Ultrasound Neuromodulation PDF

02 February 2024 21:51 Source Notes Non-invasive transcranial ultrasound stimulation for neuromodulation (Darmani et al., 2022) Introduction 1. Historical Roots (1920s-1950s): Ultrasound's application in neuromodulation dates back to the 1920s. E. Newton Harvey's early work recognized the stimulator...

02 February 2024 21:51 Source Notes Non-invasive transcranial ultrasound stimulation for neuromodulation (Darmani et al., 2022) Introduction 1. Historical Roots (1920s-1950s): Ultrasound's application in neuromodulation dates back to the 1920s. E. Newton Harvey's early work recognized the stimulatory effect of sound waves on biological tissues, including neuronal tissue. This period is significant for establishing the foundational concept that ultrasound can affect cellular processes. 2. Initial Demonstrations of Neuromodulation (1950s): In the 1950s, the Fry brothers demonstrated reversible suppression of spontaneous neuronal activity using ultrasound. This was a pivotal discovery, showing that ultrasound could specifically target neuronal functions in a reversible manner. 3. Focused Ultrasound Studies (1958): William Fry's work in 1958 on cats, where he targeted the lateral geniculate nucleus with ultrasound to suppress visually evoked potentials, highlighted the potential for targeted brain modulation using ultrasound. This study is crucial for illustrating the precision with which ultrasound can be used to modulate specific brain areas. 4. Evidence Accumulation: Over the following decades, numerous studies (Takagi et al. 1960; Lele 1963; Gavrilov et al. 1996; Velling and Shklyaruk 1988) consistently demonstrated ultrasound's effects on the nervous system, yet it remained underrecognized for its potential in non-invasive neuromodulation. This period signifies a gap between discovery and application in the field. 5. Renaissance Period (Late 2000s): A resurgence in interest occurred in the late 2000s with William Tyler’s research. His findings that ultrasound could open voltage-gated sodium (Na+) and calcium (Ca2+) channels in hippocampal slice cultures marked a turning point. This was significant for demonstrating a direct, mechanistic understanding of how ultrasound influences neuronal activity. 6. Ultrasound-Induced Motor Responses (2010): In 2010, Tyler's group showed that ultrasound focused on the motor cortex of awake mice produced motor responses. This study was crucial as it demonstrated the application of TUS in awake, behaving animals, suggesting potential for practical therapeutic uses. 7. Recent Developments: Since these seminal findings, there has been a renewed interest in using ultrasound for transient brain modulation. The growth in this field reflects a broader acknowledgment of TUS's potential in both animal models and human subjects, signifying a shift towards practical and clinical applications. 8. Critical Analysis - Early Stage Limitations: PSYC0031 Cognitive Neuroscience Page 1 8. Critical Analysis - Early Stage Limitations: The initial phases of TUS research were marked by limited understanding and technological constraints, which likely contributed to its underrecognition in neuromodulation. The early studies, while groundbreaking, were limited in their scope and technological sophistication, which might have hindered the broader acceptance and development of TUS methods. 9. Impact of Tyler’s Research: Tyler’s research played a critical role in reinvigorating the field by demonstrating a clearer mechanistic pathway (opening of ion channels) for TUS in neuromodulation. This breakthrough provided the much-needed link between ultrasound application and its direct effects on neuronal activities. 10. Transition to Practical Applications: The transition from understanding the basic effects of ultrasound on the nervous system to its application in modulating specific brain activities (e.g., motor responses in mice) marks a significant development. It bridges the gap between theoretical understanding and practical, therapeutic applications, paving the way for the current surge in TUS research. Sensory Effects of TUS 11. Auditory Components and Neuromodulation: Studies have shown that auditory components may contribute to neural or behavioral responses from TUS, but neuromodulation also occurs independently of auditory effects. This is evidenced by experiments with cultured neurons, retinal cells, and brain slices, which lack auditory systems. 12. Research in Deaf Models: Experiments conducted on chemically or genetically deaf mice have demonstrated that neuromodulatory effects occur irrespective of auditory capabilities, suggesting that TUS effects are not primarily auditory in nature. 13. Site-Specific Effects: Experiments targeting specific brain regions, such as the frontal eye field and the somatosensory cortex, have elicited behavioral and sensory responses, respectively. This supports the notion that TUS's primary effects are not due to acoustic side effects. 14. Addressing Auditory Confounds: In human studies, auditory effects have been successfully masked using simultaneous audible stimuli, thus eliminating the confounding auditory EEG signals and confirming that TUS can operate beyond mere auditory stimulation. 15. Modeling Wave Propagation: Advanced modeling has provided insights into how acoustic pressure from TUS can propagate shear waves, potentially reaching off-target structures like the cochlea and producing audible sound. 16. Challenges in Human and Large Mammal Studies: Unlike in rodents, motor responses such as muscle twitches have not been observed in humans or other large mammals. This could be due to differences in skull characteristics and experimental setups, highlighting a challenge in translating findings from animal models to humans. 17. Tactile Sensations: TUS may produce tactile sensations due to vibrations or thermal effects. Although not systematically studied, these PSYC0031 Cognitive Neuroscience Page 2 thermal effects. Although not systematically studied, these effects have been reported anecdotally in various labs. 18. Minimizing Sensory Confounds: Effective solutions to minimize sensory confounds in TUS applications include modifying the ultrasound wave envelope and applying masking noise during sonication. 19. Critical Analysis - Sensory Effects: The presence of sensory effects, both auditory and tactile, underlines the importance of careful experimental design in TUS studies. It also raises questions about the specific mechanisms of neuromodulation and how they can be isolated from sensory stimuli. 20. Future Research Directions: Systematic investigation of sensory confounds and the development of more refined methods to control or eliminate these effects are necessary to advance the field. TUS for Neuromodulation in Animal Studies 21. Exploration of Parameter Space: The parameter space for ultrasound neuromodulation is vast and largely unexplored. This makes exhaustive examination of parameter combinations challenging, especially considering the costs and unknown risks associated with novel parameters. 22. Role of Preclinical Animal Experiments: Animal studies are essential for guiding human studies, offering a safer environment to test new parameters and assess their effects. These studies can provide critical data on the safety, efficacy, and mechanisms of action of TUS. 23. Historical Context: Since the earliest neuromodulation experiments in cats, animal models have been instrumental in the development of TUS. They have helped establish the foundational knowledge about TUS's effects on neural activity. 24. Safety and Efficacy Demonstration: Animal models are crucial for demonstrating the safety and efficacy of stimulation parameters, which is a prerequisite for human trials. 25. Neuronal Mechanism Investigation: Animal studies have played a significant role in investigating the neuronal mechanisms of action of TUS, providing insights into how TUS influences brain activity at a cellular level. 26. Modeling and Simulation Studies: Alongside animal experiments, modeling and simulation studies are vital for predicting the efficacy of ultrasound effects and ensuring reproducibility of results. 27. Critical Analysis - Animal Studies: The reliance on animal studies underscores the challenges in translating findings to human applications. Differences in anatomy and physiology between species, especially concerning the brain and skull, mean that results in animals might not always directly apply to humans. 28. Need for Comprehensive Testing: Comprehensive testing in animal models, including various species and a wide range of parameters, is necessary to understand the full scope and limitations of TUS. PSYC0031 Cognitive Neuroscience Page 3 understand the full scope and limitations of TUS. 29. Translational Challenges: There are significant challenges in translating findings from animal models to human applications, including differences in brain size, skull thickness, and susceptibility to ultrasound effects. 30. Future Directions in Animal Research: Future research in animal models should aim to explore a broader range of parameters and species to better understand the generalizability of TUS effects and refine protocols for human application. Combining TUS with Neuroimaging and Neurostimulation Techniques 31. Integration with MRI and Spectroscopy: TUS effects on cognitive functions can be assessed using MRI and magnetic resonance spectroscopy (H-MRS). These techniques provide insights into the function of specific brain regions and their interaction with others in distributed networks. 32. fMRI and rsfMRI: Functional MRI (fMRI) and resting-state fMRI (rsfMRI) detect whole-brain activity changes related to blood flow. Studies have combined TUS with fMRI to investigate the impact of neuromodulation on brain activity, demonstrating increases in BOLD signals in targeted areas. 33. H-MRS: Proton magnetic resonance spectroscopy (1H-MRS) noninvasively measures molecular concentrations in brain tissues, including levels of excitatory and inhibitory neurotransmitters. It can provide insights into the metabolic and biochemical mechanisms underlying TUS neuromodulation. 34. Other MRI Techniques: Diffusion MRI (dMRI) and arterial spin labeling (ASL) assess TUS-induced changes in brain microstructure and cerebral blood perfusion. These can be used for both immediate and delayed effects of TUS. 35. EEG: Electroencephalography (EEG) is well-suited for investigating the immediate brain response to TUS and its modulatory effects. It can measure both evoked potentials and ongoing oscillatory activity. However, EEG has limitations in detecting deep brain or non-radial sources. 36. TMS: Transcranial magnetic stimulation (TMS) combined with TUS can provide insights into the effects of TUS on cortical excitability and intracortical circuits. TMS's high temporal resolution is useful for distinguishing between excitatory and inhibitory contributions. 37. Spatial Resolution Comparison: TMS and TUS have different spatial resolutions. TMS affects larger brain volumes, while TUS can target smaller, more precise areas. This difference is crucial for understanding their individual and combined effects on brain activity. 38. Safety Considerations in Combining Techniques: When using these combined techniques, safety considerations like the acoustic coupling of TUS transducers and potential interactions between different stimulation methods are critical. PSYC0031 Cognitive Neuroscience Page 4 interactions between different stimulation methods are critical. Safety Considerations for TUS Exposure 39. Acoustic Energy Deposition: TUS relies on the transient deposition of acoustic energy onto brain tissue, which can lead to thermal and nonthermal bioeffects. The selection of sonication parameters is crucial to avoid injury and minimize discomfort. 40. Regulatory Guidelines: Currently, there are no definitive guidelines for safe energy deposition to the brain for TUS. However, the FDA provides intensity limits for diagnostic ultrasound that can guide TUS experiments. 41. Histological Studies for Safety Assessment: Histologic analysis of brain tissue post-sonication in animal and limited human studies have been conducted to assess any potential cell damage or other adverse effects. To date, most studies have found TUS to be safe, with no significant indications of cell damage. 42. Adverse Events: No serious adverse events have been causally attributed to low-intensity TUS. Common transient side effects are similar to those seen with other non-invasive brain stimulation techniques. Conclusions and Future Perspectives 43. Potential of TUS: TUS has shown promise as a non-invasive technique with greater depth penetration and higher spatial resolution than current non-invasive brain stimulation (NIBS) methods. 44. Advancing Neuroscience Research: TUS could significantly advance neuroscience research and potentially offer novel treatments for neurological and psychiatric disorders. 45. Need for Further Studies: More animal and human studies are necessary to understand the mechanisms of action of TUS, establish safety limits, develop effective protocols, and define optimal parameters for various disorders. 46. Role in Treatment of Brain Disorders: Well-designed randomized controlled trials are needed to establish TUS's role in treating brain disorders. Non-invasive Human Brain Stimulation in Cognitive Neuroscience: A Primer (Parkin et al., 2015) 1. Historical Solidity and Replicability of TMS: The document emphasizes the solid foundation and replicability of TMS effects in cognitive studies across laboratories, especially in the sensory domain, language functions, and the study of action perception, preparation, and production. 2. Mechanism and Application of TMS: TMS can disrupt ongoing activity or be used neuromodulatorily to induce plasticity. It's a versatile tool in cognitive neuroscience, providing insights into the functioning of the human brain. PSYC0031 Cognitive Neuroscience Page 5 3. Variety in TMS Application: TMS can be applied as single pulses, multiple pulses, or repetitively (like rTMS and theta-burst stimulation). Each variant has unique physiological and behavioral effects and the choice of application depends on the hypothesis and purpose of the experiment. 4. Physiological Effects of Different TMS Variants: Single-pulse TMS generally has excitatory effects, while repetitive 1 Hz rTMS is often used as an inhibitory intervention. The effects of higher frequencies (5 Hz and 10 Hz) are not entirely clear and might depend on the intensity of the stimulation. 5. Theta Burst Paradigms: These paradigms are based on solid physiological studies, with continuous theta burst having long-term inhibitory effects and intermittent theta burst tending to have excitatory effects. However, their specific use in cognitive contexts is less explored. 6. Temporal Precision of TMS: Single- and double-pulse TMS offer insights into the timing of psychological processes. The methodological integrity of these experiments is crucial, covering aspects such as task specificity, location specificity, and timing. 7. Importance of Cortical Localization in TMS: The document highlights the importance of precise cortical localization in TMS experiments. While some classic studies required less specificity, current cognitive neuroscience often necessitates precise anatomical targeting. 8. State-Dependent TMS: This concept is significant in understanding TMS effects in cognitive experiments. The state of cortical excitability can significantly influence the outcomes of TMS, demonstrating the need for a nuanced approach to understanding and applying TMS. 9. TMS Intensity Considerations: Choosing the appropriate intensity for cognitive experiments is complex. It involves balancing absolute intensity, relative intensity to motor threshold, and considerations of cortical state, which vary within and between individuals. 10. Control Site Selection: The choice of a control site is critical for inferring results from TMS experiments. It should ideally be active and part of the circuitry being tested to provide meaningful inferences about location specificity and inter-hemispheric interactions. 11. Combining TMS with Other Methods: The document discusses the combination of TMS with EEG and fMRI, highlighting the gains made in understanding perceptual and task-dependent processes, the spatial and temporal spread of TMS-induced activity, and the importance of pre-stimulus cortical state. PSYC0031 Cognitive Neuroscience Page 6 of pre-stimulus cortical state. Magnetic stimulation studies of visual cognition (Walsh & Cowey, 1998) Introduction to Non-invasive Brain Stimulation Prevalence and Advancement: Non-invasive brain stimulation has become widespread in cognitive neuroscience, leading to significant advances in understanding cognition and perception. Clinical Potential: These methods hold promise for therapeutic applications in various psychological and neurological disorders. Methodological Diversity: Includes techniques like TMS and different forms of tES (tDCS, tACS, and tRNS), each with unique applications and effects. Transcranial Magnetic Stimulation in Cognition Robust Foundations: TMS has been effectively used in studying sensory functions, language, action perception/preparation, and parietal cortex functions. Expansion into New Areas: TMS is now being applied to investigate functions in the ventral stream, such as face and body perception. Stimulus Timing, Frequency, and Localization in TMS Diverse Application Methods: TMS can be applied in various forms like single pulse, repetitive pulse, and theta-burst stimulation, each having distinct physiological, localization, and behavioral effects. Effect Mechanisms: The choice of TMS frequency depends on desired excitatory or inhibitory effects, influenced by cortical state and task demands. Methodological Considerations in TMS Studies Importance of Precision: Single- and double-pulse TMS provide insights into the timing of cognitive processes and require careful control of task, location, and timing. State-Dependent TMS: This approach considers the initial state of brain regions, using adaptation paradigms to influence stimulation effects, thus enhancing experimental accuracy. TMS Intensity and Control Sites Intensity Challenges: Choosing the appropriate stimulation intensity is complex, as it does not directly correlate with cortical disruption across different brain regions. Control Site Selection: The choice of control sites in TMS studies is crucial for accurate inference. Ideally, the control site should be part of the circuitry being tested for better specificity. Combining TMS with Other Methods Integration with EEG and fMRI: TMS combined with EEG or fMRI enhances understanding of perceptual and cognitive processes, offering insights into pre-stimulus cortical states and subsequent physiological activities. TMS and fMRI Integration Diverse Applications: TMS is used in conjunction with fMRI in different forms, either inside the scanner or before scanning, revealing distal effects and state-dependent influences on cognitive functions. Inducing Plasticity with TMS Clinical and Cognitive Implications: TMS can induce cortical plasticity, showing potential for both behavioral change studies and clinical applications, especially in conditions like stroke. PSYC0031 Cognitive Neuroscience Page 7 Transcranial Electrical Stimulation in Cognitive Neuroscience tES in Cognitive Enhancement: tES, encompassing tDCS, tACS, and tRNS, is widely explored for enhancing various cognitive functions. However, the field lacks the maturity and standardization seen in TMS. Control Conditions in tDCS, tACS, and tRNS Critical Assumptions: The effects of tES are not as straightforward as previously assumed, with complexity in factors like polarity, intensity, duration, and montage. Experimental Design: Effective tES experiments require wellthought control sites and tasks, with careful consideration of stimulation parameters for reliable results. tES Application to Addictive Behavior Potential in Treating Addiction: tES shows promise in treating drug addiction, a field lacking effective pharmacological interventions. However, challenges like replicability, identifying appropriate cognitive/neural targets, and understanding neuroplasticity under drug influence remain. Public Communication of Results Need for Responsible Communication: The simplicity and accessibility of tES devices necessitate careful public communication to prevent overhyped claims and misuse. The scientific community must differentiate between scientifically interesting findings and those with clinical or practical implications. PSYC0031 Cognitive Neuroscience Page 8