While schizophrenia generally begins as an acute psychotic episode in young adults, it appears to emerge more gradually in children. The appearance of the disorder is often preceded by developmental disturbances, such as lags in motor and speech/language development. These developmental problems can often be associated with more distinct brain abnormalities.

The diagnostic criteria are the same as for adults (read more about schizophrenia), except that symptoms appear prior to age 12. Children with schizophrenia frequently see or hear things that don't really exist, and often hold paranoid and bizarre beliefs. These symptoms may be accompanied by attention problems, impaired memory and reasoning, speech impairments, inappropriate, or flattened affect, poor social skills, and depressed mood. Misdiagnosis of schizophrenia in children is common. Symptoms are prevalent in the child's life and are not limited to specific situations. Children with schizophrenia tend to be cut off from normal relationships and are unlikely to show any interest in friendships with others.

Since 1992 researchers at the National Institute of Mental Health in Bethesda have scanned over 1,000 children and adolescents with high-resolution brain MRIs. What makes this study unique is the fact that these children return to the clinic to be re-scanned every 2 years. Many children are now receiving their 5th scan, and have grown up in the meantime, leaving a remarkable time-lapse movie as record of how their brain has developed. The resulting treasure-chest of brain scans charts brain growth in unprecedented detail. Among those patients scanned at NIMH were 40 adolescents with early-onset schizophrenia (EOS), who were scanned repeatedly as their disorder developed. These patients had detailed cognitive and clinical evaluations; they satisfied DSM-III-R/DSM-IV criteria for diagnosis of schizophrenia before the age of 12. Since their symptoms are continuous with the adult disorder, their brain scans and repeated neuropsychiatric tests hold key information on how schizophrenia develops in the teenage years.

In a longitudinal brain imaging study of adolescents, MRI scans revealed fluid filled cavities in the middle of the brain enlarging abnormally between ages 14 and 18 in teens with early onset schizophrenia, suggesting a shrinkage in brain tissue volume. These children lost four times as much gray matter, neurons and their branch-like extensions, in their frontal lobes as normal teens. This gray matter loss engulfs the brain in a progressive wave from back to front over 5 years, beginning in rear structures involved in attention and perception, eventually spreading to frontal areas responsible for organizing, planning, and other "executive" functions impaired in schizophrenia. Since losses in the rear areas are influenced mostly by environmental factors, the researchers suggest that some non-genetic trigger contributes to the onset and initial progression of the illness. The final loss pattern is consistent with that seen in adult schizophrenia. Adult-onset patients' brains may have undergone similar changes when they were teens that went unnoticed because symptoms had not yet emerged, suggest the researchers.

	Mapping Brain Changes in Schizophrenia. Derived from high-resolution magnetic resonance images (MRI scans), the above images were created after repeatedly scanning 12 schizophrenia subjects over five years, and comparing them with matched 12 healthy controls, scanned at the same ages and intervals. Severe loss of gray matter is indicated by red and pink colors, while stable regions are in blue. STG denotes the superior temporal gyrus, and DLPFC denotes the dorsolateral prefrontal cortex. (Reprinted with permission from Thompson PM et al., Proceedings of the National Academy of Sciences of the USA, 98[20]:11650-11655)

In studying the schizophrenic patients, we were stunned to see a spreading wave of tissue loss that began in a small region of the brain, the parietal cortices (see accompanying image, top row, red colors). This deficit pattern, which we recently reported in the Proceedings of the National Academy of Sciences, moved across the brain like a forest fire. It destroyed more tissue as the disease progressed (red colors, bottom row), eventually engulfing the rest of the cortex after a period of 5 years. The 3D maps are color coded to show different degrees of change, revealing where gray matter is significantly reduced in disease.

At their first scan (an average of 1.5 years after initial diagnosis), patients showed a 10% gray matter deficit in a small region of the cortex. This deficit, observed at the age of 13, was initially confined to parietal brain regions involved in spatial association. Over the 5 succeeding years, this brain tissue loss swept forward into sensory and motor regions, and by the age of 18, into dorsolateral prefrontal and temporal cortices, which were not initially affected. This pattern was replicated in independent groups of male and female patients. Each showed a similar pattern of spreading deficits, reaching a 20%-25% average loss. Overall, regions of loss corresponded with the impairments in neuromotor, auditory, visual search, and frontal executive functions that characterize schizophrenia. The frontal eye fields lost tissue fastest, at about 5 percent per year, perhaps consistent with the eye-tracking and smooth eye pursuit deficits often reported in patients.

This dynamic wave of brain tissue loss also correlated with worsening psychotic symptoms and mirrored the progression of neurological and cognitive deficits associated with the disorder. Specifically, patients with fastest loss in temporal cortices had worst positive symptoms (including hallucinations and delusions). Since temporal loss rates were a good predictor of positive symptoms at follow-up, future studies in larger samples will be able to assess whether these losses link more specifically with auditory rather than visual hallucinations. In addition, gray matter loss in the frontal cortices correlated with increased negative symptoms (such as lack of emotional responses and poverty of speech). The resulting deficits are consistent with the physiological hypothesis that negative symptoms of schizophrenia may partly derive from reduced dopaminergic activity in frontal cortices. We are currently developing digital mapping methods to isolate which specific frontal deficits (e.g., dorsolateral prefrontal, orbitofrontal) link most tightly with negative symptoms.