Self-Frustration of Expectations in Major Depressive Disorder: The Syncytiopathy Hypothesis of Depression Revisited

This paper is a further elaboration of my model of the pathophysiology of major depressive disorder focusing on imbalances of glial-neuronal interactions in tripartite synapses and the glial network (syncytium). Basically, it is proposed that the connexin proteins building gap junctions in the glial syncytium are underexpressed or dysfunctional in major depression, called syncytiopathy. As a compensatory effect the astrocytic receptors in tripartite synapses are overexpressed. This leads to protracted synaptic information processing because of a relative lack of neurotransmitter substances for the occupancy of astrocytic receptors. Based on a new biophysical formal description of astrocytic receptors as expectation variables it can be shown that the protracted processing of sensory information frustrate the full comprehension of the expected event, since it cannot be grasped in time. Moreover, expectation frustration may stress the glial syncytium aggravating memory impairment. This cyclic process of dysbalanced synaptic information processing is characterized as self-frustration of expectations explanatory for the main cognitive dysfunctions in major depression as slowing down processing speed, deficits in attention and working memory. The main result of the study is that patients with major depression cannot fully acknowledge the existence of an intended event.

“Too Soon on Earth”: A Biophilosophical Model of Schizophrenia. Some Implications for Humanoid Robots

This paper presents a new explanatory model for schizophrenia based upon philosophical, molecular and neurobiological hypotheses as well as on years of experience in observing and treating these patients. To start with, a novel interpretation of the Hegelian concept of mediation is presented. Mediation is defined as the rejection of non-realizable programs, such as thoughts and ideas, at a certain point in time in the evolution of a living system. Whenever a system treats non-realizable programs as if they were realizable, its ability to “test the reality” is lost, and consequently a loss of ego-boundaries may occur. On the molecular level, I will try to show how “non-splicing” of introns during the mRNA splicing process is equivalent to a loss of the rejection function corresponding to mediation. At the cellular level in the brain, mediation can be explained in terms of glial-neuronal interactions. Glia exert a spatio-temporal boundary setting function determining the grouping of neurons into functional units. Mutations in genes that result in non-splicing of introns can produce truncated (“chimeric”) neurotransmitter receptors. I propose that such dysfunctional receptors are generated in glial cells and that they cannot interact properly with their cognate neurotransmitters. The glia will then lose their inhibitory-rejecting function with respect to the information processing within neuronal networks. This loss of glial boundary setting could be an explanation for the loss of ego or body boundaries in schizophrenia. Pertinent examples of case studies are given attempting to deduce the main symptoms of schizophrenia from the proposed hypothesis. Some implications for the design of delusional robots are also discussed. Finally, the evolutionary potency of non-coding introns is philosophically interpreted that schizophrenics may be “too soon on earth”.

Adaptation to Fluctuating Neuronal Signal Traffic for Brain Connectivity

Brain connectivity is commonly studied in terms of causal interaction or statistical dependency between brain regions. In this analysis paper, we draw attention to the constraining effect the dynamics of fiber tract connections may impose on neuronal signal traffic. We propose a model developed by Copelli and Kinouchi (l.c.) for a different purpose to safeguard signal transmission for brain connectivity by ensuring dynamic adaptation of signal reception to a wide frequency range of traffic flow over connecting fiber tracts. Gap junction connectivity would confer to neuronal groups the capacity of acting as collectives for dynamical adaptability to impinging neural traffic thereby forestalling traffic congestion and overload. It is suggested that applying this model to signal reception in brain connectivity would deliver the required functionality as a collective achievement of the interrelations between neurons and gap junctions, the latter regulated by glia.

Self-Structuring of Motile Astrocytic Processes within the Network of a Single Astrocyte

Dynamic structuring and functions of perisynaptic astrocytic processes and of the gap junction network within a single astrocyte are outlined. Motile perisynaptic astrocytic processes are generating microdomains. By contacting and retracting of their endfeet an appropriate receptor pattern is selected that modulates the astrocytic receptor sheath for its activation by neurotransmitter substances, ions, transporters, etc. This synaptic information processing occurs in three distinct time scales of milliseconds to seconds, seconds to minutes, hours or longer. Simultaneously, the interconnecting gap junctions are activated by building a network within the astrocyte. Frequently activated gap junction cycles become embodied in gap junction plaques. The gap junction network formation and gap junction plaques are governed and controlled in the same time scales as synaptic information processing. Biomimetic computer systems may represent an alternative to limitations of brainphysiological research. The model proposed allows the interpretation of affective psychoses and schizophrenia as time disorders basically determined by a shortened, prolonged or lacking time scale of synaptic information processing.

The Astrocyte as a Mediator for Self-Reflexive Agents

A model of synapse-astrocyte interactions is proposed which enables repeated neuron-to-neuron connections from the single synapse to the network level. Specifically, the possibility that astrocytes may be organized in networks and processes of a single astrocyte may enable intracellular signaling loops via gap junctions is suggested as a plausible biophysical correlate for hierarchical signaling organization of cyclic pathways. This process ultimately translates to abstract planning, intention and execution of complex actions. The formalism applied is called proemial counting and it enables the generation of cycles of various length in the astroglial network, interpreted as intended action programs. Furthermore, the implementation of a model of the reticular formation in a robot brain based on glial-neuronal interactions is suggested. Finally, the implementation of robot brains with self-reflexive capabilities is discussed.

Significance of the astrocyte domain organization for qualitative information structuring in the brain

Astrocytes, the dominant glial cell type, modulate synaptic information transmission. Each astrocyte is organized in non-overlapping domains. Here, a formally based model of the possible significance of astrocyte domain organization is proposed. It is hypothesized that each astrocyte contacting n neurons with m synapses via its processes generates dynamic domains of synaptic interactions based on qualitative criteria so that it exerts a structuring of neuronal information processing. The formalism (morpho-grammatics) describes the combinatorics of the various astrocytic receptor types for occupancy with cognate neurotransmitters. Astrocytic processes are able both to contact synapses and retract from them. Rhythmic oscillations of the astrocyte may program the domain organization, where clock genes may play a role in rhythm generation. For the interpretation of a domain organization a player of a string instrument is used as a paradigm. Since astrocytes form networks (syncytia), the interactions between astrocyte domains may be comparable to the improvisations in a jazz ensemble. Given the fact of a high combinational complexity of an astrocyte domain organization, which is formally demonstrable, and an uncomputable complexity of a network of astrocyte domains, the model proposed may not be testable in biological brains, but robotics could be a real alternative.

Astrocyte-Synapse Receptor Coupling in Tripartite Synapses: A Mechanism for Self-Observing Robots

A model of an intentional self-observing system is proposed based on the structure and functions of astrocyte-synapse interactions in tripartite synapses. Astrocyte-synapse interactions are cyclically organized and operate via feedforward and feedback mechanisms, formally described by proemial counting. Synaptic, extrasynaptic and astrocyte receptors are interpreted as places with the same or different quality of information processing described by the combinatorics of tritograms. It is hypothesized that receptors on the astrocytic membrane may embody intentional programs that select corresponding synaptic and extrasynaptic receptors for the formation of receptor-receptor complexes. Basically, the act of self-observation is generated if the actual environmental information is appropriate to the intended observation processed by receptor-receptor complexes. This mechanism is implemented for a robot brain enabling the robot to experience environmental information as “its own”. It is suggested that this mechanism enables the robot to generate matches and mismatches between intended observations and the observations in the environment, based on the cyclic organization of the mechanism. In exploring an unknown environment the robot may stepwise construct an observation space, stored in memory, commanded and controlled by the intentional self-observing system. Finally, the role of self-observation in machine consciousness is shortly discussed.

Computer system for simulation of human perception. Some implications for the pathophysiology of the schizophrenic syndrome

After the description of a brain model based on glial-neuronal interactions, a computer system for simulation of human perception, called clocked perception system, is proposed. The computer system includes a receptor field with sensors, each of which receives data with specific characteristics. These data are passed to processors, whereby only those connections between sensors and processors are released that are suited for an evaluation of the data according to a combination of specific data dictated by a phase program circuit. The computer system also includes a selector circuit that discards those dictated program commands that lead to a “senseless” computation result. A motor program circuit for the control of effectors may be connected to the computer system which at least contributes to the movement of the receptor field in order to bring the receptor field closer to suitable data with specific characteristics for better execution of the program. From disorders of the computer system implications are deduced for the pathophysiology of the schizophrenic syndrome. Finally, a novel treatment approach to this syndrome is proposed.

Disintegration of the Astroglial Domain Organization May Underlie the Loss of Reality Comprehension in Schizophrenia: A Hypothetical Model

A pathophysiological model of the loss of reality comprehension in schizophrenia is proposed. Based on a formalism it is hypothesized that astroglial domains exert an information-categorizing function which becomes progressively lost in the schizophrenic process, caused by functional and structural disintegration of astroglial domains. Unconstrained synaptic neurotransmission functionally disintegrates the astroglial domains. Microdomains located between perisynaptic astroglial processes and the synaptic membrane are interpreted as elementary functional units categorizing synaptic information processing. Unconstrained diffusion of neurotransmitters into the extrasynaptic space leads to the dysfunction of microdomain formation. In parallel, atrophic processes of astroglia progressively break up the connectivity between synaptic and extrasynaptic compartments disrupting astroglial domains. Basically, the organization of astroglia into definite functional and structural units (modules) of astroglial-synaptic information processing may enable the brain to comprehend ontological realms such as subjects and objects in the environment and their distinct qualities. This fundamental capability of cognition is lost in schizophrenia. It is suggested that this ontological confusion of astroglial domain boundaries progressively disorganizes reality comprehension and may represent the basic pathology in schizophrenia underlying the main symptoms of the disorder. Finally, the testing of the model is shortly discussed.

Psychobiological Model of Bipolar Disorder: Based on Imbalances of Glial-Neuronal Information Processing

A psychobiological model of the etiopathology of bipolar disorder is proposed. Based on genetic-epigenetic and chronobiological factors a hyperintentional personality structure, if faced with non-feasible intentional programs in the environment, suffers from inner and outer stress. This stress situation leads to imbalances in information processing in glial-neuronal synaptic units, called tripartite synapses. In depression the overexpression of astrocytic receptors and of gap junctions in the astroglial network causes a prolonged information processing which affects the behavior generating systems in the brainstem reticular formation. Because the activation of the behavior generating systems is protracted, they are unable to select an appropriate mode of behavior (e.g. communicating, eating, working, sleeping, etc.) from sensory information in real time. Inversely, in mania astrocytic receptors and gap junctions are underexpressed causing a shortened synaptic information processing with rapid changes in behavior. Switching may represent a coping-attempt with depression by mania and vice versa. Towards a comprehensive model of the pathophysiology of bipolar disorder the role of microglia and their devastating effects on glial-neuronal interactions are outlined. Finally, the testing of the model is discussed.

Pathophysiology of Schizophrenia Based on Impaired Glial-Neuronal Interactions

The model of impaired glial-neuronal interactions in schizophrenia is based on the core hypothesis that non-functional astrocyte receptors may cause an unconstrained synaptic information flux such that glia lose their modulatory function in tripartite synapses. This may lead to a generalization of information processing in the neuronal networks responsible for delusions and hallucinations on the behavioral level. In this acute paranoid stage of schizophrenia, non-functional astrocytic receptors or their loss decompose the astrocyte domain organization with the effect that a gap between the neuronal and the glial networks arises. If the illness progresses the permanent synaptic neurotransmitter flux may additionally impair the oligodendrocyte-axonic interactions, accompanied by a “creeping” decay of oligodendroglia, axons and glial gap junctions responsible for severe cognitive impairment. Here we may deal with after-effects caused by the basic fault of information processing in tripartite synapses. The gaps between the neuronal and glial networks prohibit the neuronal reality testing of intentional programs presumably generated in the glial networks, called schizophrenic dysintentionality. In non-schizophrenic delusions glia may not be disturbed, but exhausted extrasynaptic information processing may cause an unconstrained synaptic flux responsible for delusions.

Novel Treatment Approach in Schizophrenia: Substitution of Glial Binding Proteins

In chronic schizophrenia, synaptic information processing is unbalanced, as shown in a model of glial-neuronal synaptic units, called tripartite synapses. The glial component of the synapse exerts a modifying function in neurotransmission since the astrocyte activated by neurotransmitters produces gliotransmitters that negatively feedback to the presynapse. It is hypothesized that in schizophrenia nonfunctional astrocytic receptors cannot be activated, thus losing their modulating function. This causes a generalization of information processing in the neuronal networks such that the brain is unable to distinguish between subjects and objects in the environment. Delusions, hallucinations and cognitive impairment occur on the behavioral level. In a model of a cholinergic tripartite synapse, it is shown that glial binding proteins modify neurotransmission by occupancy with cognate neurotransmitters temporarily turning off neurotransmission on the presynapse. Most recently, glial binding proteins have been engineered. It is proposed that the substitution of glial binding proteins may balance synaptic information processing in schizophrenia since these proteins exert a modulatory function comparable to functional astrocytic receptors. Rap- id technical developments may enable this novel treatment approach in schizophrenia.

Insatiable Narcissism Underlying Addictive Behavior: Outline of a Biosystematic Model

This study is a contribution to basic research on narcissism shown on addictive behavior. A new biosystematic model of narcissism underlying addictive behavior is outlined. Basically, normal narcissism is defined as the self-reference of living systems maintaining their circular organization and identity. The communication between narcissistic systems follows the narcissistic logic of fitting or non-fitting of structures (a third possibility is excluded) shown on geometric diagrams. From this model of narcissistic interactions with the environment, addictive behavior is deduced. If the narcissistic desire for the ideal objects cannot be satisfied in the environment, the narcissist attempts to cope with this lack of intended objects by abuse of addictive substances. This leads to an overexpression of receptors in pertinent brain areas that may underly craving on the behavioral level, interpreted as pseudo satisfaction of narcissistic desires—destiny becomes an addiction. In conclusion, the significance of the biosystematic model of narcissism for the understanding of addictive communication and the psychopathology of depression is briefly discussed.