ipsilateral biases in this choice behavior. We found that brief, low-intensity ultrasound stimuli (300 ms, 0.6 MPa, 270 kHz) delivered to the animals’ left/right frontal eye fields bias the animals’ decisions to the right/left visual hemifield. The effect was modest, about on the order of that produced when injecting moderate amounts of potent neuromodulatory drugs into the same regions in this task. The polarity of the effects suggested a neuronal excitation within the stimulated regions. No effects were observed when we applied the same stimuli to control brain regions not involved in oculomotor target selection. Together, using an established paradigm, we found that transcranial ultrasound is capable of modulating neurons to the extent of biasing choice behavior of non-human primates. A demonstration of tangible, brain-region-specific effects on behavior of primates constitutes a critical step toward applying this noninvasive neuromodulation method in investigations of how specific neural circuits are involved in specific behaviors or disease signs.

scholarly journals Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mehmet S. Ozdas ◽  
Aagam S. Shah ◽  
Paul M. Johnson ◽  
Nisheet Patel ◽  
Markus Marks ◽  
...  
Keyword(s):  
Focused Ultrasound ◽  
Drug Carriers ◽  
Mri Contrast Agents ◽  
Mri Contrast ◽  
Systemic Injection ◽  
Non Invasive ◽  
Brain Circuits ◽  
Cavitation Detection ◽  
The Brain ◽  
Target Effects

Abstract Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.

scholarly journals Interindividual variability of electric fields during transcranial temporal interference stimulation (tTIS)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jill von Conta ◽  
Florian H. Kasten ◽  
Branislava Ćurčić-Blake ◽  
André Aleman ◽  
Axel Thielscher ◽  
...  
Keyword(s):  
Electric Fields ◽  
Interindividual Variability ◽  
Brain Regions ◽  
Single Subject ◽  
Non Invasive ◽  
Left Hippocampus ◽  
Potential Benefits ◽  
Stimulation Technique ◽  
Deep Brain ◽  
Stimulation Of

AbstractTranscranial temporal interference stimulation (tTIS) is a novel non-invasive brain stimulation technique for electrical stimulation of neurons at depth. Deep brain regions are generally small in size, making precise targeting a necessity. The variability of electric fields across individual subjects resulting from the same tTIS montages is unknown so far and may be of major concern for precise tTIS targeting. Therefore, the aim of the current study is to investigate the variability of the electric fields due to tTIS across 25 subjects. To this end, the electric fields of different electrode montages consisting of two electrode pairs with different center frequencies were simulated in order to target selected regions-of-interest (ROIs) with tTIS. Moreover, we set out to compare the electric fields of tTIS with the electric fields of conventional tACS. The latter were also based on two electrode pairs, which, however, were driven in phase at a common frequency. Our results showed that the electric field strengths inside the ROIs (left hippocampus, left motor area and thalamus) during tTIS are variable on single subject level. In addition, tTIS stimulates more focally as compared to tACS with much weaker co-stimulation of cortical areas close to the stimulation electrodes. Electric fields inside the ROI were, however, comparable for both methods. Overall, our results emphasize the potential benefits of tTIS for the stimulation of deep targets, over conventional tACS. However, they also indicate a need for individualized stimulation montages to leverage the method to its fullest potential.

scholarly journals A Noninvasive Approach to Optogenetics Using Focused Ultrasound Blood Brain Barrier Disruption for the Delivery of Radioluminescent Particles

2020 ◽  
Author(s):  
Megan Rich ◽  
Eric Zhang ◽  
Ashley Dickey ◽  
Haley Jones ◽  
Kelli Cannon ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Regions ◽  
Brain Barrier ◽  
Receptor Subtype ◽  
Spatiotemporal Resolution ◽  
Light Emitting ◽  
Non Invasive ◽  
Blood Brain ◽  
Essential Components

AbstractOptogenetics, the genetic incorporation of light-sensitive proteins such as Channelrhodopsin-2 (ChR2) into target mammalian neurons, has enabled activation, silencing, and receptor subtype specific neuromodulation with high spatiotemporal resolution. However, the essential components of the ontogenetic system require invasive procedures with very few non-invasive alternatives preventing its use as a translational tool. The implantation of light emitting fibers deep within brain structures is both technically demanding and causes tissue scarring in target brain regions. To overcome these limitations, while maintaining the highly-tuned components of optogenetics we have developed a novel noninvasive alternative. Our approach replaces fibers with light-emitting radioluminescent particles (RLPs) that can be activated non-invasively with X-ray exposure. Here, we report successful noninvasive delivery of RLPs to target brain regions using MRI-guided focused ultrasound (FUS) blood brain barrier opening. In addition, FUS BBBO can be used to deliver viral vectors for light sensitive channel expression. Combined, these components can provide a completely non-invasive optogenetic system.

scholarly journals Focused ultrasound excites neurons via mechanosensitive calcium accumulation and ion channel amplification

2020 ◽  
Author(s):  
Sangjin Yoo ◽  
David R. Mittelstein ◽  
Robert Hurt ◽  
Jerome Lacroix ◽  
Mikhail G. Shapiro
Keyword(s):  
Ion Channels ◽  
Large Scale ◽  
Focused Ultrasound ◽  
Brain Regions ◽  
Cellular Mechanisms ◽  
Temperature Changes ◽  
Non Invasive ◽  
Neuroscience Research ◽  
Ultrasonic Stimulation ◽  
Further Development

ABSTRACTUltrasonic neuromodulation has the unique potential to provide non-invasive control of neural activity in deep brain regions with high spatial precision and without chemical or genetic modification. However, the biomolecular and cellular mechanisms by which focused ultrasound excites mammalian neurons have remained unclear, posing significant challenges for the use of this technology in research and potential clinical applications. Here, we show that focused ultrasound excites neurons through a primarily mechanical mechanism mediated by specific calcium-selective mechanosensitive ion channels. The activation of these channels results in a gradual build-up of calcium, which is amplified by calcium- and voltage-gated channels, generating a burst firing response. Cavitation, temperature changes, large-scale deformation, and synaptic transmission are not required for this excitation to occur. Pharmacological and genetic inhibition of specific ion channels leads to reduced responses to ultrasound, while over-expressing these channels results in stronger ultrasonic stimulation. These findings provide a critical missing explanation for the effect of ultrasound on neurons and facilitate the further development of ultrasonic neuromodulation and sonogenetics as unique tools for neuroscience research.

scholarly journals Early treatment of HER2-amplified brain tumours with targeted nk-92 cells and focused ultrasound improves survival

2015 ◽  
Vol 42 (S1) ◽  
pp. S11-S11
Author(s):  
RD Alkins ◽  
A Burgess ◽  
R Kerbel ◽  
WS Wels ◽  
K Hynynen
Keyword(s):  
Brain Tumours ◽  
Focused Ultrasound ◽  
Transcranial Ultrasound ◽  
Adjuvant Chemoradiotherapy ◽  
Her2 Receptor ◽  
Non Invasive ◽  
Dismal Prognosis ◽  
Cancer Line ◽  
Treatment Paradigm ◽  
Epithelial Tumours

Background: Malignant brain tumors have a dismal prognosis, with residual after surgery necessitating adjuvant chemoradiotherapy. We previously demonstrated that targeted Natural Killer (NK-92) cells could be delivered to the brain using a combination of MRI-guided focused ultrasound and Definity microbubbles. Once in the CNS, they can track to malignant tissues without inflicting collateral damage. The HER2 receptor is expressed by epithelial tumours including both breast and glioblastoma; breast tumors with HER2-amplification have a higher risk of CNS metastasis, and poorer prognosis. Methods: We investigated whether multiple combined treatments of targeted NK-92 cells and focused ultrasound with microbubbles could slow tumour growth and improve survival in an orthotopic HER2-amplified rodent brain tumour model using a human breast cancer line as a prototype. Results: Early daily treatments with targeted NK-92 cells and ultrasound improved survival and decreased tumour volumes compared with bi-weekly treatments, or either treatment alone. The intensive treatment paradigm resulted in cure in 50% of subjects. Conclusions: Many tumour proteins could be exploited for targeted therapy with the NK-92 cell line, and combined with the mounting safety evidence for transcranial ultrasound, this may soon provide a non-invasive and highly targeted treatment option for patients with brain tumours.

scholarly journals Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Mina Kandić ◽  
Vera Moliadze ◽  
Jamila Andoh ◽  
Herta Flor ◽  
Frauke Nees
Keyword(s):  
Chronic Pain ◽  
Musculoskeletal Pain ◽  
Brain Stimulation ◽  
Brain Regions ◽  
Mechanistic Models ◽  
Imaging Studies ◽  
Non Invasive ◽  
Brain Circuits ◽  
The Brain

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed.

scholarly journals Angiopoietin-Like Growth Factor Involved in Leptin Signaling in the Hypothalamus

2021 ◽  
Vol 22 (7) ◽  
pp. 3443
Author(s):  
Yunseon Jang ◽  
Jun Young Heo ◽  
Min Joung Lee ◽  
Jiebo Zhu ◽  
Changjun Seo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Brain Regions ◽  
Whole Body ◽  
Signal Transducers ◽  
Leptin Signaling ◽  
Stat3 Phosphorylation ◽  
Hypothalamic Regulation ◽  
Induced Signal ◽  
Body Energy ◽  
Transcription 3

The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons.

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