Schizophrenia: Serial Order Processing Deficit?

James Houk
Department of Physiology, Northwestern University

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     Last modified: April 28, 2007
     Presentation date: 08/12/2007 12:50 PM in MCC
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Abstract
When a sequence of k spatial targets are observed and then maintained in working memory, normal subjects have no difficulty recalling k=1-4 targets. However, schizophrenia patients make huge errors for k=3 or 4 (Fraser et al 2004). Based on the Beiser-Houk (1998) model of loops between basal ganglia and cerebral cortex, the deficit is likely to reside in the caudate nucleus of the neostriatum where spiny neurons compete with each other in a pattern classification operation. This leads to a prominent deficit in serial order processing. My hypothesis contrasts with the widespread belief that a core feature of schizophrenia is a deficit in working memory residing in the dorso-lateral prefrontal cortex (Lewis & Gonzalez-Burgos 2006).

In an imaging study of serial order recall in normal subjects, we observed a statistically significant decrease in the BOLD (Blood Oxygen Level Dependent) signal that was recorded from the caudate nucleus (Houk et al 2007). Our Decode contrast compared serial order recall from working memory with the execution of the same movements under visual guidance. Since BOLD is sensitive to changes in blood flow, caused mainly by synaptic activity (Logothetis 2002), this was a puzzling result ? an area of the brain that actively participates in serial order recall was showing a decrease in blood flow, most likely due to a decrease in synaptic activity. In an attempt to understand this puzzle, we used a specific model of serial order processing based on the general model introduced in Agents of the Mind (Houk 2005). When the competition between spiny neurons in the caudate nucleus was modeled by presynptic, as opposed to postsynaptic, inhibition, the model performed better in the presence of noise while also explaining the decrease in BOLD. Presynaptic inhibition was not only computationally more powerful, it also decreased synaptic activity in the network of competing spiny neurons.

How does competition mediated by presynaptic inhibition relate to schizophrenia? The central paradox of schizophrenia (Crow 1997) is that the genetic deficit survives in about 1% of the population in spite of a fecundity disadvantage. I will propose that a DNA sequence change that improved GABAb presynaptic receptor function occurred in primates and led to the evolution of language, intelligence and complex social relations. Improved pattern classification could explain the survival of the gene in the population, whereas a genetic polymorphism that encodes a protein having reduced activity with a 1% incidence could explain the central paradox of schizophrenia (Houk et al 2007).

References:

Beiser DG, Houk JC. (1998) Model of cortical-basal ganglionic processing: Encoding the serial order of sensory events. Journal of Neurophysiology. 79: 3168-3188.
Crow T (1997) Is schizophrenia the price that Homo sapiens pays for language? Schizophrenia Research 28: 127-141
Fraser D, Park S, Clark G, Yohanna D, Houk JC (2004) Spatial serial order processing in schizophrenia. Schizophrenia Research. 70: 203-213.
Houk JC (2005) Agents of the mind. Biological Cybernetics 92: 427-437.
Houk JC, D Fraser, A Fishbach, SA Roy, LS Simo, C Bastianen, D Wald, PJ Reber (2007). Action selection in subcortical loops through basal ganglia and cerebellum. Phil Trans Roy Soc B: 362: September issue http://www.journals.royalsoc.ac.uk/content/w4077317t235g045/
Lewis DA, Gonzalez-Burgos1m G (2006). Pathophysiologically based treatment interventions in schizophrenia. Nature Medicine 12: 1016-1022.
Logothetis N (2002) The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal. Phil. Trans. R. Soc. Lond. B 357: 1003-1037.