1. Development of focused transcranial magnetic stimulation for rodents by copper-array shields We demonstrated using magnetic shield to achieve magnetic focusing without sacrificing significant amount of throughput. The shield is composed of multiple layers of copper ring arrays, which utilize induced current to generate counter magnetic fields. We experimentally set up a two-pole stimulator system to verify device simulation. A transient magnetic field probe was used for field measurements. The focusing effect highly depends on the geometric design of shield. A tight focal spot with a diameter of smaller than 5 mm (plotted in MATLAB contour map) can be achieved by using copper ring arrays. With properly designed array structures and ring locations, the combined original and induced counter fields can produce a tightly focused field distribution with enhanced field strength at a depth of 7.5 mm beyond the shield plane, which is sufficient to reach many deep and critical parts of a mouse brain. (Meng et al., IEEE Transactions on Magnetics, in press) We have also developed an innovative concept to dramatically enhance the efficiency of TMS coil, a major challenge associated with small coil size. We have applied a new wire-wrapping method to break the circular symmetry of the field pattern, achieving focused electric field distribution. In vivo, experiments demonstrate reproducible contralateral single-limb activation and motor evoked potential (MEP). According to the mouse motor cortex map by Tennant et al., mouse hindlimb representation is about 1mm anteroposteriorly, and is in close proximity to the forelimb and trunk motor cortex, suggesting the focality of our TMS is about 1mm. Our coil design principles may provide guidelines for the development of the next generation TMS tools that target more focused areas in the human brain. (Meng et al., Brain Stimulation, 2018) 2. Neurophysiological basis of multi-scale entropy of brain complexity and its relationship with functional connectivity Recently, non-linear statistical measures such as multi-scale entropy (MSE) have been introduced as indices of the complexity of electrophysiology and fMRI time-series across multiple time scales. In this work, we investigated the neurophysiological underpinnings of complexity (MSE) of electrophysiology and fMRI signals and their relations to functional connectivity (FC). MSE and FC analyses were performed on simulated data using neural mass model-based brain network model with the Brain Dynamics Toolbox, on animal models with concurrent recording of fMRI and electrophysiology in conjunction with pharmacological manipulations, and on resting-state fMRI data from the Human Connectome Project. Our results show that the complexity of regional electrophysiology and fMRI signals is positively correlated with network FC. The associations between MSE and FC are dependent on the temporal scales or frequencies, with higher associations between MSE and FC at lower temporal frequencies. Based on literature and our data, we propose that the complexity of regional neural signals may serve as an index of the brain's capacity of information processing- increased complexity may indicate greater transition or exploration between different states of brain networks, thereby a greater propensity for information processing. (Wang, et al., Front Neuroscience, 2018) 3. Longitudinal observations using simultaneous fMRI, multiple channel electrophysiology recording, and chemical microiontophoresis in the rat brain Concurrent resting-state fMRI (rsfMRI) data collection and electrophysiological recording in combination with microiontophoretically injected modulatory chemicals allows for improved understanding of the relationship between resting state BOLD and neuronal activity. In this study, simultaneous fMRI, multi-channel intracortical electrophysiology and focal pharmacological manipulation data were acquired longitudinally in rats for up to 2 months. Our artifact replacing technique is optimized for combined LFP and rsMRI data collection. Our results showed that intracortical implantation of a multichannel microelectrode array resulted in minimal distortion and signal loss in fMRI images inside a 9.4T MRI scanner. rsfMRI-induced electrophysiology artifacts were replaced using an in-house developed algorithm. Microinjection of AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) enhanced dopaminergic neuronal activity in the ventral tegmental area (VTA) and altered LFP signal and fMRI functional connectivity in the striatum. Our model consists of longitudinal concurrent fMRI and multichannel intracortical electrophysiological recording during microinjection of pharmacological agents to modulate neural activity in the rat brain. We used commercial micro-electrodes and recording system and can be readily generalized to other labs. (Jaime et al., J Neurosci Methods, 2018) 4. Neural pathways and their functional relevance revealed by optogenetic stimulation and fMRI FMRI with optogenetic stimulation is a powerful tool to investigate brain circuits underlying specific functions. This project is to develop protocols to investigate neural pathways and their functional relevance of the medial prefrontal cortex (MPFC) and insula, both have been shown to plays an important role in substance use disorders. Preclinical research suggests an involvement of MPFC in positive emotion or reward. Here, we incorporated optogenetic stimulation and whole brain fMRI to examine brain circuits underlying positive emotional effects induced by MPFC stimulation. Rats quickly learned to respond on a lever for MPFC photostimulation. FMRI showed that MPFC photostimulation activated many regions known to receive MPFC afferents. Particularly, the activation of hypothalamus, agranular insula, and ventral striatum was positively correlated with the lever press. The insula is known to receive interoceptive signals and plays a critical role in emotionan functions. A functional distinction between the anterior and posterior insular has been proposed. Here, we investigate the downstream brain activation associated with anterior or posterior insular stimulation, with the aim to understand the functional profile of the insula and to further explore its role in addiction related behaviors. Findings from the study would help to identify brain circuits that underlie addiction behaviors and would be used as a therapeutic target for treatment. (Hu et al., Manuscript in preparation) 5. FMRI of brain dynamics in the mouse self-administering optogenetic stimulation This project is to develop a method that permits fMRI of whole brain dynamics while a mouse being actively performing a goal-directed task. FMRI has been successfully used to detect dynamic activity of the brain that is engaged in interactive tasks in humans, but it has not yet been applied in preclinical studies with animal models. Here we performed a proof-of-principle study to demonstrate that dynamic activity of the whole brain can be monitored while mice actively engage in tasks. As an interactive task, we used an intracranial self-stimulation (ICSS) procedure, in which animals acquire and maintain operant behavior reinforced by focal brain stimulation. That is, ICSS shows focal stimulations capacity to produce goal-directed behavior, thereby reward or goal-directed motivation. We chose to produce ICSS with the stimulation of the medial prefrontal cortex (mPFC). Toward this end, the present study detected the whole brain activity of mice engaging mPFC ICSS. We believe that this study showcases how the new fMRI protocol can contribute for understanding functional networks. (Cover et al., Manuscript under review)
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