PROJECT SUMMARY ‘Binding’ refers to the process whereby elements encoded by multiple brain areas are integrated into a coherent whole during perception, cognition, and action. The elements may be perceptual (such as the color, shape, location, motion, and texture of a visual object), but they may also include executive function and the integration of meaning, instructions, and movements. Disruption in cortical neural binding may also be implicated in the pathophysiology of many forms of neuropsychiatric disease, however, the mechanisms by which highly diverse neural information is integrated in the human cortex are largely unknown. Current explanations often rely on hierarchical multimodal convergence, or on synchronized high frequency oscillations, but these remain largely untested in the human brain. Several properties of recently observed human cortical ripples are consistent with ‘binding-by-synchrony’, including their broad anatomical and behavioral distribution, phase-modulation of local firing, and especially their co-occurrence and phase-locking between widely separated locations. Thus far, our group and others have demonstrated that co-rippling is enhanced during memory recall in waking, and in NREM sleep, possibly associated with memory consolidation. The proposed study will test if cortical ripples possess other properties crucial to a possible role in binding. Aim 1 will test if cortical neurons in different areas interact more strongly when their locations engage in co-occurring ripples by recording populations of single neurons in different segments of the cortex during spontaneous behavior using established microelectrode technologies. Aim 2 asks if cortical rippling and co-rippling occur in behavioral contexts that elicit binding beyond memory recall during waking, and consolidation during NREM. To achieve these aims, this proposal includes the acquisition of novel human intracranial recording data and the analysis of a large collection of human electrophysiology data that has grown over the last decade. This unique dataset includes multi-hour and multi-day continuous recordings of local field potentials and single neuron firing in multiple cortical areas in humans, using two patient groups and several micro-arrays. Together, these aims will test if widespread co-occurring and phase-locked cortical ripples may serve as a substrate for one of the foundational functions of the human brain: to bind disparate content into a unified experience. Ultimately, illuminating the interactions between neurons during cortical ripples may be critical for understanding the temporal organization of neuronal network activity, and may provide the foundation to help better understand human cognitive disfunction.