Animal MRI/MRS Methodological Development for Drug Addiction Applications

National Institute On Drug Abuse

Investigators

Linked publications & trials

Abstract

1. Functional organization of the brain networks in rats revealed by graph-theory based network analysis of fMRI data This project is to investigate the functional organization of brain networks and its role in balancing cost and efficiency in the communication of the rat brain. Network analyses of structural connectivity in the brain have highlighted a set of highly connected hubs that are densely interconnected, forming a rich-club substrate in diverse species. Here, we demonstrate the existence of rich-club organization in functional brain networks of rats. Densely interconnected rich-club regions are found to be distributed in multiple brain modules, with the majority located within the putative default mode network. Rich-club members exhibit high wiring cost (as measured by connection distance) and high metabolic running cost (as surrogated by cerebral blood flow), which may have evolved to achieve high network communications to support efficient brain functions. Furthermore, by adopting a forepaw electrical stimulation paradigm, we find that the rich-club organization of the rat functional network remains almost the same as in the resting state, whereas path motif analysis reveals significant differences, suggesting the rat brain reorganizes its topological routes by increasing locally oriented shortcuts but reducing rich-club member-involved paths to conserve metabolic running cost during unimodal stimulation. Together, our results suggest that the neuronal system is organized and dynamically operated in an economic way to balance between cost minimization and topological/functional efficiency. (Liang et al., Cerebral Cortex, 2017) 2. Systems and methods for training and imaging an animal in an awaken state This project is to develop systems that are used for training and fMRI scanning of animals in an awaken, behaving state. Current techniques for imaging animals in an awaken state aim to train them to remain still for a prolonged period of time during imaging with the aid of a body restraint along with head fixation using a bite bar and/or ear bars or head mount. However, physically restraining the animal can induce stress, thereby resulting in unavoidable movement of the stressed animal in many cases. Due to the limitations of imaging animals in an awaken state, a majority of animal imaging is conducted when the animal is under anesthesia. However, anesthetics compromise brain functions of the animal under anesthesia, while some anesthetics can directly interact with the pharmacological compounds being tested, thereby potentially skewing data being collected. As such, there is a need for improvements in systems and methods for imaging of animals in an awaken state. We have developed systems and methods for training a rodent to maintain its head substantially motionless during an imaging procedure. The system includes a frame with a head post that is attached to the head of the animal and a treadmill having a plurality of rollers that the animal is in operative contact. This arrangement trains the animal to remain substantially motionless when disposed within an imaging apparatus. (Lu et al., US patent, US 20160192891 A1). 3. Neural pathways and their functional relevance revealed by optogenetic stimulation and fMRI This project is to combine optogenetic stimulation and fMRI to investigate brain circuits that underlying specific functions. The medial prefrontal cortex (MPFC) plays an important role in mood regulation. Deep brain stimulation (DBS) delivered at the MPFC has been found to have treatment efficacy in major depression. Preclinical research suggests an involvement of this region in positive emotion or reward. For example, rats learn to self-stimulate with high-frequency electricity delivered at the MPFC. In the present study, 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. Our finding may shed light on brain circuits involved in therapeutic effects of recent deep brain stimulation studies in major depression, in which the MPFC plays an important role. (Hu et al., presented in ISMRM 2017). 4. Neurophysiological basis of resting state functional connectivity This project is to investigate neurophysiological basis of resting-state functional connectivity using simultaneous fMRI and electrophysiological recording in the rat brain. Spontaneous ongoing neuronal activity is a prominent feature of the mammalian brain. Temporal and spatial patterns of such ongoing activity have been exploited to examine large-scale brain network organization and function. However, the neurophysiological basis of this spontaneous brain activity as detected by resting-state fMRI remains poorly understood. In this study, multi-site local field potentials (LFP) and blood oxygenation level-dependent (BOLD) fMRI were simultaneously recorded in the rat striatum along with local pharmacological manipulation of striatal activity. Results demonstrate that delta () band LFP power negatively, while beta () and gamma () band LFPs positively correlated with BOLD fluctuation. Furthermore, there was strong cross-frequency phase-amplitude coupling (PAC), with the phase of LFPs significantly modulating the amplitude of the high frequency signal. Enhancing dopaminergic neuronal activity significantly reduced ventral striatal functional connectivity, LFP-BOLD correlation, and the PAC effect. These data suggest that different frequency bands of the LFP contribute distinctively to BOLD spontaneous fluctuation and that PAC is the organizing mechanism through which low frequency LFPs orchestrate neural activity that underlies resting state functional connectivity. After receiving comments from reviewers on the manuscript of the study, we have re-analyzed some of the data and the manuscript is now under revision. (Manuscript submitted for publication) 5. Development of focused magnetic field for non-invasive brain stimulation of the rodent brain This study is to develop focused magnetic field for transcranial magnetic stimulation (TMS) of the rodent brain. TMS is one of the most widely used methods for brain stimulation in the treatment of neurological and psychiatric diseases, such as depression and drug addiction. Current commercial TMS stimulators cannot provide well targeted stimulation, particularly in small animals such as rodents. Due to fast field divergence, the effective distance in TMS is limited to around 1.5 cm. We demonstrated the use of 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 in the ring to generate counter magnetic fields. We experimentally set up a two-pole stimulator system. A transient magnetic field probe was used for field measurements. The shield effect not only depends on the design of shield structure but also the intensity of original magnetic field from the stimulator. A higher original magnetic field can produce stronger counter field and achieve better focusing. A tight focal spot with a diameter of 0.5cm was achieved by using 4 layers of copper ring arrays. Such a multilayer based shield structure will be tested in targeted noninvasive stimulation of the rat brain. A paper on this study has been submitted for publication and some re-analyses of the data have been done based on comments from reviewers. (Manuscript submitted for publication).