Clinical diseases have helped us to understand many complex cellular and biochemical processes. For example, a group of clinical disorders namely "inborn errors of metabolism" has led us to the discovery of the nature of inheritance and subsequently the relationship between the genes and polypeptides. Similarly, clinical disorders of memory may provide us with bits and pieces of information that can help us to understand the mechanism of memory.                                                                                            

Coincidence of the following facts argues for taking a similar type of approach. 1) Cognitive disorders of unknown pathology are being treated successfully by pharmaceutical agents with known mechanism of action. 2) Known mechanism of action of many pharmacological agents cannot explain how they act to relieve the symptoms in different organic and psychiatric disorders. 3) Improvement or worsening of different types of memories during treatment of different organic diseases of known causes has been reported. These conditions provide opportunities to examine semblance hypothesis for feasible explanations. The following are some of the examples.

1. Vadakkan K.I (2009) Delusions, cognitive impairment and the therapeutic effect of dopamine receptor antagonists in schizophrenia - An explanation through the semblance hypothesis of memory. Society for Neuroscience conference, Chicago. Abstract: 644.3/U18

Based on semblance hypothesis, functional LINKs are formed between the postsynaptic membranes of synapses (mainly those belonging to different neurons) during learning. Continued learning result in further addition of functional LINKs causing gradual expansion of LINKed postsynapses. These interconnected functional LINKs are named as “islets” of functionally LINKed postsynapses. During retrieval of memory in the presence of a cue stimulus, the functional LINKs formed during learning help to induce specific postsynaptic events at the synapses that belongs the learned item. This creates synaptic hallucination of sensory input from the learned item resulting in virtual sensation of a sensory stimulus, named as synaptic semblance. Provided sufficient summation of excitatory postsynaptic potentials (EPSPs) occurs, the postsynaptic events at the synapses representing the learned item can also induce action potentials in their neurons leading to the activation of a network representing the learned item. This induces network semblance, the major contributor of memory. Maintaining the islets of functionally LINKed postsynapses intact is crucial for maintaining the integrity of associatively learned items, since the specificity of the semblance resulting from a cue depends on the previously formed functional LINKs.

Cognitive impairment:

Any misconnection between the islets of functionally LINKed postsynapses reduces the formation of specific semblances (by producing unwanted semblances through the misconnections with the unrelated islets of LINKed postsynapses) that are required for specific memory retrieval. This causes difficulties in achieving specific semblances for memory and results in cognitive impairment.

Delusions and hallucinations:

For the same reason as above, any misconnections between the islets (of functionally LINKed postsynapses) can lead to memories that are not associatively learned. Instead, memories of unassociated sensory inputs occur. This can lead to the symptoms of delusions and hallucinations.

Mechanism of action of dopamine receptor antagonists:

It was not yet possible to explain how dopamine receptor antagonists block delusions and hallucinations in schizophrenia. A possible explanation for the effect of dopamine receptor antagonists can be drawn as following. Dopamine implicated in motivation-induced learning¹ is likely to promote the formation of functional LINKs between the postsynapses. Therefore, it can be argued that the dopamine antagonists can prevent delusions by blocking the misconnections between the islets (LINKable by transient functional LINKs). This prevents sensations of unassociated learned items preventing the symptoms of delusions and hallucinations.

Figure 1 Schematic representation of misconnections between the islets of functionally LINKed postsynapses that can lead to delusions/illusions in schizophrenia

Top row shows semblance formation from the islets of functionally LINKed postsynapses in the normal brain. Left panel: Postsynaptic membranes are shown in small circles (broken arrow). Functionally LINKed postsynapses form islets of functionally LINKed postsynapses (solid arrow). Right panel: Left side: Semblance formed from islet I₁ when depolarized by a cue stimulus, during memory retrieval. Right side: The possible semblance formation from the islet I₂ provided it is activated. Normally when a cue stimulus activates islet I₁ alone, semblance formation takes place only from the islet I₁ and not from the islet I₂.

The bottom row shows the consequence of misconnection between the two islets of LINKed postsynapses in schizophrenia. Left panel: When a cue stimulus reaches the islet I₁, the depolarization spreads to the postsynapses in islet I₂ through the misconnection between the two islets of LINKed postsynapses. Right panel: This leads to the formation of semblances from both the islets I₁ and I₂ causing mixing of the semblances. This can lead to perception of sensations that were not associatively learned in the past leading to the symptoms of schizophrenia. In addition, specificity of the memories will be lost since non-specific semblances formed will dilute the specific nature of the semblance expected for a specific memory.

2. Bottini, G., Paulesu, E., Sterzi, R., Warburton, E., Wise, R. J., Vallar, G., Frackowiak, R. S. and Frith, C. D. (1995). Modulation of conscious experience by peripheral sensory stimuli. Nature 376, 778-81

         This work has shown that the vestibular system aided conscious tactile perception in an individual who lost the tactile perception due to damage of the tactile sensory pathways at areas before its convergence with the fibers from the vestibular system. Normally, vestibular and tactile systems share projections to the putamen, insula, somatosensory cortex II, premotor cortex and supramarginal gyrus. The study reported that the vestibular system introduced bias in the neural system involved in body representation. The physiological mechanism of this phenomenon is not yet known. Based on semblance hypothesis, many functional LINKs would have formed between the vestibular system and the touch sensation at the locations of convergence of these sensations (in this patient, at orders of neurons after the region of brain damage) during life of the individual. At a later time, vestibular sensations alone induced semblances at the LINKed postsynapses for the touch sensation.

Three major evidences evolve from this study. 1) Semblances occur at the functional LINKs at the region of convergence of different sensations 2) The study was not using any specific cue that were associatively learned to test the subject. Therefore, the sensations of touch perceived by the subject indicate that the functional LINKs are transferable and were being used in computations, by the nervous system, for the net semblance of specific touch perception. This study indicates that semblances at the functional LINKs at the locations of convergence were used for the conscious perception of touch. Thus, semblances at the functional LINKs are directly associated with conscious state and perception, two states derived using semblance 3) Physical presence of the sensory system that conducts sensations of touch is not required for the conscious perception of touch sensation. (It is possible that the sensory fibers that identify the location of tactile sensory inputs were intact in this patient). The vestibular sensory inputs reach the locations of convergence at higher order of neurons beyond the locations of brain damage. The ability to explain these findings in terms of the basic units of the hypothesis provides support for the hypothesis.

References:

1. Wang M, Vijayraghavan S, Goldman-Rakic PS (2004) Selective D2 receptor actions on the functional circuitry of working memory. Science 303: 853-6