Etiology and components of working memory and attention deficits in schizophrenia patients and their first-degree relatives: behavioral, functional and structural imaging studies


Neurocognitive deficits are core features of schizophrenia that may determine functional outcome. Work in our lab has identified working memory (WM) deficit as a cardinal cognitive symptom of schizophrenia. WM is a limited-capacity, active short-term memory system that guides and controls behavior and is mediated by the neural circuitry that includes the dorsolateral prefrontal cortex. A majority of schizophrenic patients and about half of their healthy first-degree relatives show WM deficits, which emerge by mid-adolescence in high-risk individuals who do not otherwise show signs of psychosis. WM deficits are also linked to poor social functioning, which prevent successful rehabilitation. We aim to identify the components that are central to WM deficit, their neural correlates and the consequences of WM deficit in other behaviors that determine outcome. Once the loci of abnormal processes and mechanisms of WM are specified, it will be possible to devise remediation strategies to enhance WM. Thus, this work provides an essential basis for future development of therapeutic interventions that can target the specific types of deficits experienced by individuals with schizophrenia.


Cognitive and neuroanatomical data suggest that selective attention and affect modulate encoding and maintenance in WM but schizophrenic patients are unable to effectively integrate attention and affect to guide goal-directed behavior. We examine the roles of perceptual, attentional and affective factors in encoding to specify both optimal and detrimental encoding conditions. Encoding affects all forms of memory and thus has far-reaching consequences. In addition to impaired encoding, there is evidence that abnormal attentional control and affect impair WM maintenance, so we need to identify where the vulnerabilities of schizophrenic patients lie.


We are currently using fMRI and Near-Infrared Optical Imaging (a non-invasive method which has been approved for use in infants) to probe the roles of prefrontal and parietal cortices in normal and abnormal WM. We examined the neural correlates of correct and error performance to understand the difference between remembering and forgetting in the brain. We found that healthy subjects activate right middle frontal gyrus during the maintenance phase of spatial WM on correct trials but this activation is absent on error trials. In schizophrenic patients, we observed a similar pattern but in the left middle frontal gyrus, which suggests that the hemispheric implementation of the same spatial WM process is reversed.


We have begun to identify components of WM deficit in relation to functional neuroanatomy but much remains to be done. Even a small improvement in WM can improve chances for good outcome and successful rehabilitation. Atypical antipsychotic drugs on the whole have not been effective in remediating WM deficit but our analysis of WM errors indicate that errors originate from distinct sources (eg. encoding problems, maintenance deficit, disinhibition of response) and different types of errors respond differentially to treatments. Moreover, there are significant sex differences in dopamine receptor function (e.g. greater cortical dopamine release in women. Riccardi et al, in press) which may influence WM. Therefore, it is important to identify the types of WM errors made by schizophrenic patients and implement more individualized treatment strategies, depending on the types of deficit; this approach should increase the efficacy.


In sum, these projects aim to identify the key components of WM deficits in schizophrenia patients, and their unaffected siblings. Identification and elucidation of core neurocognitive deficits of schizophrenia will contribute towards the understanding of the complex interplay between cortical functions and cognitive deficits in schizophrenia. Moreover, specifying abnormal mechanisms within WM in relation to attention, affect and brain function and structure could lead to targeted strategies that might ameliorate WM deficits and improve adaptive functioning in schizophrenia.


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