Animal MRI/MRS Methodological Development for Drug Addiction Applications

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1. Converging Structural and Functional Evidence for a Rat Salience Network The salience network (SN) is dysregulated in many neuropsychiatric disorders, including substance use disorder. Initially described in humans, identification of a rodent SN would provide the ability to mechanistically interrogate this network in preclinical models of neuropsychiatric disorders. We used modularity analysis on resting-state functional MRI data of rats (n=32) to parcellate rat insula into functional subdivisions and to identify a potential rat SN based on functional connectivity patterns from the insular subdivisions. We then used mouse tract tracing data from the Allen brain atlas to confirm the networks underlying structural connectivity. We next compared functional connectivity profiles of the SN across rat, marmoset (n=10) and humans (n=30). Finally, we assessed rat SNs response to conditioned cues in rats (n=21) with a history of heroin self-administration. We identified a putative rat SN, which consists of primarily the ventral anterior insula and anterior cingulate cortex, based on functional connectivity patterns from the ventral anterior insular division. Functional connectivity architecture of the rat SN is supported by the mouse neuronal tracer data. Moreover, the anatomical profile of the identified rat SN is similar to that of non-human primates and humans. Finally, we demonstrate that the rat SN responds to conditioned cues and increases functional connectivity to the Default Mode Network during conditioned heroin withdrawal. In conclusion, the neurobiological identification of a rat SN together with a demonstration of its functional relevance provides a novel platform with which to interrogate its functional significance in normative and neuropsychiatric disease models. (Tsai et al., Biological Psychiatry, in press) 2. Design of Focal Deep Transcranial Magnetic Stimulation Coil Conventional transcranial magnetic stimulation (TMS) coils are limited by the depth-focality tradeoff rule. The emission field intensity from coils with either small or large apertures will diverge quickly at less than one aperture diameter distance away from the coil. To utilize a better depth-focality tradeoff rule and accomplish deep and focused stimulation, a new approach needs to be employed. We have designed a new type of TMS coil that can deliver spot size adjustable stimulations to deeper brain regions. By comparing its stimulation depth and focality with 50 other coils, our study concluded the proposed method to have broken the depth-focality tradeoff rule. Both theoretical calculations and experimental data collectively demonstrated an adjustable focality controlled by the tuned angle of the coils conductive windings. Our TMS coil design plots a new curve in the depth-focality profile with better performance than all the existing conventional coil designs in the tradeoff rule. 3. Focal Transcranial Magnetic Stimulation in Awake Rats: Enhanced Glucose Uptake in Deep Cortical Layers Transcranial magnetic stimulation (TMS) is an emerging neuromodulation tool. However, preclinical models of TMS are limited. The aim of the study was to develop a method for performing TMS in awake rats and to characterize neuronal response to TMS by mapping glucose uptake following TMS administration. A headpost was implanted into rat skull serving as a refence to guide TMS target. Motor threshold measurement was used as the metric to assess the consistency in TMS delivery across animals and across sessions. Using a fluorescent glucose analogue (2-NBDG) as a marker of neuronal activity, we mapped glucose uptake in response to TMS of the rat motor cortex. Our results showed the average motor threshold (n = 41) was 34.6 6.3 % of maximum stimulator output (MSO). The variability of motor threshold across animals was similar to what has been reported in human studies. Furthermore, there was no significant difference in motor threshold measured across 3 separate days. Enhancement in fluorescent signals were TMS dose (power)-dependent, which centered around the motor cortex, covering an area medial-laterally 2 mm, rostral-caudally 4 mm at 55 % MSO, and 3 mm at 35 % MSO. The count of total cells with significant fluorescent signal was: 107 23 (55 % MSO), 73 11 (35 % MSO) and 42 11 (sham, 5% MSO). In conclusion, our method allows for consistent motor threshold assessment for longitudinal studies. Notably, cells with fluorescent signal enhancement were consistently aggregated in deep cortical layers, with minimal enhancement in superficial layers. To our knowledge, this is the first study of focal TMS in awake rodents. (Samantha et al., J. Neurosci Methods, 2020). 4. A Microprocessor-based Controlling System for Transcranial Magnetic Stimulation Transcranial magnetic stimulation (TMS) is a non-invasive technique for brain neurostimulation at specific cortical regions. During TMS, a waveform pulse stimulation is sent to a coil placed on the subjects scalp, in which the magnetic field generated by the coil induced an electric field in the brain cortex. Currently, the leading TMS research make efforts to enhance the technical development for modeling and magnetic field generation for deep brain penetration such as the circuit topology and coil design. Besides, the stimulation parameters (waveform, pulse duration, stimulation frequency and amplitude) also play an important role in stimulating target cortical area. In this project, a microprocessor-based system for controlling the generation of magnetic field by the TMS device is developed. The TMS electric field intensity, which is proportional to the voltage of the storage capacitor, can be configured quickly using the digital-to-analog (DAC) module. The pulse duration, which is eligible to control the switching device (insulated-gate bipolar transistor IGBT) between the storage capacitor and the induced coil, can be adjusted by the internal timer/counter inside the microprocessor. Furthermore, the designed frequency patterns for specific treatment purposes (rTMS, cTBS, iTBS) are generated by monitoring the previous pulse width frequency. At the moment, the control unit has been tested together with the monophasic TMS device at different energy levels to monitor the artifacts before delivering it to the clinical services. It should be noted that the desinged controlling system is suitable for controlling either single coil or multiple coils TMS device. In the multi-coil TMS, separated coils can be controlled independently or simultaneously which provide the promising application of delivering stimulation pulses in different locations without moving the coils.