Schizophrenia is widely considered to be a genetically mediated neurodevelopmental disorder,1,2
with symptoms typically emerging in late adolescence or early adulthood, followed by a steady clinical decline throughout life, consistent with a neuroprogressive process. 3
The prodromal phase preceding the onset of the formal symptoms of schizophrenia includes positive psychotic symptoms, negative symptoms,4,5
and cognitive deficits that include distractibility.6
Individuals experiencing prodromal symptoms have a significantly greater probability of developing the illness,4,6
suggesting that specific aspects of prodromal symptoms may reflect vulnerability markers for developing schizophrenia.7
However, prodromal symptoms, which overlap with experiences and behaviors of similar-aged individuals, many of whom do not develop schizophrenia, are mild and have low predictive value as vulnerability markers. Therefore, the current behavioral and symptomatic criteria for the prodromal stage are neither sufficiently sensitive nor specific for reliable early diagnosis of psychotic disorders. Consequently, there is a critical need for identifying markers that are more closely tied to neural function and linked to the pathophysiologic mechanisms of schizophrenia, and therein augment the validity and specificity of clinical features preceding illness onset.
It is generally accepted that interactions along the frontostriate pathways form the basis for higher executive functions and the organization, selection, and generation of task-appropriate thoughts and behaviors.8
It is well established that continuous performance–type tasks such as the forced choice visual oddball task yield robust activation that localizes brain regions associated with visual executive processing and selective attention.9–16
Studies in ultra-high-risk individuals show impaired behavioral performance on continuous performance tasks and indicate that impaired attention is (1) evident in schizophrenic patients regardless of clinical state, (2) detectable before illness onset, (3) present in first-degree relatives, and (4) predictive of later behavioral disturbances in susceptible individuals.17
Deficits on tasks of visual selective attention, executive function, working memory, and response inhibition18–21
have been associated with prefrontal functional abnormalities in schizophrenic patients,22–32
beginning as early as the first episode of illness.33
Frontal and striatal regions are thus prominently implicated in the pathophysiology of schizophrenia, and further show structurally abnormal neuroanatomic findings.34–37
Evidence of structural abnormality comes from cytoarchitectural analysis of postmortem patient brains,38,39
and disorganized prefrontal white matter.41,42
Midbrain regions, which provide major afferents to prefrontal cortical regions, have reduced thalamic volumes43,44
and disrupted subcortical function in schizophrenia.45,46
alterations in subcortical regions have been associated with deficits in sensory filtering, behavioral control, and flexibility.
In high-risk adolescents, performance deficits in attention and executive function tasks17
that are associated with frontostriatal cortical dysfunction and, more recently, findings of decreased gray matter in inferior frontal cortex and in the cingulate cortex51
have been reported to precede the clinical expression of illness. These attention impairments are comparable in severity with impairments observed in adult clinical cases and are the strongest predictors of evolving into schizophrenia.17
Similarly, first-degree relatives of individuals with schizophrenia and persons diagnosed as having schizotypal personality disorder display attention and executive function deficits that are early clinical markers in the diathesis for schizophrenia.52,53
Together, these findings implicate a functional deficit in brain regions responsible for attention and executive function during the prodromal stage. Examining frontostriatal dysfunction, associated with the early and chronic stages of schizophrenia, may lead to the identification of novel vulnerability markers present during the prodrome of illness. To date, there have been no published functional magnetic resonance imaging (fMRI) studies in high-risk populations experiencing prodromal symptoms. The characterization of a postulated neuroprogressive pathologic finding associated with the onset of schizophrenia motivated our efforts.
The aims of this study were (1) to use fMRI to examine the functional integrity of frontostriatal regions in an ultra-high-risk group experiencing prodromal symptoms; (2) to examine the relationship of frontostriatal function to stage of illness; and (3) to assess specific aspects of prefrontal deficits related to selective attention and executive function that facilitate goal-directed behavior through the selection of task-relevant stimuli and filtering of task-irrelevant novel stimuli. Using a cross-sectional experimental design, we studied 3 groups of patients (ultra-high-risk, early, and chronic) selected for their stage of illness, and a fourth control group. We hypothesized that patients in the early and chronic stages would show evidence of frontostriatal abnormality, reflected in reduced extent and intensity of activation, and that ultra-high-risk individuals would exhibit milder abnormality of the same form.