Theoretical investigation of the scope of sequential ligand tuning using a bifunctional scorpionate tris(1,2,4-triazolyl)borate-based architecture

The donor properties of a series of tripodal mixed N-donor/carbene ligands derived through sequential alkylation of hydrotris(1,2,4-triazolyl)borate have been investigated by density functional theory (DFT) methods. The structures of complexes of the form [Mo(L)(CO)3]- were optimized (L = [HB(1,2,4-triazolyl)n(1,2,4-triazol-5-ylidene)3-n]- (n = 0 – 3), hydrotris(pyrazolyl)borate, hydrotris(3,5-dimethylpyrazolyl)borate and hydrotris(imidazol-2-ylidene)borate) and nuCO frequencies for these complexes and partial charges of their Mo(CO)3 fragments were determined. Results show that ligand donation is highly tunable when compared to similar experimentally known ligands with a shift in the symmetric nuCO stretching mode of -39 cm -1 on going from the tris(1,2,4-triazolyl)borate complexes to that of the triscarbene hydrotris(1,2,4-triazol-5-ylidene) and an increase in partial charge (distributed multipole analysis) of the Mo(CO)3 fragment from -0.23 to -0.48

Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research

Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits

Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research

Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits

Improving light delivery for optogenetics using wavefront shaping

New developments in neuroscience are enabling us to understand the brain at unprecedented temporal and spatial resolution. One of these exciting new techniques is optogenetics, which allows select neuronal populations of the brain to be targeted to express light sensitive ion channels. These enable optical control of the electrophysiological state of the cell, enabling neurons to be activated or deactivated using light. However, due to the strongly scattering nature of biological tissue in the brain, tightly focusing light to a specific voxel is not possible with conventional optical techniques. In this poster we will present the results of our recent work to develop new optical wavefront shaping tools which enable us to focus light inside strongly scattering media and discuss the outlook for such tools for improving light delivery for techniques such as optogenetics. The focus of our work is to use an optical wavefront shaping technology termed Time-Reversed Ultrasound- Encoded (TRUE) focusing [1,2]. This strategy uses ultrasound to form an ultrasonic focus at depths beyond the optical diffusion limit. This ultrasound focus modulates photons passing through it via the acousto-optic effect, shifting their frequency by the ultrasound frequency. Then, by detecting these ultrasound-tagged photons, we can measure the optical wavefront corresponding to the tagged photons and selectively time-reverse this optical field using a technique called Digital Optical Phase Conjugation (DOPC) [3]. This wavefront is then used to send photons back into the scattering tissue in such a way that they travel in a time-reversed fashion, constructively interfering at the location of the ultrasound focus. This allows us to focus light in highly scattering media beyond the optical diffusion limit at ultrasonic resolution (~30 micrometers at 50 MHz). In this poster we will present results from recent work using the TRUE focusing technique to perform optogenetic stimulation. We demonstrate in 300 and 500 micrometer thick living brain slices that the TRUE focusing technique can be used to improve the spatial resolution of optogenetic stimulation compared to conventional optical methods. Furthermore, we will discuss the outlook and challenges facing the development of wavefront shaping techniques such as TRUE focusing for applications in neuroscience and other areas of biotechnology. References: [1] Xu, Xiao, Honglin Liu, and Lihong V. Wang. Time-reversed ultrasonically encoded optical focusing into scattering media. Nature photonics 5.3 (2011): 154-157. [2] Wang, Ying Min, et al. Deep-tissue focal fluorescence imaging with digitally time-reversed ultrasound- encoded light. Nature communications 3 (2012): 928. [3] Cui, Meng, and Changhuei Yang. Implementation of a digital optical phase conjugation system and its application to study the robustness of turbidity suppression by phase conjugation. Optics express 18.4 (2010)

Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome

Hemiconvulsion–hemiplegia–epilepsy syndrome (HHE) is a rare outcome of prolonged hemiconvulsion that is followed by diffuse unilateral hemispheric edema, hemiplegia, and ultimately hemiatrophy of the affected hemisphere and epilepsy. Here, we describe the case of a 3-year-old male with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication that developed HHE after a prolonged febrile seizure and discuss the pathogenesis of HHE in the context of the patient’s complex genetic background

Interferometric speckle visibility spectroscopy (ISVS) for human cerebral blood flow monitoring

Infrared light scattering methods have been developed and employed to non-invasively monitor human cerebral blood flow (CBF). However, the number of reflected photons that interact with the brain is low when detecting blood flow in deep tissue. To tackle this photon-starved problem, we present and demonstrate the idea of interferometric speckle visibility spectroscopy (ISVS). In ISVS, an interferometric detection scheme is used to boost the weak signal light. The blood flow dynamics are inferred from the speckle statistics of a single frame speckle pattern. We experimentally demonstrated the improvement in the measurement of fidelity by introducing interferometric detection when the signal photon number is low. We apply the ISVS system to monitor the human CBF in situations where the light intensity is ∼100-fold less than that in common diffuse correlation spectroscopy (DCS) implementations. Due to the large number of pixels (∼2 × 10⁵) used to capture light in the ISVS system, we are able to collect a similar number of photons within one exposure time as in normal DCS implementations. Our system operates at a sampling rate of 100 Hz. At the exposure time of 2 ms, the average signal photoelectron number is ∼0.95 count/pixel, yielding a single pixel interferometric measurement signal-to-noise ratio (SNR) of ∼0.97. The total ∼2 × 10⁵ pixels provide an expected overall SNR of 436. We successfully demonstrate that the ISVS system is able to monitor the human brain pulsatile blood flow, as well as the blood flow change when a human subject is doing a breath-holding task

Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome

Hemiconvulsion–hemiplegia–epilepsy syndrome (HHE) is a rare outcome of prolonged hemiconvulsion that is followed by diffuse unilateral hemispheric edema, hemiplegia, and ultimately hemiatrophy of the affected hemisphere and epilepsy. Here, we describe the case of a 3-year-old male with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication that developed HHE after a prolonged febrile seizure and discuss the pathogenesis of HHE in the context of the patient’s complex genetic background

Time-reversed ultrasonically encoded (TRUE) focusing for deep-tissue optogenetic modulation

The problem of optical scattering was long thought to fundamentally limit the depth at which light could be focused through turbid media such as fog or biological tissue. However, recent work in the field of wavefront shaping has demonstrated that by properly shaping the input light field, light can be noninvasively focused to desired locations deep inside scattering media. This has led to the development of several new techniques which have the potential to enhance the capabilities of existing optical tools in biomedicine. Unfortunately, extending these methods to living tissue has a number of challenges related to the requirements for noninvasive guidestar operation, speed, and focusing fidelity. Of existing wavefront shaping methods, time-reversed ultrasonically encoded (TRUE) focusing is well suited for applications in living tissue since it uses ultrasound as a guidestar which enables noninvasive operation and provides compatibility with optical phase conjugation for high-speed operation. In this paper, we will discuss the results of our recent work to apply TRUE focusing for optogenetic modulation, which enables enhanced optogenetic stimulation deep in tissue with a 4-fold spatial resolution improvement in 800-micron thick acute brain slices compared to conventional focusing, and summarize future directions to further extend the impact of wavefront shaping technologies in biomedicine