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And men ought to know that from nothing else but thence [from the brain] come joys, delights, laughter and sports, and sorrows, griefs, despondency, and lamentations. And by this, in an especial manner, we acquire wisdom and knowledge, and see and hear, and know what are foul and what are fair, what are bad and what are good, what are sweet, and what unsavory… And by the same organ we become mad and delirious, and fears and terrors assail us… All these things we endure from the brain, when it is not healthy… In these ways I am of the opinion that the brain exercises the greatest power in the man. This is the interpreter to us of those things which emanate from the air, when it [the brain] happens to be in a sound state.

—Hippocrates (460–370 BC)1

Since ancient times, humans have tried to understand what accounts for thoughts and feelings. Alcmaeon of Croton (5th century BC) believed sense organs were connected to the brain via vessels and that the brain was the seat of consciousness.2 Hippocrates (460–370 BC) was prescient in his realization that not only perception, cognition, emotion, and behavior are governed by the brain, but that disorders of these functions also arise in the brain. Alternatively, Aristotle (384–322 BC) later believed that the heart was the center of thought and emotions.3,4 Across the ensuing centuries, artists and scientists (such as DaVinci and Rembrandt) gradually learned more about the nervous system through detailed (neuro)anatomic studies with careful dissection. By the 19th century, studies of brain lesions associated with specific behavioral manifestations (such as the pioneering work of Paul Broca) helped to bridge the gap between anatomy and functional specialization. In the 20th century, work by Kluver and Bucy demonstrated the link between emotional function and medial temporal lobe structures in primate models, and Papez and MacLean made important contributions to our understanding of how the limbic system is associated with emotions in humans.3

With the advent of modern scientific methods, there has been an explosion of knowledge pertaining to neural function and its link to emotion, cognition, and behavior. Animal models, from rodents though nonhuman primates, have provided detailed information ranging from molecular to cellular to systems-level insights. These models have greatly informed our understanding of how human brain organization can be linked to human experiences. However, there are limitations to animal models, both in examining normal brain function (such as complex language, a uniquely human function) and especially in studying brain disorders that affect complex, higher-order functions, such as psychiatric disorders, for which accurate animal models often do not exist. And while human post-mortem studies can yield important information regarding anatomy, physiology, and even molecular processes, by definition, the autopsied brain is not in a state that can reflect active, functional processes.

The advent of functional neuroimaging ...

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