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Working Memory, the Dorsolateral Prefrontal Cortex, and Schizophrenia.           

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A large portion of schizophrenic symptoms can also be described as reflecting (or contributing to) specific cognitive deficits in memory and reasoning ability (executive functions). The existence of formal thought disorder and attentional disabilities in schizophrenic patients suggest that the mental disease may be resulting in the loss of specific reasoning abilities. The set of cognitive processes used to actively maintain and manipulate information for use in mental abstraction and reasoning or controlling behavior is known as working memory. 

As discussed earlier, the DLPFC has been linked to many of the negative symptoms of schizophrenia as also seen in those with DLPFC damage, and with direct DLPFC stress loading through tasks such as: the Stroop, delayed-response tasks, and the WCS. The link between DLPFC function, working memory, and negative symptoms of schizophrenia required more than one study. First, Weinberger et al (1986) provided empirical proof of the DLPFC dysfunction in schizophrenics by linking cerebral blood flow (rCBF) deficits to the DLPFC. Linking the DLPFC functioning to working memory functions, Perlstein et al (2001) showed how specific working memory tasks, previously not tested for, did rely on DLPFC activation. The study also showed that working memory deficits positively correlate to level of schizophrenic thought disorganization.     

Regional cerebral blood flow or rCBF is a measurement of blood circulation levels to specific areas of the brain using a xenon inhalation technique developed by Orbist et al. The studied participants inhale the xenon gas and imaging technology can detect where the radioactive chemicals saturated in the blood stream flow throughout the body and brain.   By monitoring rCBF while the patients participated in the Wisconsin Card Sort (WCS), a task relying heavily on working memory, Weinberger et al (1986) suggested that the DLPFC's link to negative symptoms arises from a deficit in blood flow to that region, lowering its activation levels. Patients' performance on the WCS positively correlated with the level of blood flow to the DLPFC suggests that many of the negative symptoms present in schizophrenics may be a function of working memory deficits.

           In the study conducted by Weinberger et al. blood flow to the DLPFC was investigated in twenty schizophrenic patients and 25 non schizophrenics. All participants were subjected to three separate conditions or tasks in which rCBF in 32 cortical regions were determined. The first of the three tasks was labeled the resting condition. In that period of time participants were instructed to remain still while the experimenters slowly activated the Xenon inhalation devise (participants were not aware of this). This condition allowed participants to become acclimated with the experimental conditions.

            The next two conditions were counterbalanced among the participants in random order to discount the possible effect of task order on results. These two tasks were together labeled the activation condition and consisted of participants performing either the Wisconsin Card Sort (WCS) or the number matching control task while experimenters assessed rCBF. Past research has shown a statistically significant link between the Wisconsin Card Sorting task and the DLPFC; damage to that area of the frontal cortex negatively predicted a good performance with the task. The number matching condition served as a control for the other tasks by eliciting cognitive processes not as significantly reliant on the DLPFC.

            Results showed an increase of rCBF to the DLPFC in the normal participants during the WCS and no increase during the NM conditions while schizophrenics showed no increase in rCBF to the DLPFC in either condition. This empirical data provides evidence to support the theory that a physiologic dysfunction in the dorsolateral prefrontal cortex of the frontal lobe exists in schizophrenic patients. More specifically, rCBF to the DLPFC significantly correlated with performance among the schizophrenic patient group. The more blood flow to the DLPFC the better they performed. Although this definitely links the DLPFC to schizophrenia, it doesn't prove whether dysfunction in that area is a cause of schizophrenic cognitive deficits or perhaps just a marker or coexisting characteristic of the disease. Know the answer to this question we have to look at studies which have directly investigated the role of the DLPFC in working memory.

  Although prior to recent studies, many researchers used tasks such as the WCS to identify frontal lobe specificity, many researchers agree that the WCS and many other tasks are too complex and do not isolate working memory functions alone. In addition to task function, it has also become apparent that schizophrenics may suffer other cognitive deficits that could confound experimental results such as the inability to control attention and focus.  

Perstein et al (2001) conducted a study to control for all the possible confounds of past research on working memory and the DLPFC. With the use of a technologically updated medical imaging technique, magnetic resonance imaging (fMRI), the research team manipulated working memory load on 17 schizophrenic patients and 16 healthy control subjects.  To eliminate the complexity of tasks that do not single out working memory functions, researchers used the sequential-letter memory task.  This task required the participants to identify the digit initially presented zero, one, two, or three frames before the one currently viewable.  The accomplishment of this task requires participants to actively store and compare units of separate information at differing working memory loads.  The dependent variables or measured results, surrounded accuracy, answering response time, and fMRI images of participants’ brain activity.

            Response times were found to be significantly longer for the schizophrenic patients as compared to the healthy subjects. More importantly, there were differences in DLPFC activation between the schizophrenics and the control group.  As the working memory load became larger, activation levels of the DLPFC between increasingly differed between groups.  At the two digit loading level, patients began to drop off in DLPFC activation.

            Perlstein et al’s (2001) study suggests that there is a significant role of the DLPFC in working memory, correlating its activation negatively with cognitive disorganization, a symptom of schizophrenia possibly responsible for many of the negative symptoms. More specifically, they recorded dysfunction on the right side of the DLPFC and interestingly, a negative correlation of region activation existed between the (Right) DLPFC and Broca’s area, a language specific cortical region of the brain. These results clearly suggest working memory and the right DLPFC dysfunction as playing significant roles in schizophrenic symptoms.  Although much of the symptoms thought to be related to these cortical areas are categorized as negative, there is rising evidence of an interaction with positive symptoms as well.