Pathological Effects of Cortical Architecture on Working Memory in Schizophrenia

Abstract

Neural connectivity of the prefrontal cortex is essential to working memory. Reduction of prefrontal connectivity and abnormal prefrontal dopamine modulation are common characteristics associated with schizophrenia.

Two experiments separately modeled the effects of exaggerated pruning and of synaptic depression to imitate schizophrenic performance in a prefrontal neural network. In the first model, effects of cortical pruning were simulated with a set of scale-free networks of neurons and compared with empirical results from the Sternberg working memory task. The second set of simulations were based on the synaptic theory of working memory. Simulations of this model measured memory duration in relation to synaptic facilitation and depression constants and in relation to the level of neural connectivity.

In the first set of simulations, modulating levels of cortical pruning resulted in a gain or loss in accuracy and speed of memory recollection. In the second set of simulations, increased facilitation time constants and decreased inhibitory time constants resulting in longer memory durations, and overly connected networks resulted in very low memory durations.

In the first model, the decline in memory performance can be attributed to the emergence of pathological memory behavior brought about by the warping of the basins of attraction. Collectively, the simulations demonstrate that a reduction of prefrontal cortical hubs can lead to schizophrenia like performance in neural networks, and may account for pathological working memory in the disorder.

References

• 1 Albert R, Barabasi AL. Statistical mechanics of complex networks.  Reviews of modern physics. 2002;  74 (1) 47-97
• 2 Altamura M, Elvevåg B, Blasi G. et al . Dissociating the effects of Sternberg working memory demands in prefrontal cortex.  Psychiatry Research: Neuroimaging. 2007;  154 (2) 103-114
• 3 Baddeley A. Working memory. Oxford: Oxford University Press; 1986
• 4 Bassett DS, Bullmore E, Verchinski BA. et al . Hierarchical Organization of Human Cortical Networks in Health and Schizophrenia.  J Neurosci. 2008;  28 (37) 9239-9248
• 5 Carlsson A. The neurochemical circuitry of schizophrenia.  Pharmacopsychiatry. 2006;  39 (S 01) S10-S14
• 6 Chafee MV, Goldman-Rakic PS. Inactivation of parietal and prefrontal cortex reveals interdependence of neural activity during memory-guided saccades.  J Neurophysiol. 2000;  83 1550-1566
• 7 Cohen JD, Forman SD, Braver TS. et al . Activation of prefrontal cortex in a non-spatial working memory task with functional MRI.  Human brain mapping. 1994;  1 293-304
• 8 Cohen JD, Servan-Schreiber D. A Theory of Dopamine Function and Its Role in Cognitive Deficits in Schizophrenia.  Schizophr Bull. 1993;  19 (1) 85
• 9 Diwadkar VA, Flaugher B, Jones T. et al . Impaired associative learning in schizophrenia: Behavioral and computational studies.  Cogn Neurodyn. 2008;  2 (3) 207-219
• 10 Durstewitz D, Seamans JK. The computational role of dopamine D1 receptors in working memory.  Neural Netw. 2002;  15 (4-6) 561-572
• 11 Érdi P, Ujfalussy B, Diwadkar V. The schizophrenic brain: A broken hermeneutic circle.  Neural Network World. 2009;  19 413-427
• 12 Érdi P, Ujfalussy B, Zalányi L. et al . Computational approach to schizophrenia: Disconnection syndrome and dynamical pharmacology.  American Institute of Physics. 2007;  1028 65-87
• 13 Fuster JM. The prefrontal cortex-an update: Time is of the essence.  Neuron. 2001;  30 319-333
• 14 Fuster JM. The prefrontal cortex: anatomy, physiology, and neuropsychology of the frontal lobe. 2nd edition.. New York: Raven Press; 1989
• 15 Hoffman RE, Dobscha SK. Cortical pruning and the development of schizophrenia: A computer model.  Schizophrenia Bulletin. 1989;  15 (3) 477
• 16 Honey CJ, Kotter R, Breakspear M. et al . Network structure of cerebral cortex shapes functional connectivity on multiple time scales.  Proc Natl Acad Sci U S A. 2007;  104 10240-10245
• 17 Hopfield JJ. Neural networks and physical systems with emergent collective computational abilities.  Proc Natl Acad Sci U S A. 1982;  79 (8) 2554-2558
• 18 Koh PO, Undie AS, Kabbani N. et al . Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients.  Proc Natl Acad Sci U S A. 2003;  100 (1) 313-317
• 19 Lewis DA, Gonzalez-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia.  Neuropsychopharmacology. 2008;  33 141-165
• 20 Loh M, Rolls ET, Deco G. A Dynamical Systems Hypothesis of Schizophrenia.  PLoS Comput Biol. 2007;  3 2255-2265
• 21 McCarley RW, Wible CG, Frumin M. et al . MRI anatomy of schizophrenia.  Biol Psychiatry. 1999;  45 1099-1119
• 22 Mongillo G, Barak O, Tsodyks M. Synaptic theory of working memory.  Science. 2008;  319 1543-1546
• 23 Negyessy L, Goldman-Rakic PS. Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex.  J Comp Neurol. 2005;  488 464-475
• 24 Rolls ET, Loh M, Deco G. et al . Computational models of schizophrenia and dopamine modulation in the prefrontal cortex.  Nat Rev Neurosci. 2008;  9 696-709
• 25 Ruppin E. NMDA receptor delayed maturation and schizophrenia.  Med Hypotheses. 2000;  54 693-697
• 26 Siekmeier PJ, Hoffman RE. Enhanced semantic priming in schizophrenia: A computer model based on excessive pruning of local connections in association cortex.  Br J Psychiatry. 2002;  180 (4) 345-350
• 27 Sippy T, Cruz-Martin A, Jeromin A. et al . Acute changes in short-term plasticity at synapses with elevated levels of neuronal calcium sensor-1.  Nat Neurosci. 2003;  6 1031-1038
• 28 Sporns O, Chialvo DR, Kaiser M. et al . Organization, development and function of complex brain networks.  Trends Cogn Sci. 2004;  8 418-425
• 29 Sternberg S. High-Speed Scanning in Human Memory.  Science. 1966;  153 (3736) 652-654
• 30 Vijayraghavan S, Wang M, Birnbaum SG. et al . Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory.  Nat Neurosci. 2007;  10 376-384

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