Neuropsychiatry:
Hyperintentional Self-Observation in Major Depressive
Disorder. Combined Biological and Behavioral Treatment
by Bernhard
Mitterauer, MD
Prof. em.
(University of Salzburg)
Volitronics-Institute
for Basic Research
Wals, Austria
John
Pellam John Pellam John Pellam John Pellam John Pellam John Pellam John Pellam
John Pellam John Pellam John Pellam The BWW Society The Bibliotheque World Wide
Society The Institute for Positive Global Solutions Pellam Journal of Science
Journal of Global Issues and Solutions
Abstract
A new combined treatment of
major depressive disorder is proposed. It is based on a hypothetical model of
hyperintentional self-observation generated in tripartite synapses and their
network. Hyperintentional self-observation makes the patient incapable of
realizing his/her intentions in the environment in real time and the modes of
normal behavior (sleeping, eating, working, etc.) are disturbed. This
depressive suffering causes a loss of existential self-understanding,
experienced as depressive mood. The biological treatment with antidepressants which
balance synaptic information processing through reuptake inhibition of
neurotransmitter substances can be improved by action therapeutic strategies.
Although the testing of the underlying pathophysiology of the model is limited,
the elucidation of the impaired self-understanding of hyperintentional
self-observation is possible during the behavioral treatment process.
Introduction
Depression is a worldwide
psycho-bio-social disorder. Generally, the concept of self-observation plays a
central role in all sciences. In the past, we started out with a psychological
theory of self-observation mainly based on biocybernetic models of the observer
[1, 2, 3, 4]. Recently, quantum physics request a brain theory of self-observation
as conditio sine qua non for every natural and interdisciplinary science [5].
Here, I propose a brain theory of self-observation controlled by subjective
intentional programs generated in tripartite synapses and their networks
(syncytia) [6, 7].
In the present paper major
depression is defined as hyperintentional self-observation. Based on the
diagnostic criteria of depression [8], the hypothetical model is outlined.
After the description and interpretation of the etiopathology of hyperintentional
self-observation, the brain-biological treatment is discussed. Moreover, the
combination of current antidepressant drugs with the behavioral treatment
strategy, termed action therapy, may exert significant mood stabilizing
effects.
Despite rapid technical
progress the testing of the pathophysiological model remains limited. However,
one can explore the impaired action pattern of the patient and stepwise give
back the lost self-understanding on the behavioral level.
Diagnostic criteria of hyperintentional
self-observation in major depressive disorder
In addition to the Diagnostic
and Statistical Manual of Mental Disorders (DSM-5) [8], the conception of a
basic depressive disorder can be diagnosed as follows [modified after 9]:
1) Psychobiological hyperintentionality
responsible for non-feasible self-observations.
2) Inability to realize one or
more biological modes of behavior such as sleeping, eating, working, etc., in
the sense of “I cannot do what I could do”.
3) Compulsion to behave in one or
more modes of behavior, “I have to do”.
4) Ability to describe this
disordered behavior by self-observation, but no subjective explanation for it.
5) Loss of self-understanding.
Hypothetical model
Basically, patients with a
major depression suffer from subjective hyperintentionality. This means that
the self-observing brain is able to observe actual events in the environment,
but this information does not activate actions that are intended to be realized.
It is hypothesized that disorders in the astrocytic syncytium may represent a
major component of the pathophysiology of depression, termed syncytiopathy
[10]. If the expression of connexin proteins in the syncytium is downregulated,
a compensatory upregulation of astrocytic receptors may occur, leading to an
overexpression of these receptors. Overexpressed astrocytic receptors could
embody subjective intentions of the self-observing patient. Since the
overexpression of various astrocytic receptor types may fundamentally cause a
depressive mood, these patterns of astrocytic receptors must be balanced into a
physiological level of neuronal-glial interactions.
The increase of
neurotransmitter substances by antidepressants as a primary treatment can
balance the synaptic information processing, but it has no significant effect
on the hyperintentionality, since only the number of astrocytic receptors is
satisfied and not the self-observing patient. Here we deal with a kind of
keeping calm without real effects on the patients’ intentions to actually
experience feasible actions in the environment in the sense of a regained
self-understanding. Therefore, a parallel behavioral treatment is necessary to
stepwise activate the action potential in order for events not only to be
observed, but also generated and experienced by the patient himself. During
this therapeutic process the patient experiences and understands the difference
between realizable and unrealizable intentions or between intention and
destiny.
Hyperintentional self-observation in tripartite synapses and in the syncytium
causing depression
As already discussed,
astrocytes interconnected by gap junctions build an astrocytic syncytium. Gap
junctions are composed of connexin proteins that are activated by substances of
the neuronal system as the primary pathway based on Ca2+ wave
propagation between astrocytes. In the astrocytic syncytium the expression of
connexins and of various receptor types are regulated by a complex transcription
network [11]. If the expression of connexins is downregulated, caused by
genetic, epigenetic, stress factors, etc. [12], a compensatory upregulation of
astrocytic receptors may occur, leading to an overproduction of these
receptors. Such an excess of astrocytic
receptors causes an imbalance of synaptic information transmission, because of
a relative lack of neurotransmitters for the occupancy of astrocytic receptors
and, as a result, neurotransmission is protracted [13]. In addition, the
downregulation of connexins may negatively influence intracellular signalling
within the syncytium, since not enough connexin proteins can be produced for a
complete coupling of all possible interactions between astrocytes. Supposing
that this glial network structure embodies incomplete intentional programs,
receptor overexpression can be interpreted as embodiment of
hyperintentionality. Most importantly, these synaptic locations cannot process
sensory information in real time, since synaptic information processing is
protracted, which may be responsible for a depressed mood with typical symptoms
on the behavioral level [14].
Tripartite synapses and the glial syncytium
A tripartite synapse consists
not only of the presynapse and the postsynapse as neuronal components, but also
of the astrocyte as the glial component. Glial cells are capable of expressing
the same extending variety of receptors as neurons [15]. This synaptic
structure processes information between the neuronal and the glial network
(syncytium): the astrocytic syncytium is composed of gap junctions and gap
junction plaques. Gap junction plaques may function in both memory [16] and
intentional programs [17]. Synaptic information processing occurs within time
scales of milliseconds to seconds, seconds to minutes, minutes to hours or
longer [18, 19]. I hypothesize that intentional programs are embodied in the
glial syncytium and that they select appropriate receptor patterns on the
astrocyte according to repeated neuronal sensory activation. An astrocyte
exerts dynamic structuring and functions via its numerous perisynaptic
processes [20]. 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 [21]. Each astrocyte contacts by
its processes n- synapses generating tripartite synapses. This structure of
glial-neuronal interaction is called astrocytic domain organization [22].
Most importantly, gap
junctions operate between perisynaptic astrocytic processes originating from a
single astrocyte [23] in the sense of reflexive gap junctions [24],
constituting an autonomous network within a single astrocyte. The gap junction
network selects repeated activation of glial receptors by neurotransmitter
occupancy and feeds forward this selected pattern to perisynaptic astrocytic
processes modifying their movement dynamics. Integrated information processing
within the astrocytic body feeds back to perisynaptic astrocytic processes in a
pulsating manner [25, 26]. This model of glial-neuronal interaction in the
tripartite synapse describes an elementary mechanism of self-observation [7].
The quantum mechanical action
cycle theory allows the interpretation of synaptic glial-neuronal interaction
as a model of self-observation. It is possible to describe the information from
the neuronal synapse as description of the observation in the environment (via
perception systems), the information structuring by the motile astrocytic
processes as explanations, and the interactions between the astrocytes via gap
junctions as description of the explanation of the observed in the sense of an intentional
programming within the glial network. Since each domain is organized within a
finite structure, it is possible to characterize their domain organization as
standpoints of self-observation [27].
Biological treatment
With regard to the glial cell
system the effects of antidepressant drugs can be experimentally shown [28,
29]. Basically, antidepressants inhibit the reuptake of neurotransmitter
substances via transporter inhibition. Augmentation of transmitter substances
by antidepressants balance postsynaptic receptor activation, but may not directly
work on astrocytic receptors.
Although the balancing effect of
antidepressants enables processing of sensory information in real time, the
overexpressed receptor pattern on astrocytes may not be balanced in the network
operations. This means that clinical remission of depression is basically
generated by neurotransmitter saturation of the overexpressed astrocytic
receptor pattern within tripartite synapses and is not primarily exerted
through actual sensory information from the environment, but by transmitter
reuptake inhibition.
Concerning the effects of
antidepressants on glia some findings are significant for the model proposed.
Experimental investigations identified a pronounced up- or downregulation of
glial proteins such as NDRG2 [30]. Increased expression of Connexin 43 (a major
component of astrocytic gap junctions) in the prefrontal cortex following
chronic treatment with fluoxetine is reported [31]. In a chronic stress-model
of depression in rats a stress-induced reduction of hippocampal GFAP expression
was reversed by treatment with the tricyclic antidepressant clomipramine [32].
The most consistent finding on astrocytic activation was observed after
electroconvulsive stimulation (ECS) [33].
Moreover, it has been demonstrated
that astrocytes in the intact mouse prefrontal cortex exhibit functional 5-HT
receptors and are targets for antidepressant drugs. These findings provide
evidence that astrocytic function can be directly modulated by SSRIs. However,
the relevance of these astrocytic therapeutic effects of SSRI is unclear [34].
Most relevantly, the discovery
that ketamine (N-methyl-D-asparate glutamate receptor antagonist NMDA) rapidly
increases the number and functions of synaptic connections has focused the
attention on synaptogenesis suggesting that disruption of synaptogenesis and
loss of connections underlies the pathophysiology of depression [35]. Ketamine
can produce rapid und robust antidepressant effects in patients with
treatment-resistant major depressive disorder and bipolar depression [36].
Although current experimental findings and interpretations focus on the
neuronal system, I have hypothesized that in therapy-resistant depression a
significant excess of NMDA receptors on astrocytes is causing a severe lack of
glutamate which cannot be balanced by reuptake inhibitory drugs, and the
blockade of the excess of NMDA receptors in astrocytes may rapidly balance
synaptic information processing. Since ketamine could act on various neuronal
and glial cell types, my hypothesis should also refer to pertinent experimental
findings with supporting arguments [37].
Behavioral treatment
The most common
psychotherapeutic approach in depression is cognitive therapy. The behavioral
treatment proposed here mainly concerns the clinical treatment of patients
suffering from a severe major depression. As already discussed, the biological
treatment with antidepressant drugs leads to a restitution of depressive behavior
but hyperintentionality persists. The behavioral treatment strategy proposed
enables the patient to stepwise observe events in the environment generated in
real time by himself. This is an experience of event-related acting again.
Hence, actions do not occur as self-reflections within the brain, but are
comprehending intentions in the environment: “to grasp what I do”. I speak of
action therapy of depression [9]. What are the action strategies with the aim
to reconstitute a balance between intentions and corresponding actions in the
environment?
Importantly,
these four basic steps of an action therapy of depression must be applied dependent
on the course of mood elevation.
Biological testing of the model
Basically, the
counting of the number of receptors on astrocytes should be possible. For
instance, optogenetic techniques enable an increasingly exact method to show
cells in the brain in vivo. Hence, optogenetic techniques could compare normal
astrocytic receptor expression or activation with overexpressed astrocytic
receptor patterns. Fully aware of the fact that actual intentions and mood
states cannot be elucidated in animal experiments, testing of human
hyperintentionality in the brain is principally limited. The biological
argument for this principal impossibility is the fact that the many
perisynaptic astrocytic processes of a single astrocyte contact about 2.000.000
synapses and the network between astrocytes comprises a superastronomic amount
of synapses [22].
However, the
investigation of the expression of connexins in tissue of post-mortem brains
with depression may be possible [38]. If downregulation of astrocytic connexins
can be identified, the astrocytic syncytium is incomplete leading to impaired
intentional programming. Moreover, the brain region investigated is important.
Antidepressants lead to functional inactivation of connexin 43 in the
hippocampus and exert an increased activity of the cortex [39]. It is
hypothesized that connexin 43 gap junctions and connexin channels exert
different effects on stress and antidepressant drug response [39]. What the
genetic mechanisms responsible for a downregulation of astrocytic connexin
concerns, one should be cautious to look for specific “depression genes” [11].
Importantly, the variability in the human genome has far too exceeding
expectations. New approaches are necessary to understand the contribution of
structural variants to depressive disease [40]. Most interesting is the
experimental indication that ketamine blocks NMDA receptors causing a rapid
antidepressant effect. If this effect also works on astrocytic NMDA receptors,
this balancing of synaptic information processing may exert a normalization of
connexin expression in the astrocytic syncytium. It should be mentioned that at
specific brain locations both glial gap junctions and tripartite synapses can
be overexpressed, e.g. in the hippocampus, where emotions are generated.
Together,
exciting technical progress [41] can enable experimental findings in tripartite synapses and their network leading to a better biological
explanation and testing of the model of depression proposed. However,
limitations of experimental research require an improvement of our
understanding of patients suffering from depression on the behavioral level and
by treatment experiences [42].
Prospects
The psyche of a
patient suffering from depression is existentially determined by nonfeasible
hyperintentional programs in the sense of an unfulfilled destiny of a permanent
existence of his/her great individuality. Since the patient feels the loss of
permanent existence and is incapable of acting in real time, the combined
biological and behavioral therapy proposed can cope with major depressive
disorder. The rationale is based on an improvement of depression with
antidepressants and action therapy. The latter enables a stepwise normalization
of the subjective hyperintentionality that is caused by persistent mental
self-observation, but without the experience of acting according to actual
events in the environment.
Although we
have developed an appropriate questionnaire for the diagnosis of depression
that works out well, its validation on a representative sample is still
necessary. Admittedly, the therapeutic method outlined mainly concerns the
clinical treatment of severe major depression, but it exerts significant mood
stabilizing effects in general practice as well. Basically, such a combined
treatment can explain the subjective reality in which the suffering from
depression is generated. Empathic communication is paving the way towards regaining
an intended existence in the environment.
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Acknowledgement
I am very grateful to Birgitta
Kofler-Westergren for preparing the final version of the paper.
© 2016 The Bibliotheque: World Wide Society