Abstract: Understanding how the brain interprets activity in the sensory cortex is central to basic neuroscience and is also important for efforts to develop cortical sensory prosthetics, which use electrical stimulation of the cortex to evoke percepts. However, the rules by which cortical activity is interpreted by downstream circuits remain poorly understood. In this talk, I will describe work using electrical and optogenetic intracortical microstimulation (ICMS) combined with behavioral measurements in mice and monkeys. These experiments show that, with practice, animals can detect stimulation delivered to nearly any area of the cerebral cortex with similar thresholds. Despite this, multiple lines of evidence indicate that artificial stimulation of the visual cortex cannot readily be integrated into coherent perceptions of forms or patterns. I will then discuss recent work in animals and humans examining how naturally occurring cortical signals are interpreted during perception and decision-making. These studies reveal an unexpected asymmetry: increases in neuronal firing strongly influence behavior, whereas decreases in firing rate of similar or even greater magnitude have little or no measurable impact. This finding suggests that downstream circuits rely primarily on increases in spiking activity when extracting information from cortical populations. Together, these results highlight fundamental constraints on how the brain reads activity from the sensory cortex and point to important limits on the interpretability of artificially evoked cortical signals.