Schizophrenia prefrontal cortex, activity

Keefe RS, Roitman SE, Harvey PD, Blum CS, DuPre RL, et al. 1995. A pen-and-paper human analogue of a monkey prefrontal cortex activation task Spatial working memory in patients with schizophrenia. Schizophr Res 17 ... 

Initiation of behaviour Mesolimbic pathway to nucleus accumbens from VTA (AIO) Mesocortical pathways to prefrontal cortex from VTA (AIO) Animals Increases locomotor activity and intracranial self-stimulation Humans Hallucinations, psychoses (reward, reinforcement) Animals Decreases activity and self-stimulation Humans Reduces positive symptoms of schizophrenia D2 ... 

Figure 17.9 Schematic representation of the proposed activity profile of an ideal neuroleptic. The figure shows DA pathways to the prefrontal cortex, mesolimbic nucleus accumbens and striatum the effects required for an ideal drug on the DA influence and symptoms there and to what extent they are met by most typical and atypical neuroleptics and by clozapine. Note that while all atypical neuroleptics induce few extrapyramidal w side-effects (EPSs) few of them, apart from clozapine, have much beneficial effect in overcoming negative symptoms of schizophrenia ...

It appears that an ideal neuroleptic may need to reduce DA activity in the mesolimbic system (nucleus accumbens) to counter the positive symptoms of schizophrenia, increase it in the prefrontal cortex to overcome negative symptoms and have little or possibly no effect on it in the striatum so EPSs do not arise (Fig. 17.9). No wonder we still await the ideal drug. 

The net effect is to push the brain in a very REM dream-like direction. PET studies of schizophrenic patients brains show deficient frontal cortical activation and limbic overactivation. The working hypothesis of schizophrenia investigators is that psychosis results when the overactive mesolimbic pathway is released from deficient cortical control. This is formally identical to our hypothesis of dream psychosis the dorsolateral prefrontal cortex is deactivated and the limbic system is hyperactivated. 

This initial finding of abnormal hippocampal function during memory retrieval in schizophrenia has been clarified by several subsequent studies. First, patients with schizophrenia rely less on the recruitment of the hippocampus and show more widespread activation of the prefrontal cortex during the retrieval of previously learned information (Weiss et al., 2003). Second, the ability to classify new items as previously not experienced is impaired in schizophrenia and is associated with decreased activation and smaller volume of the hippocampus (Weiss et al., 2004). Third, hippocampal recruitment in schizophrenia is impaired specifically during a relational, but not during a nonrelational memory task (Ongur et al., 2006). 

Glantz LA, Lewis DA. Reduction of synaptophysin immunore-activity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity. Arch. Gen. Psychiatry 1997 54 660-669. 

The treatment of the negative symptoms of schizophrenia has always proved challenging. The reduced cognitive abilities and social withdrawal that typify negative symptoms and contribute in a major way to the adequate function of schizophrenics (701). Negative functions are thought to occur from decreased dopamine neurotransmission in the prefrontal cortex. Recent findings show this to be associated with the inheritance of an allele for catechol-o-methyl transferase (COMT), which increases the thermal stability and thus activ-... 

It is thought that there is an abnormality of dopamine receptors or increased release of dopamine in the mesolimbic and mesocortical pathways in schizophrenics. However, no reproducible changes in dopaminergic systems have been found in schizophrenia and the abnormality may be in another system that is somehow linked to dopaminergic neurones. More recently, it has been suggested that schizophrenia may be a developmental disorder of the prefrontal cortex where there is actually a deficiency of dopamine, which leaves dopamine activity in the mesolimbic pathway unbalanced. 

---