AUTHOR=Xie Kun, Fox Grace E., Liu Jun, Lyu Cheng, Lee Jason C., Kuang Hui, Jacobs Stephanie, Li Meng, Liu Tianming, Song Sen, Tsien Joe Z. TITLE=Brain Computation Is Organized via Power-of-Two-Based Permutation Logic JOURNAL=Frontiers in Systems Neuroscience VOLUME=10 YEAR=2016 URL=https://www.frontiersin.org/articles/10.3389/fnsys.2016.00095 DOI=10.3389/fnsys.2016.00095 ISSN=1662-5137 ABSTRACT=There is considerable scientific interest in understanding how cell assemblies—the long-presumed computational motif—are organized so that the brain can generate intelligent cognition and flexible behavior. The Theory of Connectivity proposes that the origin of intelligence is rooted in a power-of-two-based permutation logic (N = 2i–1), producing specific-to-general cell-assembly architecture capable of generating specific perceptions and memories, as well as generalized knowledge and flexible actions. We show that this power-of-two-based permutation logic is widely used in cortical and subcortical circuits across animal species and is conserved for the processing of a variety of cognitive modalities including appetitive, emotional and social information. However, modulatory neurons, such as dopaminergic (DA) neurons, use a simpler logic despite their distinct subtypes. Interestingly, this specific-to-general permutation logic remained largely intact although NMDA receptors—the synaptic switch for learning and memory—were deleted throughout adulthood, suggesting that the logic is developmentally pre-configured. Moreover, this computational logic is implemented in the cortex via combining a random-connectivity strategy in superficial layers 2/3 with nonrandom organizations in deep layers 5/6. This randomness of layers 2/3 cliques—which preferentially encode specific and low-combinatorial features and project inter-cortically—is ideal for maximizing cross-modality novel pattern-extraction, pattern-discrimination and pattern-categorization using sparse code, consequently explaining why it requires hippocampal offline-consolidation. In contrast, the nonrandomness in layers 5/6—which consists of few specific cliques but a higher portion of more general cliques projecting mostly to subcortical systems—is ideal for feedback-control of motivation, emotion, consciousness and behaviors. These observations suggest that the brain’s basic computational algorithm is indeed organized by the power-of-two-based permutation logic. This simple mathematical logic can account for brain computation across the entire evolutionary spectrum, ranging from the simplest neural networks to the most complex.