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COGNITIVE DYSFUNCTION IN SCHIZOPHRENIA IMPLIES THAT IT IS A DEVELOPMENTAL BRAIN DISEASE

NEW ORLEANS — A new concept of schizophrenia has emerged in the last decade, in which cognitive deficits, not psychosis, are at the heart of the disease. And while medications may ease psychotic symptoms, cognitive dysfunction continues to plague the person with schizophrenia and may determine the long-term outcome. The evidence for — and the implications of — this emerging theory were outlined by two neuroscientists at a symposium here at the last Annual Meeting of the Society for Neuroscience.

THE ESSENCE OF SCHIZOPHRENIA

The psychotic symptoms of schizophrenia — hallucinations and delusions — are the “most remarkable” and the easiest to diagnose, according to Raquel Gur, MD, PhD, Professor in the Departments of Psychiatry, Neurology, and Radiology at the University of Pennsylvania School of Medicine in Philadelphia, “but cognitive dysfunction is the essence of the disorder. The deficits in cognition are profound, progressive, and present at the onset of illness.” These deficits affect attention, memory, executive function, and verbal abilities.

Along with symptoms such as lack of engagement and depression, they leave the patient “overwhelmed by daily tasks and have the largest impact on functional abilities,” Dr. Gur said.

Schizophrenia often starts in adolescence, and because this is normally a time of dynamic change, family members and teachers often don't think about schizophrenia when the symptoms first appear. “As a result, it can go unchecked for many years,” Dr. Gur said. Typically, it will be three to five years between the first observed behavioral changes and the diagnosis of full-blown schizophrenia. “By the time it becomes symptomatic in late adolescence or the early twenties, the person has been ill for a number of years,” she said.

CHANGES IN THE BRAIN

The changes in the brain that lead to schizophrenia appear at a critical stage of brain development, while synaptogenesis is taking place, Dr. Gur said, “depriving the individual of the ability to reach early adulthood equipped to navigate through life.”

The effects of these changes are readily seen on cognitive tests, including those for mental flexibility — the ability to recategorize and reinterpret information in multiple ways as a function of context. For example, a subject is shown three stars and one square, and asked, “Which one doesn't belong?” The sizes and outlines of the shapes may differ so that there could be multiple logical answers to the question, which are elicited by repeated questioning by the examiner. While healthy subjects can discover different ways to reclassify the objects when prodded, the person with schizophrenia cannot.

“What we find is that people with schizophrenia are stuck in first gear,” Dr. Gur said. “They cannot switch.” Spatial and memory tasks are also profoundly affected. “Across the board, there are large deficits in cognitive function, from one to three standard deviations,” she said. In common with learning disabilities and attention deficit-hyperactivity disorder, men are more affected than women both in number and in severity, performing approximately 20 to 30 percent worse in some tests.

These deficits are present at the onset of symptoms, and tend to worsen early in the disease, “suggesting a dynamic process in the prefrontal cortex that is unfolding in front of our eyes in these patients,” said Dr. Gur. And while neuroleptic treatment can reduce the psychotic symptoms, they do not help cognition. “Despite symptomatic improvement, the cognitive deficit remains,” she said.

Figure

Dr. Edward Jones: “One of the things we know too little about is the extent to which relatives of schizophrenics display an underlying brain disorganization, comparable to schizophrenia, but which never crosses the threshold” to symptomatic disease.

NEUROIMAGING STUDIES

Underlying these deficits are pervasive changes in the brain, according to Dr. Gur. Brain volume is decreased compared with controls, and the MRI changes are already evident at the onset of symptoms. “A decrease in grey matter in the dorsal parts of the frontal lobe declines even further over the first two years of disease. Concomitantly you see the decrease in abstraction,” Dr. Gur said. “Anatomy goes with cognition.”

The effects can also be seen with functional neuroimaging, in which schizophrenia patients show reduced blood flow and a more diffuse activation in frontal regions during cognitive tasks than healthy controls, a condition that schizophrenia researchers call “hypofrontality.” “Patients don't have an efficient way of accessing the system that is important in performing these tasks,” she said.

“In schizophrenia we see fMRI aberrations at several stages critical for brain development,” Dr. Gur concluded. “Early in neurogenesis, patients with schizophrenia are disposed to getting off the normal trajectory,” so that when they reach the stage of synaptogenesis in adolescence, “they do not have the basic support needed to maintain cognitive function.”

BIOLOGICAL BASIS FOR DYSFUNCTION

The biological basis of cognitive dysfunction in schizophrenia was explored further by Edward Jones, MD, PhD, Director of the Center for Neuroscience at the University of California-Davis. “A decade ago, schizophrenia had been aptly characterized as the graveyard of neuropathology,” he said. But advances in imaging techniques have changed that, allowing a much deeper look into the schizophrenic brain.

Neuroanatomists have looked “just about everywhere” for the anatomical correlates of schizophrenia. “Two robust observations have withstood the test of time and reproducibility,” said Dr. Jones. “There is dilatation of the lateral ventricles, which can extend into the third ventricles.” The dilatation is present from first clinical manifestations and does not progress, he said, with the implication that it has a developmental origin. “This is indicative of a loss of connectivity among key cortical areas involved in cognition,” he said. Tied to this finding is the second observation: “However we measure it, the dorsolateral prefrontal cortex is hypoactive.” Together, these findings imply that “key areas are disconnected from one another, leading to individuals disconnected from the reality of the external world.”

A COMPLEX GENETIC PICTURE

Genes clearly play an important role in schizophrenia, Dr. Jones continued. Fifty percent of monozygotic twin pairs are both affected, indicating a high genetic component. On the other hand, he said, “50 percent of the twins escape from expression of symptoms. Coupled with genetics, therefore, there must be other factors” that affect disease expression and severity. “One of the things we know too little about is the extent to which relatives of schizophrenics display an underlying brain disorganization, comparable to schizophrenia, but which never crosses the threshold” to symptomatic disease, he said.

Genome-wide scans have suggested there are susceptibility genes on more than a quarter of the chromosomes, indicating the genetic complexity of the disorder. Studies of differential expression between schizophrenic and control brains indicate large numbers of genes are expressed at higher or lower levels in the dorsolateral prefrontal cortex of the schizophrenic brain. Many of these genes fall into three broad classes, influencing neurotransmission, myelination, and neural metabolic pathways, said Dr. Jones.

He cited neuregulin, involved in regulating the action of N-methyl-D-aspartate (NMDA); catechol o-methyl transferase, which alters the amount of dopamine available for release and reuptake; and RGS4 (regulator of G-protein signaling 4), involved in a variety of signaling pathways. “These are only three examples of possible susceptibility genes acting to affect connectivity,” Dr. Jones said. “It is probably inappropriate at this stage to suggest that any of these genes are necessarily the only genes that confer susceptibility. Rather, I think expression profiling studies tend to show that they represent part of a much broader profile.” The final result might be over-pruning of synapses at adolescence, which remains “one of the best theories,” he said. The expression profiles are done on the brain.

Figure

These are MRI scans of identical twins. The twin on the right has schizophrenia; the twin on the left is healthy. In the twin with schizophrenia, the lateral cerebral ventricles are dilated.

OUTSIDE COMMENTARY

“Cognitive disability has long been known to be part of the syndrome of schizophrenia,” said Robert Freedman, MD, Professor in the Departments of Psychiatry and Pharmacology at the University of Colorado Health Sciences Center.

“These disabilities have become an important target for new therapies for several reasons,” Dr. Freedman continued. “First, the antipsychotic medications currently available do not fully reverse these deficits.” Second, these deficits, as measured by neuropsychological testing, are more highly correlated with long term psychosocial disabilities such as inability to hold a job or to have a family than are the more obvious overt psychotic symptoms such as hallucinations or delusions.

“Psychiatrists feel indebted to Hughlings Jackson for his insight that the negative symptoms of a brain illness, in this case the loss of cognitive function in schizophrenia, may be more troubling to the patients than the positive symptoms.”

Daniel Weinberger, MD, Director of the Genes, Cognition, and Psychosis Program at the National Institute of Mental Health, agrees that cognitive deficits lie at the heart of schizophrenia.

The severity of cognitive symptoms is also the best predictor of overall recovery, he said, much more so than psychosis, he said. “The worse the cognitive symptoms, the worse the outcome.”

The new focus on cognitive dysfunction in schizophrenia has “revolutionized how people understand the disease,” he said, and has led to a more intense focus on developing treatments, although little progress has yet been made. “To actually improve cognition has been a challenge,” said Dr. Weinberger. While there are drugs that increase arousal, alertness, and attention, these do not have a large effect. “It is not just turning on a switch,” he said, “and it is not clear how to improve it.”

ARTICLE IN BRIEF

✓ Two leading schizophrenia researchers discuss evidence for the emerging theory that cognitive deficits, not psychosis, are at the heart of the disease.