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.