小動物におけるEEGとfMRIの同時計測法の確立

Tohoku University川島隆太課

Optogenetic Brain Interfaces

The brain is a large network of interconnected neurons where each cell functions as a nonlinear processing element. Unraveling the mysteries of information processing in the complex networks of the brain requires versatile neurostimulation and imaging techniques. Optogenetics is a new stimulation method which allows the activity of neurons to be modulated by light. For this purpose, the cell-types of interest are genetically targeted to produce light-sensitive proteins. Once these proteins are expressed, neural activity can be controlled by exposing the cells to light of appropriate wavelengths. Optogenetics provides a unique combination of features, including multimodal control over neural function and genetic targeting of specific cell-types. Together, these versatile features combine to a powerful experimental approach, suitable for the study of the circuitry of psychiatric and neurological disorders. The advent of optogenetics was followed by extensive research aimed to produce new lines of light-sensitive proteins and to develop new technologies: for example, to control the distribution of light inside the brain tissue or to combine optogenetics with other modalities including electrophysiology, electrocorticography, nonlinear microscopy, and functional magnetic resonance imaging. In this paper, the authors review some of the recent advances in the field of optogenetics and related technologies and provide their vision for the future of the field.United States. Defense Advanced Research Projects Agency (Space and Naval Warfare Systems Center, Pacific Grant/Contract No. N66001-12-C-4025)University of Wisconsin--Madison (Research growth initiative; grant 101X254)University of Wisconsin--Madison (Research growth initiative; grant 101X172)University of Wisconsin--Madison (Research growth initiative; grant 101X213)National Science Foundation (U.S.) (MRSEC DMR-0819762)National Science Foundation (U.S.) (NSF CAREER CBET-1253890)National Institutes of Health (U.S.) (NIH/NIBIB R00 Award (4R00EB008738)National Institutes of Health (U.S.) (NIH Director’s New Innovator award (1-DP2-OD002989))Okawa Foundation (Research Grant Award)National Institutes of Health (U.S.) (NIH Director’s New Innovator Award (1DP2OD007265))National Science Foundation (U.S.) (NSF CAREER Award (1056008)Alfred P. Sloan Foundation (Fellowship)Human Frontier Science Program (Strasbourg, France) (Grant No. 1351/12)Israeli Centers of Research Excellence (I-CORE grant, program 51/11)MINERVA Foundation (Germany

The mechanisms of tinnitus: perspectives from human functional neuroimaging

In this review, we highlight the contribution of advances in human neuroimaging to the current understanding of central mechanisms underpinning tinnitus and explain how interpretations of neuroimaging data have been guided by animal models. The primary motivation for studying the neural substrates of tinnitus in humans has been to demonstrate objectively its representation in the central auditory system and to develop a better understanding of its diverse pathophysiology and of the functional interplay between sensory, cognitive and affective systems. The ultimate goal of neuroimaging is to identify subtypes of tinnitus in order to better inform treatment strategies. The three neural mechanisms considered in this review may provide a basis for TI classification. While human neuroimaging evidence strongly implicates the central auditory system and emotional centres in TI, evidence for the precise contribution from the three mechanisms is unclear because the data are somewhat inconsistent. We consider a number of methodological issues limiting the field of human neuroimaging and recommend approaches to overcome potential inconsistency in results arising from poorly matched participants, lack of appropriate controls and low statistical power

Oxygen Polarography in the Awake Macaque: Bridging BOLD fMRI and Electrophysiology

Blood oxygen level dependent (BOLD) fMRI is the predominant method for evaluating human brain activity. This technique identifies brain activity by measuring blood oxygen changes associated with neural activity. Although clearly related, the nature of the relationship between BOLD fMRI identified brain activity and electrophysiologically measured neural activity remains unclear. Direct comparison of BOLD fMRI and electrophysiology has been severely limited by the technical challenges of combining the two techniques. Microelectrode electrophysiology in non-human primates is an excellent model for studying neural activity related to high order brain function similar to that commonly studied with BOLD fMRI in humans, i.e. attention, working memory, engagement. This thesis discusses the development of, validation of, and first results obtained using a new multi-site oxygen polarographic recording system in the awake macaques as a surrogate for BOLD fMRI. Oxygen polarography measures tissue oxygen which is coupled to blood oxygen. This tool offers higher resolution than BOLD fMRI and can be more readily combined with electrophysiology. Using this new tool we evaluated local field potential and oxygen responses to an engaging visual stimulus in two distinct brain systems. In area V3, a key region in the visual system and representative of stimulus driven sensory cortex, we show increased tissue oxygen and local field potential power in response to visual stimulus. In area 23 of the posterior cingulate cortex (PCC), a hub of the default-mode network we show decreased oxygen and local field potential in response to the same stimulus. The default-mode network is a set of brain regions identified in humans whose BOLD fMRI activity is higher at rest than during external engagement, arguing that they sub-serve a function that is engaged as the default-mode in humans. Our results provide new evidence of default-mode network activity in the macaque similar to that seen in humans, provide evidence that the BOLD identified default-mode suppression reflects neural suppression and overall support a strong relationship between neural activity and BOLD fMRI. However, we also note that the LFP responses in both regions show substantial nuances that cannot be seen in the oxygen response and suggest response complexity that is invisible with fMRI. Further the nature of the relationship between LFP and oxygen differs between regions. Our multi-site technique also allows us to evaluate inter-regional interaction of ongoing oxygen fluctuations. Inter-regional correlation of BOLD fMRI fluctuations is commonly used as an index of functional connectivity and has provided new insight into behaviorally relevant aspects of the brains organization and its disruption in disease. Here we demonstrate that we can measure the same inter-regional correlation using oxygen polarography. We utilize the increased resolution of our technique to investigate the frequency structure of the signals driving the correlation and find that inter-regional correlation of oxygen fluctuations appears to depend on a rhythmic mechanism operating at ~0.06 Hz

Imaging of epileptic activity using EEG-correlated functional MRI.

This thesis describes the method of EEG-correlated fMRI and its application to patients with epilepsy. First, an introduction on MRI and functional imaging methods in the field of epilepsy is provided. Then, the present and future role of EEG-correlated fMRI in the investigation of the epilepsies is discussed. The fourth chapter reviews the important practicalities of EEG-correlated fMRI that were addressed in this project. These included patient safety, EEG quality and MRI artifacts during EEG-correlated fMRI. Technical solutions to enable safe, good quality EEG recordings inside the MR scanner are presented, including optimisation of the EEG recording techniques and algorithms for the on-line subtraction of pulse and image artifact. In chapter five, a study applying spike-triggered fMRI to patients with focal epilepsy (n = 24) is presented. Using statistical parametric mapping (SPM), cortical Blood Oxygen Level-Dependent (BOLD) activations corresponding to the presumed generators of the interictal epileptiform discharges (IED) were identified in twelve patients. The results were reproducible in repeated experiments in eight patients. In the remaining patients no significant activation (n = 10) was present or the activation did not correspond to the presumed epileptic focus (n = 2). The clinical implications of this finding are discussed. In a second study it was demonstrated that in selected patients, individual (as opposed to averaged) IED could also be associated with hemodynamic changes detectable with fMRI. Chapter six gives examples of combination of EEG-correlated fMRI with other modalities to obtain complementary information on interictal epileptiform activity and epileptic foci. One study compared spike-triggered fMRI activation maps with EEG source analysis based on 64-channel scalp EEG recordings of interictal spikes using co-registration of both modalities. In all but one patient, source analysis solutions were anatomically concordant with the BOLD activation. Further, the combination of spike- triggered fMRI with diffusion tensor and chemical shift imaging is demonstrated in a patient with localisation-related epilepsy. In chapter seven, applications of EEG-correlated fMRI in different areas of neuroscience are discussed. Finally, the initial imaging findings with the novel technique for the simultaneous and continuous acquisition of fMRI and EEG data are presented as an outlook to future applications of EEG-correlated fMRI. In conclusion, the technical problems of both EEG-triggered fMRI and simultaneous EEG-correlated fMRI are now largely solved. The method has proved useful to provide new insights into the generation of epileptiform activity and other pathological and physiological brain activity. Currently, its utility in clinical epileptology remains unknown

Development and Localization of Spike-Wave Seizures in Animal Models

Animal models allow for detailed investigation of neuronal function, particularly invasive localization and developmental studies not possible in humans. This thesis will review the technical challenges of simultaneous EEG-fMRI, and epileptogenesis studies in animal models, including issues related to anesthesia, movement, signal artifact, physiology, electrode compatibility, data acquisition, and data analysis, and review recent findings from simultaneous EEG-fMRI studies in epilepsy and other fields. Original research will be presented on the localization of neuronal networks involved during spike-and-wave seizures in the WAG/Rij rat, a model of human absence epilepsy. Simultaneous EEG-fMRI at 9 Tesla, complimented by parallel electrophysiology, including Multiple Unit Activity (MUA), Local Field Potential (LFP), and Cerebral Blood Flow (CBF) measurements were employed to investigate the functioning of neuronal networks. This work indicates that while BOLD signal increases in the Somaotsensory Cortex and Thalamus during SWD are associated with MUA, LFP, and CBF increases, BOLD signal decreases in the Caudate are associated with CBF decreases and relatively larger increase in LFP and smaller increase in MUA. Complimenting the localization studies, original research will also be presented on the development of spike-and-wave epilepsy in the C3H/Hej mouse, a model which will allow for more advanced genetic and molecular investigation. This work shows seizure development progressing though immature, transitional, and mature stages