Raag Airan

All Publications

• Optimized ultrasound neuromodulation for non-invasive control of behavior and physiology. Neuron Murphy, K. R., Farrell, J. S., Bendig, J., Mitra, A., Luff, C., Stelzer, I. A., Yamaguchi, H., Angelakos, C. C., Choi, M., Bian, W., DiIanni, T., Pujol, E. M., Matosevich, N., Airan, R., Gaudillière, B., Konofagou, E. E., Butts-Pauly, K., Soltesz, I., de Lecea, L. 2024

  Abstract

  Focused ultrasound can non-invasively modulate neural activity, but whether effective stimulation parameters generalize across brain regions and cell types remains unknown. We used focused ultrasound coupled with fiber photometry to identify optimal neuromodulation parameters for four different arousal centers of the brain in an effort to yield overt changes in behavior. Applying coordinate descent, we found that optimal parameters for excitation or inhibition are highly distinct, the effects of which are generally conserved across brain regions and cell types. Optimized stimulations induced clear, target-specific behavioral effects, whereas non-optimized protocols of equivalent energy resulted in substantially less or no change in behavior. These outcomes were independent of auditory confounds and, contrary to expectation, accompanied by a cyclooxygenase-dependent and prolonged reduction in local blood flow and temperature with brain-region-specific scaling. These findings demonstrate that carefully tuned and targeted ultrasound can exhibit powerful effects on complex behavior and physiology.

  View details for DOI 10.1016/j.neuron.2024.07.002

  View details for PubMedID 39079529

• Ultrasonic cerebrospinal fluid clearance improves outcomes in hemorrhagic brain injury models. bioRxiv : the preprint server for biology Azadian, M. M., Macedo, N., Yu, B. J., Fame, R. M., Airan, R. D. 2024

  Abstract

  Impaired clearance of the byproducts of aging and neurologic disease from the brain exacerbates disease progression and severity. We have developed a noninvasive, low intensity transcranial focused ultrasound protocol that facilitates the removal of pathogenic substances from the cerebrospinal fluid (CSF) and the brain interstitium. This protocol clears neurofilament light chain (NfL) - an aging byproduct - in aged mice and clears red blood cells (RBCs) from the central nervous system in two mouse models of hemorrhagic brain injury. Cleared RBCs accumulate in the cervical lymph nodes from both the CSF and interstitial compartments, indicating clearance through meningeal lymphatics. Treating these hemorrhagic brain injury models with this ultrasound protocol reduced neuroinflammatory and neurocytotoxic profiles, improved behavioral outcomes, decreased morbidity and, importantly, increased survival. RBC clearance efficacy was blocked by mechanosensitive channel antagonism and was effective when applied in anesthetized subjects, indicating a mechanosensitive channel mediated mechanism that does not depend on sensory stimulation or a specific neural activity pattern. Notably, this protocol qualifies for an FDA non-significant risk designation given its low intensity, making it readily clinically translatable. Overall, our results demonstrate that this low-intensity transcranial focused ultrasound protocol clears hemorrhage and other harmful substances from the brain via the meningeal lymphatic system, potentially offering a novel therapeutic tool for varied neurologic disorders.

  View details for DOI 10.1101/2024.06.02.597001

  View details for PubMedID 38895304

  View details for PubMedCentralID PMC11185536

• Sex dependence of opioid-mediated responses to subanesthetic ketamine in rats. Nature communications Di Ianni, T., Ewbank, S. N., Levinstein, M. R., Azadian, M. M., Budinich, R. C., Michaelides, M., Airan, R. D. 2024; 15 (1): 893

  Abstract

  Subanesthetic ketamine is increasingly used for the treatment of varied psychiatric conditions, both on- and off-label. While it is commonly classified as an N-methyl D-aspartate receptor (NMDAR) antagonist, our picture of ketamine's mechanistic underpinnings is incomplete. Recent clinical evidence has indicated, controversially, that a component of the efficacy of subanesthetic ketamine may be opioid dependent. Using pharmacological functional ultrasound imaging in rats, we found that blocking opioid receptors suppressed neurophysiologic changes evoked by ketamine, but not by a more selective NMDAR antagonist, in limbic regions implicated in the pathophysiology of depression and in reward processing. Importantly, this opioid-dependent response was strongly sex-dependent, as it was not evident in female subjects and was fully reversed by surgical removal of the male gonads. We observed similar sex-dependent effects of opioid blockade affecting ketamine-evoked postsynaptic density and behavioral sensitization, as well as in opioid blockade-induced changes in opioid receptor density. Together, these results underscore the potential for ketamine to induce its affective responses via opioid signaling, and indicate that this opioid dependence may be strongly influenced by subject sex. These factors should be more directly assessed in future clinical trials.

  View details for DOI 10.1038/s41467-024-45157-7

  View details for PubMedID 38291050

• High-throughput ultrasound neuromodulation in awake and freely behaving rats. Brain stimulation Di Ianni, T., Morrison, K. P., Yu, B., Murphy, K. R., de Lecea, L., Airan, R. D. 2023; 16 (6): 1743-1752

  Abstract

  Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity.

  View details for DOI 10.1016/j.brs.2023.11.014

  View details for PubMedID 38052373

• Pharmacokinetics-Pharmacodynamics Dissociation Indicative of Ketamine-Induced Plasticity as Revealed by Ultrasonic Ketamine Uncaging in Rat Medial Prefrontal Cortex Yu, B., Roy, K., Purohit, M., Xiang, Y., Azadian, M., Taoube, A., Kwan, A., Lopez, D., Airan, R. SPRINGERNATURE. 2023: 277-278

  View details for Web of Science ID 001126640300117

• Acoustomechanically activatable liposomes for ultrasonic drug uncaging. bioRxiv : the preprint server for biology Purohit, M. P., Roy, K. S., Xiang, Y., Yu, B. J., Azadian, M. M., Muwanga, G., Hart, A. R., Taoube, A. K., Lopez, D. G., Airan, R. D. 2023

  Abstract

  Ultrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest.

  View details for DOI 10.1101/2023.10.23.563690

  View details for PubMedID 37961368

  View details for PubMedCentralID PMC10634775

• Oscillatory effects of ketamine using focused ultrasound sensitive liposomes Yu, B., Taoube, A. K., Airan, R. D. CELL PRESS. 2023: 540A

  View details for Web of Science ID 000989629703001

• Oscillatory effects of ketamine using focused ultrasound sensitive liposomes. Biophysical journal Yu, B., Taoube, A. K., Airan, R. D. 2023; 122 (3S1): 540a

  View details for DOI 10.1016/j.bpj.2022.11.2859

  View details for PubMedID 36784798

• Noninvasive ultrasonic induction of cerebrospinal fluid flow enhances intrathecal drug delivery. Journal of controlled release : official journal of the Controlled Release Society Aryal, M., Azadian, M. M., Hart, A. R., Macedo, N., Zhou, Q., Rosenthal, E. L., Airan, R. D. 2022

  Abstract

  Intrathecal drug delivery is routinely used in the treatment and prophylaxis of varied central nervous system conditions, as doing so allows drugs to directly bypass the blood-brain barrier. However, the utility of this route of administration is limited by poor brain and spinal cord parenchymal drug uptake from the cerebrospinal fluid. We demonstrate that a simple noninvasive transcranial ultrasound protocol can significantly increase influx of cerebrospinal fluid into the perivascular spaces of the brain, to enhance the uptake of intrathecally administered drugs. Specifically, we administered small (~1 kDa) and large (~155 kDa) molecule agents into the cisterna magna of rats and then applied low, diagnostic-intensity focused ultrasound in a scanning protocol throughout the brain. Using real-time magnetic resonance imaging and ex vivo histologic analyses, we observed significantly increased uptake of small molecule agents into the brain parenchyma, and of both small and large molecule agents into the perivascular space from the cerebrospinal fluid. Notably, there was no evidence of brain parenchymal damage following this intervention. The low intensity and noninvasive approach of transcranial ultrasound in this protocol underscores the ready path to clinical translation of this technique. In this manner, this protocol can be used to directly bypass the blood-brain barrier for whole-brain delivery of a variety of agents. Additionally, this technique can potentially be used as a means to probe the causal role of the glymphatic system in the variety of disease and physiologic processes to which it has been correlated.

  View details for DOI 10.1016/j.jconrel.2022.06.067

  View details for PubMedID 35798095

• Changes In The Cerebello-thalamo-cortical Network After MR-guided Focused Ultrasound Thalamotomy. Brain connectivity Thaler, C., Tian, Q., WIntermark, M., Ghanouni, P., Halpern, C., Henderson, J., Airan, R., Zeineh, M., Goubran, M., Leuze, C., Fiehler, J., Butts Pauly, K., McNab, J. A. 2022

  Abstract

  Object In recent years, transcranial MR-guided focused ultrasound (tcMRgFUS) has been established as a potential treatment option for movement disorders, including essential tremor. So far, however, little is known about the impact of tcMRgFUS on structural connectivity. The objective of this study was to detect microstructural changes in tremor- and motor-related white matter tracts in essential tremor patients treated with tcMRgFUS thalamotomy. Methods Eleven patients diagnosed with essential tremor were enrolled in this tcMRgFUS thalamotomy study. For each patient, 3T MRI including structural and diffusion MRI were acquired and the Clinical Rating Scale for Tremor was assessed prior to the procedure as well as one year after the treatment. Diffusion MRI tractography was performed to identify the cerebello-thalamo-cortical tract (CTCT), the medial lemniscus (ML) and the corticospinal tract (CST) in both hemispheres on pre-treatment data. Pre-treatment tractography results were co-registered to post-treatment diffusion data. Diffusion tensor imaging (DTI) metrics, including fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD), were averaged across the tracts in the pre- and post-treatment data. Results The mean value of tract-specific DTI metrics changed significantly within the thalamic lesion and in the CTCT on the treated side (p<0.05). Changes of DTI-derived indices within the CTCT correlated well with lesion overlap (FA: r=-0.54, p=0.04; MD: r=0.57, p=0.04); RD: r=0.67, p=0.036). Furthermore, a trend was seen for the correlation between changes of DTI-derived indices within the CTCT and clinical improvement (FA: r=0.58; p=0.062; MD: r=-0.52, p=0.64; RD: r=-0.61 p=0.090). Conclusions Microstructural changes were detected within the CTCT after tcMRgFUS and these changes correlated well with lesion-tract overlap. Our results show that diffusion MRI is able to detect the microstructural effects of tcMRgFUS, thereby further elucidating the treatment mechanism and ultimately to improve targeting prospectively.

  View details for DOI 10.1089/brain.2021.0157

  View details for PubMedID 35678063

• Deep-fUS: A deep learning platform for functional ultrasound imaging of the brain using sparse data. IEEE transactions on medical imaging Di Ianni, T., Airan, R. D. 2022; PP

  Abstract

  Functional ultrasound (fUS) is a rapidly emerging modality that enables whole-brain imaging of neural activity in awake and mobile rodents. To achieve sufficient blood flow sensitivity in the brain microvasculature, fUS relies on long ultrasound data acquisitions at high frame rates, posing high demands on the sampling and processing hardware. Here we develop an image reconstruction method based on deep learning that significantly reduces the amount of data necessary while retaining imaging performance. We trained convolutional neural networks to learn the power Doppler reconstruction function from sparse sequences of ultrasound data with compression factors of up to 95%. High-quality images from in vivo acquisitions in rats were used for training and performance evaluation. We demonstrate that time series of power Doppler images can be reconstructed with sufficient accuracy to detect the small changes in cerebral blood volume (~10%) characteristic of task-evoked cortical activation, even though the network was not formally trained to reconstruct such image series. The proposed platform may facilitate the development of this neuroimaging modality in any setting where dedicated hardware is not available or in clinical scanners.

  View details for DOI 10.1109/TMI.2022.3148728

  View details for PubMedID 35108201

• Mu opioid receptor activation mediates (S)-ketamine reinforcement in rats: implications for abuse liability Biological Psychiatry Levinstein, M. R., Carlton, M. L., Di Ianni, T., Ventriglia, E. N., Rizzo, A., Gomez, J. L., Budinich, R. C., Shaham, Y., Airan, R. D., Zarate Jr, C. A., Bonaventura, J., Michaelides, M. 2022

  View details for DOI 10.1016/j.biopsych.2022.12.019

• Using Passively Detected Acoustic Signals to Characterize Ultrasound Gated Nanoparticles Singh, A., Xiang, Y., Sigona, M., Purohit, M., Hart, A., Hosseini-Nassab, N., Airan, R., Caskey, C., IEEE IEEE. 2021

  View details for DOI 10.1109/IUS52206.2021.9593854

  View details for Web of Science ID 000832095000497

• Ultrasonic Drug Uncaging for Noninvasive Targeted Neuropsychopharmacology Airan, R. SPRINGERNATURE. 2020: 22

  View details for Web of Science ID 000596371000047

• Histologic evaluation of activation of acute inflammatory response in a mouse model following ultrasound-mediated blood-brain barrier using different acoustic pressures and microbubble doses. Nanotheranostics Pascal, A. n., Li, N. n., Lechtenberg, K. J., Rosenberg, J. n., Airan, R. D., James, M. L., Bouley, D. M., Pauly, K. B. 2020; 4 (4): 210–23

  Abstract

  Rationale: Localized blood-brain barrier (BBB) opening can be achieved with minimal to no tissue damage by applying pulsed focused ultrasound alongside a low microbubble (MB) dose. However, relatively little is known regarding how varying treatment parameters affect the degree of neuroinflammation following BBB opening. The goal of this study was to evaluate the activation of an inflammatory response following BBB opening as a function of applied acoustic pressure using two different microbubble doses. Methods: Mice were treated with 650 kHz ultrasound using varying acoustic peak negative pressures (PNPs) using two different MB doses, and activation of an inflammatory response, in terms of microglial and astrocyte activation, was assessed one hour following BBB opening using immunohistochemical staining. Harmonic and subharmonic acoustic emissions (AEs) were monitored for all treatments with a passive cavitation detector, and contrast-enhanced magnetic resonance imaging (CE-MRI) was performed following BBB opening to quantify the degree of opening. Hematoxylin and eosin-stained slides were assessed for the presence of microhemorrhage and edema. Results: For each MB dose, BBB opening was achieved with minimal activation of microglia and astrocytes using a PNP of 0.15 MPa. Higher PNPs were associated with increased activation, with greater increases associated with the use of the higher MB dose. Additionally, glial activation was still observed in the absence of histopathological findings. We found that CE-MRI was most strongly correlated with the degree of activation. While acoustic emissions were not predictive of microglial or astrocyte activation, subharmonic AEs were strongly associated with marked and severe histopathological findings. Conclusions: Our study demonstrated that there were mild histologic changes and activation of the acute inflammatory response using PNPs ranging from 0.15 MPa to 0.20 MPa, independent of MB dose. However, when higher PNPs of 0.25 MPa or above were applied, the same applied PNP resulted in more severe and widespread histological findings and activation of the acute inflammatory response when using the higher MB dose. The potential activation of the inflammatory response following ultrasound-mediated BBB opening should be considered when treating patients to maximize therapeutic benefit.

  View details for DOI 10.7150/ntno.49898

  View details for PubMedID 32802731

  View details for PubMedCentralID PMC7425053

• Focused Ultrasound for Noninvasive, Focal Pharmacologic Neurointervention. Frontiers in neuroscience Wang, J. B., Di Ianni, T. n., Vyas, D. B., Huang, Z. n., Park, S. n., Hosseini-Nassab, N. n., Aryal, M. n., Airan, R. D. 2020; 14: 675

  Abstract

  A long-standing goal of translational neuroscience is the ability to noninvasively deliver therapeutic agents to specific brain regions with high spatiotemporal resolution. Focused ultrasound (FUS) is an emerging technology that can noninvasively deliver energy up the order of 1 kW/cm2 with millimeter and millisecond resolution to any point in the human brain with Food and Drug Administration-approved hardware. Although FUS is clinically utilized primarily for focal ablation in conditions such as essential tremor, recent breakthroughs have enabled the use of FUS for drug delivery at lower intensities (i.e., tens of watts per square centimeter) without ablation of the tissue. In this review, we present strategies for image-guided FUS-mediated pharmacologic neurointerventions. First, we discuss blood-brain barrier opening to deliver therapeutic agents of a variety of sizes to the central nervous system. We then describe the use of ultrasound-sensitive nanoparticles to noninvasively deliver small molecules to millimeter-sized structures including superficial cortical regions and deep gray matter regions within the brain without the need for blood-brain barrier opening. We also consider the safety and potential complications of these techniques, with attention to temporal acuity. Finally, we close with a discussion of different methods for mapping the ultrasound field within the brain and describe future avenues of research in ultrasound-targeted drug therapies.

  View details for DOI 10.3389/fnins.2020.00675

  View details for PubMedID 32760238

  View details for PubMedCentralID PMC7372945

• CT and CEST MRI bimodal imaging of the intratumoral distribution of iodinated liposomes QUANTITATIVE IMAGING IN MEDICINE AND SURGERY Chen, Z., Li, Y., Airan, R., Han, Z., Xu, J., Chan, K. Y., Xu, Y., Bulte, J. M., van Zijl, P. M., McMahon, M. T., Zhou, S., Liu, G. 2019; 9 (9): 1579-+

  View details for DOI 10.21037/qims.2019.06.10

  View details for Web of Science ID 000488450700010

• CT and CEST MRI bimodal imaging of the intratumoral distribution of iodinated liposomes. Quantitative imaging in medicine and surgery Chen, Z., Li, Y., Airan, R., Han, Z., Xu, J., Chan, K. W., Xu, Y., Bulte, J. W., van Zijl, P. C., McMahon, M. T., Zhou, S., Liu, G. 2019; 9 (9): 1579-1591

  Abstract

  To develop liposomes loaded with iodinated agents as nanosized CT/MRI bimodal contrast agents for monitoring liposome-mediated drug delivery.Rhodamine-labeled iodixanol (VisipaqueTM)-loaded liposomes (IX-lipo) were prepared and tested for their properties as a diamagnetic CEST contrast agent in vitro. Mice bearing subcutaneous CT26 colon tumors were injected i.v. with 1 g/kg (535 mg iodine/kg) IX-lipo, and in vivo CT and CEST MR images were acquired on day 3. CT and CEST MR images were also acquired for tumor-bearing mice co-injected with IX-lipo and tumor necrosis factor (TNF-α).In addition to CT contrast, IX-lipo exhibited a strong CEST contrast similar to its non-liposomal form, with a detectability of ~2 nM per liposome. Both CT imaging and CEST MRI showed that i.v. injection of IX-lipo resulted in a rim enhancement of CT26 tumors with a heterogeneous central distribution. In contrast, co-injection of TNF-α caused a significantly augmented CT/MRI contrast in the tumor center. The intratumoral biodistribution of IX-lipo correlated well to the rhodamine patterns observed with fluorescence microscopy.We have developed a CT/MRI bimodal imaging approach for monitoring the delivery and biodistribution of liposomes by loading them with the clinically approved X-ray/CT contrast agent iodixanol. Our approach may be easily adapted for other-FDA approved iodinated agents and thus has great translational potential.

  View details for DOI 10.21037/qims.2019.06.10

  View details for PubMedID 31667143

  View details for PubMedCentralID PMC6785501

• Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters. Biomaterials Zhong, Q., Yoon, B. C., Aryal, M., Wang, J. B., Ilovitsh, T., Baikoghli, M. A., Hosseini-Nassab, N., Karthik, A., Cheng, R. H., Ferrara, K. W., Airan, R. D. 2019; 206: 73–86

  Abstract

  Catheter-based intra-arterial drug therapies have proven effective for a range of oncologic, neurologic, and cardiovascular applications. However, these procedures are limited by their invasiveness and relatively broad drug spatial distribution. The ideal technique for local pharmacotherapy would be noninvasive and would flexibly deliver a given drug to any region of the body with high spatial and temporal precision. Combining polymeric perfluorocarbon nanoemulsions with existent clinical focused ultrasound systems could in principle meet these needs, but it has not been clear whether these nanoparticles could provide the necessary drug loading, stability, and generalizability across a range of drugs, beyond a few niche applications. Here, we develop polymeric perfluorocarbon nanoemulsions into a generalized platform for ultrasound-targeted delivery of hydrophobic drugs with high potential for clinical translation. We demonstrate that a wide variety of drugs may be effectively uncaged with ultrasound using these nanoparticles, with drug loading increasing with hydrophobicity. We also set the stage for clinical translation by delineating production protocols that are scalable and yield sterile, stable, and optimized ultrasound-activated drug-loaded nanoemulsions. Finally, we exhibit a new potential application of these nanoemulsions for local control of vascular tone. This work establishes the power of polymeric perfluorocarbon nanoemulsions as a clinically-translatable platform for efficacious, noninvasive, and localized ultrasonic drug uncaging for myriad targets in the brain and body.

  View details for PubMedID 30953907

• Noninvasive Ultrasonic Drug Uncaging Maps Whole-Brain Functional Networks. Neuron Wang, J. B., Aryal, M., Zhong, Q., Vyas, D. B., Airan, R. D. 2018; 100 (3): 728

  Abstract

  Being able to noninvasively modulate brain activity, where and when an experimenter desires, with an immediate path toward human translation is a long-standing goal for neuroscience. To enable robust perturbation of brain activity while leveraging the ability of focused ultrasound to deliver energy to any point of the brain noninvasively, we have developed biocompatible and clinically translatable nanoparticles that allow ultrasound-induced uncaging of neuromodulatory drugs. Utilizing the anesthetic propofol, together with electrophysiological and imaging assays, we show that the neuromodulatory effect of ultrasonic drug uncaging is limited spatially and temporally by the size of the ultrasound focus, the sonication timing, and the pharmacokinetics of the uncaged drug. Moreover, we see secondary effects in brain regions anatomically distinct from and functionally connected to the sonicated region, indicating that ultrasonic drug uncaging could noninvasively map the changes in functional network connectivity associated with pharmacologic action at a particular brain target.

  View details for PubMedID 30408444

• Hearing out Ultrasound Neuromodulation. Neuron Airan, R. D., Butts Pauly, K. 2018; 98 (5): 875–77

  Abstract

  Many neuroscientists are excited regarding the potential of ultrasound to yield spatiotemporally precise and noninvasive modulation of arbitrary brain regions. Here, Guo etal. (2018) and Sato etal. (2018) show that applying ultrasound to rodent brains activates acoustic responses more prominently than eliciting neuromodulation directly, suggesting potential confounds of ultrasound neuromodulation experiments.

  View details for PubMedID 29879389

• Optogenetic Control of Intracellular Signaling: Class II Opsins OPTOGENETICS: A ROADMAP Ellwardt, E., Airan, R. D., Stroh, A. 2018; 133: 63–73

  View details for DOI 10.1007/978-1-4939-7417-7_4

  View details for Web of Science ID 000432366700006

• Diffusion MRI tractography for improved transcranial MRI-guided focused ultrasound thalamotomy targeting for essential tremor. NeuroImage. Clinical Tian, Q., Wintermark, M., Jeffrey Elias, W., Ghanouni, P., Halpern, C. H., Henderson, J. M., Huss, D. S., Goubran, M., Thaler, C., Airan, R., Zeineh, M., Pauly, K. B., McNab, J. A. 2018; 19: 572–80

  Abstract

  Purpose: To evaluate the use of diffusion magnetic resonance imaging (MRI) tractography for neurosurgical guidance of transcranial MRI-guided focused ultrasound (tcMRgFUS) thalamotomy for essential tremor (ET).Materials and methods: Eight patients with medication-refractory ET were treated with tcMRgFUS targeting the ventral intermediate nucleus (Vim) of the thalamus contralateral to their dominant hand. Diffusion and structural MRI data and clinical evaluations were acquired pre-treatment and post-treatment. To identify the optimal target location, tractography was performed on pre-treatment diffusion MRI data between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus. The tractography-identified locations were compared to the lesion location delineated on 1 year post-treatment T2-weighted MR image. Their overlap was correlated with the clinical outcomes measured by the percentage change of the Clinical Rating Scale for Tremor scores acquired pre-treatment, as well as 1 month, 3 months, 6 months and 1 year post-treatment.Results: The probabilistic tractography was consistent from subject-to-subject and followed the expected anatomy of the thalamocortical radiation and the dentatothalamic tract. Higher overlap between the tractography-identified location and the tcMRgFUS treatment-induced lesion highly correlated with better treatment outcome (r = -0.929, -0.75, -0.643, p = 0.00675, 0.0663, 0.139 for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus, respectively, at 1 year post-treatment). The correlation for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex is the highest for all time points (r = -0.719, -0.976, -0.707, -0.929, p = 0.0519, 0.000397, 0.0595, 0.00675 at 1 month, 3 months, 6 months and 1 year post-treatment, respectively).Conclusion: Our data support the use of diffusion tractography as a complementary approach to current targeting methods for tcMRgFUS thalamotomy.

  View details for PubMedID 29984165

• Neuromodulation with nanoparticles SCIENCE Airan, R. 2017; 357 (6350): 465

  View details for PubMedID 28774921

• Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions. Nano letters Airan, R. D., Meyer, R. A., Ellens, N. P., Rhodes, K. R., Farahani, K., Pomper, M. G., Kadam, S. D., Green, J. J. 2017; 17 (2): 652-659

  Abstract

  Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

  View details for DOI 10.1021/acs.nanolett.6b03517

  View details for PubMedID 28094959

• MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Airan, R. D., Foss, C. A., Ellens, N. P., Wang, Y., Mease, R. C., Farahani, K., Pomper, M. G. 2017; 19 (1): 24-30

  Abstract

  A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500 Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain.Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([(18)F]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [(18)F]DCFPyL or YC-27, which competes for GCPII/PSMA binding.Dynamic PET imaging using [(18)F]DCFPyL demonstrated that target uptake reached a plateau by ∼1 h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of ∼4:1 at 45 min to ∼7:1 by 80 min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24 h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS.MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS.

  View details for DOI 10.1007/s11307-016-0985-2

  View details for PubMedID 27481359

  View details for PubMedCentralID PMC5226140

• Factors affecting characterization and localization of interindividual differences in functional connectivity using MRI HUMAN BRAIN MAPPING Airan, R. D., Vogelstein, J. T., Pillai, J. J., Caffo, B., Pekar, J. J., Sair, H. I. 2016; 37 (5): 1986-1997

  Abstract

  Much recent attention has been paid to quantifying anatomic and functional neuroimaging on the individual subject level. For optimal individual subject characterization, specific acquisition and analysis features need to be identified that maximize interindividual variability while concomitantly minimizing intra-subject variability. We delineate the effect of various acquisition parameters (length of acquisition, sampling frequency) and analysis methods (time course extraction, region of interest parcellation, and thresholding of connectivity-derived network graphs) on characterizing individual subject differentiation. We utilize a non-parametric statistical metric that quantifies the degree to which a parameter set allows this individual subject differentiation by both maximizing interindividual variance and minimizing intra-individual variance. We apply this metric to analysis of four publicly available test-retest resting-state fMRI (rs-fMRI) data sets. We find that for the question of maximizing individual differentiation, (i) for increasing sampling, there is a relative tradeoff between increased sampling frequency and increased acquisition time; (ii) for the sizes of the interrogated data sets, only 3-4 min of acquisition time was sufficient to maximally differentiate each subject with an algorithm that utilized no a priori information regarding subject identification; and (iii) brain regions that most contribute to this individual subject characterization lie in the default mode, attention, and executive control networks. These findings may guide optimal rs-fMRI experiment design and may elucidate the neural bases for subject-to-subject differences. Hum Brain Mapp 37:1986-1997, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hbm.23150

  View details for Web of Science ID 000374840600025

  View details for PubMedID 27012314

• Presurgical brain mapping of the language network in patients with brain tumors using resting-state fMRI: Comparison with task fMRI HUMAN BRAIN MAPPING Sair, H. I., Yahyavi-Firouz-Abadi, N., Calhoun, V. D., Airan, R. D., Agarwal, S., Intrapiromkul, J., Choe, A. S., Gujar, S. K., Caffo, B., Lindquist, M. A., Pillai, J. J. 2016; 37 (3): 913-923

  Abstract

  To compare language networks derived from resting-state fMRI (rs-fMRI) with task-fMRI in patients with brain tumors and investigate variables that affect rs-fMRI vs task-fMRI concordance.Independent component analysis (ICA) of rs-fMRI was performed with 20, 30, 40, and 50 target components (ICA20 to ICA50) and language networks identified for patients presenting for presurgical fMRI mapping between 1/1/2009 and 7/1/2015. 49 patients were analyzed fulfilling criteria for presence of brain tumors, no prior brain surgery, and adequate task-fMRI performance. Rs-vs-task-fMRI concordance was measured using Dice coefficients across varying fMRI thresholds before and after noise removal. Multi-thresholded Dice coefficient volume under the surface (DiceVUS) and maximum Dice coefficient (MaxDice) were calculated. One-way Analysis of Variance (ANOVA) was performed to determine significance of DiceVUS and MaxDice between the four ICA order groups. Age, Sex, Handedness, Tumor Side, Tumor Size, WHO Grade, number of scrubbed volumes, image intensity root mean square (iRMS), and mean framewise displacement (FD) were used as predictors for VUS in a linear regression.Artificial elevation of rs-fMRI vs task-fMRI concordance is seen at low thresholds due to noise. Noise-removed group-mean DiceVUS and MaxDice improved as ICA order increased, however ANOVA demonstrated no statistically significant difference between the four groups. Linear regression demonstrated an association between iRMS and DiceVUS for ICA30-50, and iRMS and MaxDice for ICA50.Overall there is moderate group level rs-vs-task fMRI language network concordance, however substantial subject-level variability exists; iRMS may be used to determine reliability of rs-fMRI derived language networks.

  View details for DOI 10.1002/hbm.23075

  View details for Web of Science ID 000370243600005

  View details for PubMedID 26663615

• Neurovascular Uncoupling in Resting State fMRI Demonstrated in Patients With Primary Brain Gliomas JOURNAL OF MAGNETIC RESONANCE IMAGING Agarwal, S., Sair, H. I., Yahyavi-Firouz-Abadi, N., Airan, R., Pillai, J. J. 2016; 43 (3): 620-626

  Abstract

  To demonstrate that the problem of brain tumor-related neurovascular uncoupling (NVU) is a significant issue with respect to resting state blood oxygen level dependent (BOLD) functional MRI (rsfMRI) similar to task-based BOLD fMRI, in which signal detectability can be compromised by breakdown of normal neurovascular coupling.We evaluated seven de novo brain tumor patients who underwent resting state fMRI as part of comprehensive clinical fMRI exams at 3 Tesla. For each of the seven patients who demonstrated evidence of NVU on task-based motor fMRI, we performed both an independent component analysis (ICA) and an atlas-based parcellation-based seed correlation analysis (SCA) of the resting state fMRI data. For each patient, ipsilesional (IL) and contralesional (CL) regions of interest (ROIs) comprising primary motor and somatosensory cortices were used to evaluate BOLD signal changes on Z score maps derived from both ICA and SCA analysis for evidence of NVU. A subsequent two-tailed t-test was performed to determine whether statistically significant differences between the two sides were present that were consistent with NVU.In seven patients, overall decreased BOLD signal (based on suprathreshold voxels in ICA and SCA-derived Z-score maps) was noted in IL compared with CL ROIs (P < 0.01), consistent with NVU.We have demonstrated that NVU can result in false negative BOLD signal changes on rsfMRI comparable to previously published findings on standard motor task-based fMRI.

  View details for DOI 10.1002/jmri.25012

  View details for Web of Science ID 000373000300010

  View details for PubMedID 26201672

• Estimating a graphical intra-class correlation coefficient (GICC) using multivariate probit-linear mixed models COMPUTATIONAL STATISTICS & DATA ANALYSIS Yue, C., Chen, S., Sair, H. I., Airan, R., Caffo, B. S. 2015; 89: 126-133

  Abstract

  Data reproducibility is a critical issue in all scientific experiments. In this manuscript, the problem of quantifying the reproducibility of graphical measurements is considered. The image intra-class correlation coefficient (I2C2) is generalized and the graphical intra-class correlation coefficient (GICC) is proposed for such purpose. The concept for GICC is based on multivariate probit-linear mixed effect models. A Markov Chain Monte Carlo EM (mcm-cEM) algorithm is used for estimating the GICC. Simulation results with varied settings are demonstrated and our method is applied to the KIRBY21 test-retest dataset.

  View details for DOI 10.1016/j.csda.2015.02.012

  View details for Web of Science ID 000357348000010

  View details for PubMedID 26190878

• Label-free in vivo molecular imaging of underglycosylated mucin-1 expression in tumour cells NATURE COMMUNICATIONS Song, X., Airan, R. D., Arifin, D. R., Bar-Shir, A., Kadayakkara, D. K., Liu, G., Gilad, A. A., van Zijl, P. C., McMahon, M. T., Bulte, J. W. 2015; 6

  Abstract

  Alterations in mucin expression and glycosylation are associated with cancer development. Underglycosylated mucin-1 (uMUC1) is overexpressed in most malignant adenocarcinomas of epithelial origin (for example, colon, breast and ovarian cancer). Its counterpart MUC1 is a large polymer rich in glycans containing multiple exchangeable OH protons, which is readily detectable by chemical exchange saturation transfer (CEST) MRI. We show here that deglycosylation of MUC1 results in >75% reduction in CEST signal. Three uMUC1(+) human malignant cancer cell lines overexpressing uMUC1 (BT20, HT29 and LS174T) show a significantly lower CEST signal compared with the benign human epithelial cell line MCF10A and the uMUC1(-) tumour cell line U87. Furthermore, we demonstrate that in vivo CEST MRI is able to make a distinction between LS174T and U87 tumour cells implanted in the mouse brain. These results suggest that the mucCEST MRI signal can be used as a label-free surrogate marker to non-invasively assess mucin glycosylation and tumour malignancy.

  View details for DOI 10.1038/ncomms7719

  View details for Web of Science ID 000353045000001

  View details for PubMedID 25813863

• Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study NEUROBIOLOGY OF DISEASE Coughlin, J. M., Wang, Y., Munro, C. A., Ma, S., Yue, C., Chen, S., Airan, R., Kim, P. K., Adams, A. V., Garcia, C., Higgs, C., Sair, H. I., Sawa, A., Smith, G., Lyketsos, C. G., Caffo, B., Kassiou, M., Guilarte, T. R., Pomper, M. G. 2015; 74: 58-65

  Abstract

  There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play.

  View details for DOI 10.1016/j.nbd.2014.10.019

  View details for Web of Science ID 000349655900006

  View details for PubMedID 25447235

• Optogenetics in Freely Moving Mammals: Dopamine and Reward. Cold Spring Harbor protocols Zhang, F., Tsai, H., Airan, R. D., Stuber, G. D., Adamantidis, A. R., de Lecea, L., Bonci, A., Deisseroth, K. 2015; 2015 (8): pdb top086330-?

  Abstract

  Brain reward systems play a central role in the cognitive and hedonic behaviors of mammals. Multiple neuron types and brain regions are involved in reward processing, posing fascinating scientific questions, and major experimental challenges. Using diverse approaches including genetics, electrophysiology, imaging, and behavioral analysis, a large body of research has focused on both normal functioning of the reward circuitry and on its potential significance in neuropsychiatric diseases. In this introduction, we illustrate a real-world application of optogenetics to mammalian behavior and physiology, delineating procedures and technologies for optogenetic control of individual components of the reward circuitry. We describe the experimental setup and protocol for integrating optogenetic modulation of dopamine neurons with fast-scan cyclic voltammetry, conditioned place preference, and operant conditioning to assess the causal role of well-defined electrical and biochemical signals in reward-related behavior.

  View details for DOI 10.1101/pdb.top086330

  View details for PubMedID 26240415

• Natural neural projection dynamics underlying social behavior. Cell Gunaydin, L. A., Grosenick, L., Finkelstein, J. C., Kauvar, I. V., Fenno, L. E., Adhikari, A., Lammel, S., Mirzabekov, J. J., Airan, R. D., Zalocusky, K. A., Tye, K. M., Anikeeva, P., Malenka, R. C., Deisseroth, K. 2014; 157 (7): 1535-1551

  Abstract

  Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.

  View details for DOI 10.1016/j.cell.2014.05.017

  View details for PubMedID 24949967

  View details for PubMedCentralID PMC4123133

• Human brain atlas for automated region of interest selection in quantitative susceptibility mapping: application to determine iron content in deep gray matter structures. NeuroImage Lim, I. A., Faria, A. V., Li, X., Hsu, J. T., Airan, R. D., Mori, S., van Zijl, P. C. 2013; 82: 449-469

  Abstract

  The purpose of this paper is to extend the single-subject Eve atlas from Johns Hopkins University, which currently contains diffusion tensor and T1-weighted anatomical maps, by including contrast based on quantitative susceptibility mapping. The new atlas combines a "deep gray matter parcellation map" (DGMPM) derived from a single-subject quantitative susceptibility map with the previously established "white matter parcellation map" (WMPM) from the same subject's T1-weighted and diffusion tensor imaging data into an MNI coordinate map named the "Everything Parcellation Map in Eve Space," also known as the "EvePM." It allows automated segmentation of gray matter and white matter structures. Quantitative susceptibility maps from five healthy male volunteers (30 to 33 years of age) were coregistered to the Eve Atlas with AIR and Large Deformation Diffeomorphic Metric Mapping (LDDMM), and the transformation matrices were applied to the EvePM to produce automated parcellation in subject space. Parcellation accuracy was measured with a kappa analysis for the left and right structures of six deep gray matter regions. For multi-orientation QSM images, the Kappa statistic was 0.85 between automated and manual segmentation, with the inter-rater reproducibility Kappa being 0.89 for the human raters, suggesting "almost perfect" agreement between all segmentation methods. Segmentation seemed slightly more difficult for human raters on single-orientation QSM images, with the Kappa statistic being 0.88 between automated and manual segmentation, and 0.85 and 0.86 between human raters. Overall, this atlas provides a time-efficient tool for automated coregistration and segmentation of quantitative susceptibility data to analyze many regions of interest. These data were used to establish a baseline for normal magnetic susceptibility measurements for over 60 brain structures of 30- to 33-year-old males. Correlating the average susceptibility with age-based iron concentrations in gray matter structures measured by Hallgren and Sourander (1958) allowed interpolation of the average iron concentration of several deep gray matter regions delineated in the EvePM.

  View details for DOI 10.1016/j.neuroimage.2013.05.127

  View details for PubMedID 23769915

• Genetic tools to manipulate MRI contrast NMR IN BIOMEDICINE Airan, R. D., Li, N., Gilad, A. A., Pelled, G. 2013; 26 (7): 803-809

  Abstract

  Advances in molecular biology in the early 1970s revolutionized research strategies for the study of complex biological processes, which, in turn, created a high demand for new means to visualize these dynamic biological changes noninvasively and in real time. In this respect, MRI was a perfect fit, because of the versatile possibility to alter the different contrast mechanisms. Genetic manipulations are now being translated to MRI through the development of reporters and sensors, as well as the imaging of transgenic and knockout mice. In the past few years, a new molecular biology toolset, namely optogenetics, has emerged, which allows for the manipulation of cellular behavior using light. This technology provides a few particularly attractive features for combination with newly developed MRI techniques for the probing of in vivo cellular and, in particular, neural processes, specifically the ability to control focal, genetically defined cellular populations with high temporal resolution using equipment that is magnetically inert and does not interact with radiofrequency pulses. Recent studies have demonstrated that the combination of optogenetics and functional MRI (fMRI) can provide an appropriate platform to investigate in vivo, at the cellular and molecular levels, the neuronal basis of fMRI signals. In addition, this novel combination of optogenetics with fMRI has the potential to resolve pre-synaptic versus post-synaptic changes in neuronal activity and changes in the activity of large neuronal networks in the context of plasticity associated with development, learning and pathophysiology.

  View details for DOI 10.1002/nbm.2907

  View details for Web of Science ID 000320730300009

  View details for PubMedID 23355411

• MRI biosensor for protein kinase A encoded by a single synthetic gene MAGNETIC RESONANCE IN MEDICINE Airan, R. D., Bar-Shir, A., Liu, G., Pelled, G., McMahon, M. T., van Zijl, P. C., Bulte, J. W., Gilad, A. A. 2012; 68 (6): 1919-1923

  Abstract

  Protein kinases including protein kinase A (PKA) underlie myriad important signaling pathways. The ability to monitor kinase activity in vivo and in real-time with high spatial resolution in genetically specified cellular populations is a yet unmet need, crucial for understanding complex biological systems as well as for preclinical development and screening of novel therapeutics.Using the hypothesis that the natural recognition sequences of protein kinases may be detected using chemical exchange saturation transfer magnetic resonance imaging, we designed a genetically encoded biosensor composed of eight tandem repeats of the peptide LRRASLG, a natural target of PKA.This sensor displays a measurable change in chemical exchange saturation transfer signal following phosphorylation by PKA. The natural PKA substrate LRRASLG exhibits a chemical exchange saturation transfer-magnetic resonance imaging contrast at +1.8 and +3.6 ppm, with a >50% change after phosphorylation with minutes-scale temporal resolution. Expression of a synthetic gene encoding eight monomers of LRRASLG yielded two peaks at these chemical exchange saturation transfer frequencies.Taken together, these results suggest that this gene may be used to assay PKA levels in a biologically relevant system. Importantly, the design strategy used for this specific sensor may be adapted for a host of clinically interesting protein kinases.

  View details for DOI 10.1002/mrm.24483

  View details for Web of Science ID 000311398600027

  View details for PubMedID 23023588

• Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures NATURE PROTOCOLS Zhang, F., Gradinaru, V., Adamantidis, A. R., Durand, R., Airan, R. D., de Lecea, L., Deisseroth, K. 2010; 5 (3): 439-456

  Abstract

  Elucidation of the neural substrates underlying complex animal behaviors depends on precise activity control tools, as well as compatible readout methods. Recent developments in optogenetics have addressed this need, opening up new possibilities for systems neuroscience. Interrogation of even deep neural circuits can be conducted by directly probing the necessity and sufficiency of defined circuit elements with millisecond-scale, cell type-specific optical perturbations, coupled with suitable readouts such as electrophysiology, optical circuit dynamics measures and freely moving behavior in mammals. Here we collect in detail our strategies for delivering microbial opsin genes to deep mammalian brain structures in vivo, along with protocols for integrating the resulting optical control with compatible readouts (electrophysiological, optical and behavioral). The procedures described here, from initial virus preparation to systems-level functional readout, can be completed within 4-5 weeks. Together, these methods may help in providing circuit-level insight into the dynamics underlying complex mammalian behaviors in health and disease.

  View details for DOI 10.1038/nprot.2009.226

  View details for Web of Science ID 000275234900006

  View details for PubMedID 20203662

• Temporally precise in vivo control of intracellular signalling NATURE Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H., Deisseroth, K. 2009; 458 (7241): 1025-1029

  Abstract

  In the study of complex mammalian behaviours, technological limitations have prevented spatiotemporally precise control over intracellular signalling processes. Here we report the development of a versatile family of genetically encoded optical tools ('optoXRs') that leverage common structure-function relationships among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochemical signalling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signalling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochemical signalling in behaving mammals, in a targetable and temporally precise manner.

  View details for DOI 10.1038/nature07926

  View details for Web of Science ID 000265412900042

  View details for PubMedID 19295515

• Brain circuit dynamics AMERICAN JOURNAL OF PSYCHIATRY Hu, E. S., Airan, R. D., Vijaykumar, R., Deisseroth, K. 2008; 165 (7): 800-800

  View details for DOI 10.1176/appi.ajp.2008.08050764

  View details for Web of Science ID 000257320100006

  View details for PubMedID 18593784

• Integration of light-controlled neuronal firing and fast circuit imaging CURRENT OPINION IN NEUROBIOLOGY Airan, R. D., Hu, E. S., Vijaykumar, R., Roy, M., Meltzer, L. A., Deisseroth, K. 2007; 17 (5): 587-592

  Abstract

  For understanding normal and pathological circuit function, capitalizing on the full potential of recent advances in fast optical neural circuit control will depend crucially on fast, intact-circuit readout technology. First, millisecond-scale optical control will be best leveraged with simultaneous millisecond-scale optical imaging. Second, both fast circuit control and imaging should be adaptable to intact-circuit preparations from normal and diseased subjects. Here we illustrate integration of fast optical circuit control and fast circuit imaging, review recent work demonstrating utility of applying fast imaging to quantifying activity flow in disease models, and discuss integration of diverse optogenetic and chemical genetic tools that have been developed to precisely control the activity of genetically specified neural populations. Together these neuroengineering advances raise the exciting prospect of determining the role-specific cell types play in modulating neural activity flow in neuropsychiatric disease.

  View details for DOI 10.1016/j.conb.2007.11.003

  View details for Web of Science ID 000252835100013

  View details for PubMedID 18093822

• High-speed Imaging reveals neurophysiological links to behavior in an animal model of depression SCIENCE Airan, R. D., Meltzer, L. A., Roy, M., Gong, Y., Chen, H., Deisseroth, K. 2007; 317 (5839): 819-823

  Abstract

  The hippocampus is one of several brain areas thought to play a central role in affective behaviors, but the underlying local network dynamics are not understood. We used quantitative voltage-sensitive dye imaging to probe hippocampal dynamics with millisecond resolution in brain slices after bidirectional modulation of affective state in rat models of depression. We found that a simple measure of real-time activity-stimulus-evoked percolation of activity through the dentate gyrus relative to the hippocampal output subfield-accounted for induced changes in animal behavior independent of the underlying mechanism of action of the treatments. Our results define a circuit-level neurophysiological endophenotype for affective behavior and suggest an approach to understanding circuit-level substrates underlying psychiatric disease symptoms.

  View details for DOI 10.1126/science.1144400

  View details for Web of Science ID 000248624500045

  View details for PubMedID 17615305