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The advent of functional imaging has led to a new wave of insights into the pathophysiology and treatment of psychiatric disorders. In this Perspective, schizophrenia is used as an example of such a psychiatric disorder to illustrate these advances. Schizophrenia is a chronic and debilitating disorder characterized by a heterogeneous group of symptoms, including positive symptoms (delusions, hallucinations, disorganized thought), negative symptoms (flattened affect, stereotyped thinking, difficulty in abstract thinking), and multifaceted cognitive deficits, most prominently in the areas of attention, memory, and executive functioning (1). Emil Kraepelin gave us the first clinical account of schizophrenia in 1896. He named it dementia praecox, literally, early or premature deterioration of one’s mental faculties. In using this term, Kraepelin was referring to the fact that the disorder often strikes in adolescence or early adulthood and runs a chronic, lifelong, disabling course. In his writing about the disorder, Kraepelin emphasized the evident cognitive impairment in individuals that he studied, which comprised deficits in attention, motivation, problem solving, learning, and memory. He was also the first to link these cognitive impairments with poor functional outcome in patients with schizophrenia, such as deficits in social functioning, independent living, and self-care abilities. The term “schizophrenia” (schizo, split; phreno, mind) was coined by the Swiss psychiatrist Eugen Bleuler in 1911. Although Bleuler disputed Kraepelin’s assumption that the disorder struck only in early adulthood and always entailed dementia-like cognitive degeneration, he agreed that cognitive impairment was a core feature of schizophrenia, or its fundamental symptom. Other “peculiar” features, such as hallucination and delusions, were considered by Blueler to be secondary or “accessory” symptoms.  The discovery of antipsychotics in the 1950s revolutionized the treatment of schizophrenia and directed emphasis toward positive symptoms. At that time, treatment with antipsychotics, with their encouraging effect on psychotic symptoms, led to the closure of most hospitals for chronic patients with severe and enduring mental illness and offered much hope for these patients to be reintegrated into society. However, by the 1960s it became obvious that a reduction in positive symptoms did not lead to recovery from schizophrenia and did not significantly improve functional outcome (2). The understanding of the fundamental deficits in schizophrenia came full circle as it came to be accepted that cognitive dysfunction plays a central role in the illness, just as Kraepelin and Bleuler had suggested at the dawn of the 20th century. Cognitive deficits are a core feature of schizophrenia, which (a) may precipitate psychotic and negative symptoms (3); (b) are relatively stable over time, with progressive deterioration after the age of 65 in some patients (4); (c) persist upon the remission of psychotic symptoms (5); (d) are related to but separate from negative symptoms (6, 7); and (e) determine functional impairment characteristic of the patients with this disorder (8).  Functional brain imaging in schizophrenia was originally intended to elucidate the underlying physiological disturbances that lead to manifest illness. This Perspective will deal mainly with attempts by researchers to understand the pathophysiology and the mechanism of drug action using functional magnetic resonance imaging (fMRI), a technique that has the obvious advantages of minimal invasiveness, no radioactivity, widespread availability, and virtually unlimited study repetitions. These attributes make it ideally suited to the study of in vivo brain function in psychiatric illness like schizophrenia, facilitating the characterization of developmental changes in brain function from childhood and throughout the clinical course of the illness, and in response to treatment. In this article, some current issues surrounding the interpretation of functional imaging data in schizophrenia will be considered. Various investigators have examined links between brain activation, cognitive functioning, and symptoms, in the hope of identifying those regions and circuits that may be abnormal in schizophrenia. Ultimately, fMRI may help delineate disease pathways based upon pathophysiological correlates that may complement nosology. If this is successful, neural network models might be built to emulate brain malfunctions for each disease. This, in turn, may lead to better therapeutic options.

Insights and treatment options for psychiatric disorders guided by functional MRI