Where and how could intentional programs be generated in the brain? A hypothetical model based on glial-neuronal interactions.

Based on glial-neuronal interaction a formalism (negative language) for the generation of intentional programs is proposed. An intentional program generates a specific multirelational structure in an inner or outer appropriate environment according to the principle of feasibility. After description of the glial spatio-temporal boundary-setting function in its interaction with the neuronal system, it is hypothesized that intentional programs may be generated in glial networks (syncytia) in line with the formalism of negative language. Gap junctions are interpreted as multirelational negation operators, generating cycles in a permutation system. These cycles could represent intentional programs that can either be realized or not in neuronal networks embodying a permutation system. The feasibility of these intentional programs is essentially dependent on appropriate environmental information. Since the realization of intentional programs in neuronal networks allows high degrees of freedom, the problem of free will is tackled, as well. Free will is defined as the subjective freedom to choose between the inner determination of intentional programs and the overdetermination of their feasibility in an appropriate environment. Finally, the possible implementation of the proposed brain model in robot brains is briefly discussed.

No association of clock gene T3111C polymorphism and affective disorders.

CLOCK was hypothesised to be related to susceptibility of affective disorders. To test subsamples of affectively disordered patients, we examined age of onset (AoO), numbers of episodes and melancholic type of clinical manifestation. Using PCR and RFLP, we investigated in patients with unipolar depression and bipolar disorder (BP) whether the CLOCK T3111C SNP is associated with affective disorders (n=102) compared to healthy controls (n=103). No differences were found either in genotype or allele frequency distributions of T3111C polymorphism between patients compared to healthy controls (p>0.2). No deviations from Hardy-Weinberg Equilibrium (HWE) were detected either in patients, or healthy controls. Results suggest that there is no association between the T3111C SNP and affective disorders in general. Data of our sample replicate prior findings of Desan et al. [Am. J. Med. Genet. 12 (2000) 418]. Subsamples of patients with high numbers of affective episodes did show some deviations in genotypes (p=0.0585).

Gene silencing: a possible molecular mechanism in remission of affective disorder.

Based upon a case report, the hypothesis is proposed that a virus infection could be responsible for remission of affective disease by causing gene silencing. A farmer of 59 had been suffering from a therapy resistant depressive episode over many months. His depressive illness seemed primarily biogenetically determined. Because of acute suicidality clinical treatment and observation became necessary. After six weeks of unsuccessful psychiatric treatment the patient caught a severe virus infection causing pneumonia and myocarditis. The physical treatment showed up to be difficult, but finally managed to cope with the virus infection. Remarkably, parallel to the decrease of physical symptoms also the mood was markedly elevated towards a full remission. At that time the patient was no longer under antidepressant medication. Many viruses have a genetic blueprint made from RNA, rather than DNA. When they infect a cell, double-stranded copies (double-stranded RNA, dsRNA) of their genetic material are produced. In response, the RNA interference (RNAi) pathway of the infected cell is activated. The enzyme Dicer first chops viral dsRNA into small segments of 21-25 basepairs in length, termed short interfering RNAs (siRNAs) and these siRNAs are used to identify intact viral RNA and to mark it for destruction. When an endogenous gene is activated, its sequence is read to produce messenger RNA (mRNA), which contains the information necessary to produce a particular protein, and improper expression of an endogenous gene could cause affective disorder in a patient. Therefore one would expect that if such a patient were infected by a virus that contained a sequence similar to the improperly expressed endogenous gene, the patient's anti-viral response would inadvertently reduce expression of the gene causing affective disorder. If mutations in genes responsible for affective disorders are identified and they turn out to cause over-expression of a particular gene, gene silencing could be an alternative therapeutic tool, especially for therapy-resistant severe depression. The therapy could involve introducing dsRNA either as synthetic RNA, or by infecting the patient with a recombinant virus containing sequence from the gene whose expression must be reduced.

The loss of self-boundaries: towards a neuromolecular theory of schizophrenia.

I start out with the hypothesis that the basic symptoms of schizophrenia are caused by a loss of self-boundaries. Phenomenologically, schizophrenic symptoms are based on the inability of the brain to delimit conceptual boundaries. At the cellular level in the brain, I have in previous work attributed a spatio-temporal boundary setting function to the glial cells such that glial cells determine the grouping of neurons into functional units. Mutations in genes that result in non-splicing of introns can produce aberrant versions of neurotransmitter receptors that lack protein domains encoded by entire exons and can also have protein sequence encoded by introns that have not been properly spliced out. I propose that such "chimeric" receptors are generated in glial cells and that they cannot interact properly with their cognate neurotransmitters. The glia will then lose their inhibitory function with respect to the information processing within neuronal networks. The loss of glial boundary-setting may result in a 'borderless' generalization of information processing such that the structuring of the brain in functional domains is almost completely lost. This loss of glial boundary setting could be an explanation of the loss of self-boundaries in schizophrenia.

The loss of ego boundaries in schizophrenia: a neuromolecular hypothesis.

Virtually all genes of higher organisms have non-coding introns interspersed between the coding exons that must be spliced out in order to generate a mature messenger RNA molecule used to encode proteins. The hypothesis proposed in this paper is based on a new interpretation of molecular splicing as a primordial rejection mechanism that has evolved through time to serve as a molecular basis for other types of rejection, including rejection of thoughts and impulses in the human brain that are incompatible with environmental conditions. Psychiatrists generally explain delusions or hallucinations of schizophrenic patients in terms of 'loss of ego boundaries' or 'inner/outer confusion'. This new model proposes that the loss of the rejection function on the molecular level (non-splicing) in turn causes a loss of the boundary-setting function of glia in their interactions with the neural system. When introns are not spliced out from genes involved in neurotransmission, a variety of outcomes are possible. In some cases the production of neurotransmitters is decreased, in other cases the transmitter receptor has intron encoded sequence elements and/or premature stop codons that do not allow for proper transmitter occupancy. Because these 'chimeric' glial receptors cannot be occupied appropriately by their transmitters, the inactivating or boundary-setting function of synaptic transmission by glial cells is disturbed or lost. The inability to reject 'intronic ideas' may result in delusions and hallucinations, and could explain why schizophrenic patients are unable to test the reality of their ideas and are absolutely convinced that everything occurring in their brain is real. Finally, the concept of 'intronic ideas' from which schizophrenic patients are suffering is interpreted from an evolutionary point of view. It is proposed that many of the thoughts of schizophrenics have occurred too early in evolution and therefore cannot be realized, but in the future some of these thoughts will fit with reality as the environment changes and will no longer be considered delusions.

Clock genes, feedback loops and their possible role in the etiology of bipolar disorders: an integrative model.

Clock genes, which are found in all higher organisms including humans, play a central role in the generation and control of circadian rhythms. For example, the amount of protein encoded by the per gene in mice oscillates with a circadian frequency. The per gene is activated by a constitutively expressed heterodimeric protein encoded by the bmal1 and clock genes, and this activation is suppressed by the PER protein itself. The negative feedback of the PER protein on the expression of the per gene provides a framework for a basic circadian autoregulatory loop in mammals. These elements of biomolecular feedback loops are interpreted within a system theory as an elementary behavioral cycle consisting of intentional programs (the per gene), environmental objects (the BMAL1-CLOCK heterodimer) and the experiential realization of the intended programs (the level of PER protein). This single model enables the deduction of disturbances, which can be transferred to the criteria of bipolar disorders. It is hypothesized that mutations in clock genes lead to disturbances in molecular feedback loops, which on a behavioral level could appear as bipolar disorders. Finally, some implications for research and treatment of bipolar disorders are discussed.

An interdisciplinary approach towards a theory of consciousness.

Instead of attacking the difficult problem of consciousness or self-consciousness directly, the theory is based on the more basic concept of reflection. A concept of reflection is suggested on four levels (recursion, reflective thinking, self-reflection, intersubjective reflection). We propose the glial-neuronal interaction as a neurobiological substrate for reflection processes. It is assumed that glia have a boundary-setting function (scaffolding, compartmentalization) in the spatio-temporal interaction with the neurons. This function could be a possible mechanism of 'dividing' the brain into different self-systems each with their own capacity of self-organization. Although the brain's different self-systems are normally integrated, they may disintegrate and show themselves in special states of the brain (e.g. multiple personality disorder). A tree of reflection consisting of a number of places (ontological loci) on which reflection processes of varying complexity take place, is suggested as the formal model. Finally, the problem of self-conscious qualitative experience (Qualia) is discussed in terms of the reflection model.

[Suicide after craniocerebral trauma]. / Selbstmord nach Schädelhirntrauma.

In the legal judgment of suicidal cases following brain trauma the emphasis is put on the causality between trauma and suicide on the one hand, and on the question of free determination of intent, on the other hand. These problems are investigated empirically in the present study and an explanatory model based on act theory is proposed. At first, an annual sample of suicides in the region of Salzburg is put through a multidimensional diagnosis (suicidal axis syndrome-Mitterauer 1981). The suicidal axis syndrome consists of the following three components: 1. Suicide attempts in the history 2. Diagnosis of exogenous or (and) endogenous brain dysfunction 3. Suicide-positive history. Of a total of 130 exactly interpretable suicide cases there were 16 cases with a brain trauma followed by an organic brain syndrome in the history. Of these, 11 had announced their suicidal attempts previously and 4 presented with a suicide-positive family history. Although the assessment of suicide in the family history is difficult due to insufficient information, the suicidal axis syndrome was definitely confirmed in 4 suicide cases. We attempt to show that at least in those cases with a suicidal axis syndrome, the free determination of intent is to be negated at the moment of suicide, and that due to the existing chronic brain syndrome a causality between trauma and suicide seems to be given in a neuropsychiatric sense.

[Dimensions of depressive behavior]. / Dimensionen depressiven Verhaltens.

This study investigates the significance of a schedule of modes of behavior by comparing depressive and non-depressive persons. Using factor analytical methods it can be shown that behavioral modes of depressives form a heterogeneous group. Furthermore, it seems that two diametrically opposed mechanisms underlie depressive behavior: increase or decrease of behavioral mode frequency.

A contribution to the discussion of the role of the genetic factor in suicide, based on five studies in an epidemiologically defined area (Province of Salzburg, Austria).

The question of what role genetic factors have in the transmission of suicidal behavior, in particular suicide itself, is discussed on the basis of five studies of an epidemiologically clearly defined region (the Province of Salzburg, Austria). The high percentage of suicide-positive family histories as compared with the literature is due to exceptionally good sources of information. It could be shown that in suicide cases also suffering from endogenous depression, both endogenous psychoses and suicides appeared to a greater extent in their families. However, in contrast to current assumptions, the suicide disposition is not just found in those with endogenous psychoses, but shows a separate genetic determination. The author concludes that the genetic factor in suicide research and in the evaluation of suicidality should be considered equally along with psychodynamic and sociodynamic factors.

[Is the suicidal person in the act of suicide in control? Forensic insurance considerations of a new explanatory medical model]. / Ist der Selbstmörder im Akt der Selbsttötung steuerungsfähig? Versicherungsrechtliche Uberlegungen zu einem neuen medizinischen Erklärungsmodell.

On the basis of extensive psychiatric research into suicide in the Province of Salzburg five stages of suicidal development are initially described: 1) consideration; 2) ambivalence; 3) decision; 4) intention; 5) completion of the action. Whereas in the first three stages both the ability to see reason and to control himself can be unaffected, in the act of self-destruction (stage 4 and 5) the suicide is in principle unable to control himself, whereby the ability to see reason may largely be maintained. This new medical model to explain suicide is discussed with regard to the law of insurance. An attempt is made to provide medical and legal aid for assessors and users of the law.

[The suicidal approach-/rejection syndrome. The assessment of suicidal risk based on communication pathology]. / Das suizidale Zuwendungs-/Abwendungssyndrom. Die Beurteilung der Suizidalität auf kommunikationspathologischer Grundlage.

In the case of attempted suicide, the patient unconsciously and/or consciously manipulates people in his surroundings in communication-intending behaviour, whereas in the case of committed suicide, the patient shows communication-rejecting behaviour. This phenomenological description of suicidal behaviour is explained in a theory of communication in such a way that communication-intending behaviour is shown by the communication-style of aggression, and communication-rejecting behaviour is characterized by the communication-style of rejection. Finally an attempt is made to describe syndromically communication-intending behaviour, characteristic of attempted suicide, or communication-rejecting behaviour, typical for committed suicide, taking into account all essential psycho-biological components. This new instrument for estimating suicidality is used in a representative sample for Salzburg of 185 attempted suicides. It is thereby shown that a syndrome of purely communication-intending behaviour or a typical communication-rejection syndrome only occurs among a small percentage. In the majority of probands both psychodynamic and biological factors are responsible for the attempted suicide.

Comparisons of psychopathological phenomena of 422 manic-depressive patients with suicide-positive and suicide-negative family history.

Psychopathological symptoms of 342 manic-depressive patients with a family history (FH) of manic-depressive illness (MDI) and suicide (FH-S-positive group) were compared with 80 manic-depressive patients with a family history of MDI but without suicide (FH-S-negative group). Frequencies of suicide tendencies, attempted suicides, rage, angry mania and delusions were evaluated. In contrast to the FH-S-positive group where suicide tendencies and attempted suicides were more frequent, the FH-S-negative group revealed a higher frequency of delusions. There was no difference between the groups concerning rage and angry mania. Comparisons regarding suicide tendencies, attempted suicides, rage, angry mania and diagnostics referring to depressive, manic, subdepressive and hypomanic phases showed no difference between the sexes.

[Role of genetic factors in suicide. Discussion based on 4 studies in an epidemiologically closed area (Salzburg Federal District, Austria)]. / Zur Rolle genetischer Faktoren beim Selbstmord. Diskutiert anhand von vier Untersuchungen in einem epidemiologisch geschlossenen Gebiet (Bundesland Salzburg, Osterreich).

The question of what role genetic factors have in the transmission of suicidal behaviour, in particular suicide itself, is discussed on the basis of four studies of an epidemiologically clearly defined region (the Bundesland Salzburg). The high percentage of suicide positive family histories as compared to the literature are due to exceptionally good sources of information. It could be shown that in suicide cases which were also suffering from endogenous depression, both endogenous psychoses and suicides appeared to a greater extent in their families. In contrast to current assumptions, however, the suicide disposition is not just found in those with endogenous psychoses, but shows a separate genetic determination. The author concludes, without wanting to generalize prematurely, that the genetic factor in suicide research and in the evaluation of suicidality equally be respected as are psychodynamic and sociodynamic factors.

[Changes in depressive symptomatology in Austria]. / Les modifications de la symptomatologie dépressive en Autriche.

A study of psychopathological manifestations of depressive in-patients, treated in the Salzburg psychiatric clinic in the last ten years, showed a masked shift of symptoms. The shift is away from guilt-feelings as well as away from religious content to a more general moral one. Also noted was a definite increase in feelings on insufficiency and hypochondric ideas. A comparison with tendencies in the Maghreb areas, in which a shift from the masked-somatic symptoms toward guilt-depression is reported, our results show here in Europe a renewed tendency of a shift from guilt-depression to hypochondric or anxiety-depression.

[Neuro- and social psychiatric aspects of suicide prevention]. / Neuro- und sozialpsychiatrische Aspekte de Selbstmordverhütung.

On the basis of extensive research in the Bundesland Salzburg the problem of assessing suicidality is focused upon. The employment of the Suicide-Axis-Syndrom (1. overt or covert suicidality, 2. diagnosis of one or more axis-syndroms after Berner, 3. suicide-positive family history), which the author proposed 1981, requires neuropsychiatric and diagnostic knowledge. Therefore physicians take a key position in the recognition and treatment of potential suicide patients. The typical suicide candidate turns away from others and seeks no more help immediately before the suicide. Institutions for suicide prevention which have soley a socialpsychiatric-psychodynamic orientation have had no notable influence on the reduction of the suicide rate.

Bipolar mood disorders: an affected sibling study. II. Symptom correlations.

Part II of the affected sibling study raises questions of symptom correlation (incidence of delusions, states of confusion, suicide tendencies and attempts, hallucinatory episodes, hypochondriac attitudes, angry manias, and depressive stupor) in mood disorders. The investigated sample (307 sibling groups, 701 hospitalized patients; selection principle: at least 1 sibling showing a bipolar or manic axial syndrome) directs our attention to the possibility that the multiplicity of specific manic and depressive syndromes derives not only from the genetic complexity of the mood-producing system but mirrors the full range of human behavior. Moods must be conceptualized as interpretative metalanguages with respect to the entire wealth of behavioral object languages.

[Family anamnestic study of 89 suicides following release from inpatient psychiatric treatment]. / Familienanamnestische Untersuchung von 89 Selbstmördern nach Entlassung aus stationärer psychiatrischer Behandlung.

This study was prompted by other large, family-history oriented studies which showed that there is no correlation between frequencies of suicide and psychosis. A multidimensional, neuro-psychiatric diagnosis program was performed on 89 cases of suicide after hospital discharge . (The time-span of the study was between June 1, 1969 and August 31, 1980.) Primarily, however, this study was oriented on family history, particularly concerning suicides and endogenous psychosis. In 69.7% of the cases a suicide-positive family history was established. In 56.2% of the suicide cases (N = 89) the simultaneous appearance of endogenous psychosis and suicide is undoubtedly significant (chi 2 = 22.94; df = 4; p less than 0.01). These findings, unique in the literature, are explained by the extraordinary good source of information in an epidemiologically clearly defined region (Bundesland Salzburg). The scant data material in many typical suicide studies concerning familial history of suicides can be explained by the lack of primary information. It is likely that studies which examine suicides in the total population would also find, by employing suitable methods, a high percentage of suicide-positive family histories. From this it is concluded that the role of genetic factors in suicides is in need of revision.

Bipolar mood disorders: an affected sibling study. I. Genetic background and course of illness.

The study uses the 'affected (and hospitalized) siblings method' to investigate aspects of correlation in the psychopathology of bipolar mood disorders. In part one, age of onset, duration of phases, and course of illness are the points of interest. The sample includes 307 sibling groups (701 hospitalized individuals). The incidence of pure or schizoaffective type mania in at least 1 sibling has been the criterion for selection. The genetic background is also presented and the question is raised whether double tainting is the rule rather than the exception. The hypothesis that schizophrenic syndromes and mood disorders develop from separate genetic pools is supported. Strong evidence against the unipolar/bipolar dichotomy is presented. The investigation brings the breadth of the cyclothymic spectrum and inhomogeneity with respect to the course of bipolar disorders into perspective.