Synaptic Elimination, Neurodevelopment, and the Mechanism of Hallucinated “Voices” in Schizophrenia

Abstract

C omputer models are central to scientific disciplines ranging from meteorology to physical chemistry. Their usefulness lies in simulating complex, interactive systems. A good model does not recreate "reality" in its entirety-if that were the case, the best model would be the real-life system itself. Instead, model construction proceeds by incorporating certain properties of the system in a much simplified form which, when simulated by computer, exhibits characteristic properties or behaviors that have been previously unexplained. For instance, a computer simulation of Jupiter's atmosphere produced a stable "storm" resembling the planet's Red Spot after its rapid spin rate and liquid composition had been accounted for (1). The simulation was useful insofar as essential physical dynamics of this previously unexplained phenomenon were captured.Brain systems composed of large numbers of interactive neural elements have been usefully explored by means of computer modeling (2, 3). In this spirit, we describe a neural network computer simulation of narrative speech perception. Although this simulation represents a vast simplification of actual cortical networks, it produced behaviors that may illuminate both normal brain development and induction of psychosis. OBSERVATIONS USED IN CONSTRUCTING THE MODELKey observations used in constructing the simulation of a speech perception neural network were as follows.1. Cortical development during adolescence is characterized by substantial reductions of synapses. Studying normal postmortem tissue obtained from the middle frontal cortex, Huttenlocher (4) found that synaptic density peaked during childhood, with a subsequent decline of 30%-40% during adolescence to reach adult levels, which remained relatively stable. Since largescale neuronal loss does not occur during this developmental period, synaptic elimination must reflect curtailed connectivity between neurons. Less than 1% of afferents to any cortical area derive from the thalamus, the primary source of noncortical input (5). Large-scale reductions of cortical synapses must therefore reflect reductions in corticocortical connections rather than tha-

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

“…For example, the expression of NCAM PSA is reduced in the hippocampal dentate of schizophrenic patients suggestive of a deficit in memory associated synaptic plasticity mechanisms (Barbeau et al, 1995). Thus, the benefits accruing from such procognitive interventions have the potential to oppose and even reverse aberrant synaptic connectivity patterning that likely underlie the developmental emergence of disorders such as autism, schizophrenia, and Alzheimer's disease (Braak and Braak, 1991;Bobinski et al, 1995;Scheff et al, 1996;Feinberg, 1982;Hoffman and McGlashan, 1997;Mirnics et al, 2001;Volkmar and Pauls, 2003).…”

Associative memory in chronic schizophrenia: a computational model

“…Among the most influential of these have been the simulations of schizophrenic performance on familiar neuropsychological measures, such as the Stroop and CPT as well as an experimental task designed to isolate the effects of sentence context on processing dominant associates (Cohen and Servan-Schreiber, 1992). In a related vein, Hoffman and McGlashan (1997) simulated hallucinated voices using a model of synaptic pruning as represented by eliminating connections that linked network units. The current study added to these investigations by incorporating relatively precise normative behavioral data to quantify both connection weights and network sizes that together were used to represent key dimensions of associative memory.…”

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“…(12) What pathophysiologies other than NMDA-hypofunction can impair the specific class of neuronal interactions that underlie cognitive coordination? Though we have focussed on NMDA-hypofunction, they could also be disrupted in other ways, such as via abnormal pruning (Hoffman & McGlashan 1993;McGlashan & Hoffman 2000), or via impaired consolidation of coordinating connections due to abnormal input during development, for example. (13) Do high-frequency rhythms provide a useful window on processes of dynamic organization and their impairment in schizophrenia?…”

“…Introductory nonmathematical reviews of this work that discuss its relevance to cognition are available (Phillips & Singer 1997a; Tononi et al 1998b). Computational theories provide ways of bridging the gap between psychiatry and neurobiology (e.g., Cohen & ServanSchreiber 1992;Hoffman & McGlashan 1993). An explicit bridge is necessary, because we will never know whether an identified neural pathology is directly responsible for the cognitive impairments with which it is found to be associated unless we know how the mechanism that is impaired gives rise to the cognitive capacities concerned.…”

“…This reduced sensitivity to task-context is most closely associated with disorganized symptoms , that is, with the same sub-group of patients who show reduced sensitivity to stimulus-context. Contextual disambiguation is also impaired in language comprehension (Cohen et al 1999a;Hoffman & McGlashan 1993;Kuperberg et al 1998), and production (Barch & Berenbaum 1997;Patterson et al 1986;Spitzer et al 1994). These deficits have also been explained in terms of a component of WM that stores task relevant contextual information in the PFC (Cohen & ServanSchreiber 1992).…”