Correction of Brain Functions Disorders Induced by Depressions
Influence of Depression, Induced by the Biosocial Factors, on Integrative Activity of the Brain and Search for the Correction Ways in the Disorders Observed
Tech Area / Field
3 Approved without Funding
Ministry of Education and Science of Georgia / Beritashvili Institute of Physiology, Georgia, Tbilisi
- University of Cambridge / Department of Zoology, UK, Cambridge\nMcMaster University, Canada, ON, Hamilton\nGui de Chauliac Hospital, France, Montpellier\nValley Cancer Institute, USA, CA, Los-Angeles\nWebsciences International, USA, CA, Los-Angeles\nUniversity of Debrecen, Hungary, Debrecen\nWaseda University / School of Sport Sciences, Japan, Saitama
Project summaryThe main goal of the Project is comparative investigation of an impact of different types of depression, induced by biosocial factors, on integrative activity of the brain (sleep-wakefulness cycle [SWC], general behavior, learning and consolidation of memory traces), and correction of the disorders observed by means of new non-pharmacological and pharmacological methods for deprivation of different phases of sleep. Considerable part of the Project is dedicated to correction of disorders of the brain integrative activity induced by undesirable side - effects of non-pharmacological and pharmacological antidepressants, with an aid of regulation of the brain metabolism.
Notwithstanding the neurobiological investigations, being in progress currently, of the mechanisms underlying development of the depressive states and approbation of a vast number of novel preparations for their treatment, the problem of search and elaboration of more appropriate pharmacological and especially non-pharmacological methods, having minimal side effects, is still fairly pressing one.
In the last several decades in the Laboratory of Neurobiology of the SWC, Institute of Physiology, Georgian Academy of Sciences it has been performed the animal experiments concerned with analysis and assessment of the adverse side - effects of both pharmacological (antidepressants) and classical non-pharmacological (with brief awakenings, water tank and disk-over-water) methods of the REM sleep deprivation (Akchvlediani et al., 1988; Oniani et al.,1988a; 1988b; 2001a; Nachkebia et al., 2002; 2003). On the basis of detailed neurophysiological, neuroetological and neuropsychological analysis of SWC and following investigation of the interrelations between the waking phase and the REM sleep in both normal SWC and deprivation of the REM sleep, the three new non-pharmacological methods selective deprivation of the REM sleep was developed: 1. Interruption of the REM sleep phase immediately after the onset of its tonic and phasic signs and its further complete substitution for fragments of active wakefulness of the same length as mean duration of REM sleep within SWC (Oniani et al.,1988a; 1988b; 2001b). This method used on depressive patients allows both total and partial deprivation REM sleep within the same night. The second variant implies a complete substitution of the REM sleep phases for fragments of active wakefulness either in the first or in the second half of the nocturnal sleep. As evidenced by the preliminary data, partial deprivation of the REM sleep phases with above method was found to be more effective when applied in the second half of the night because in depressive patients, frequency and intensity of the REM sleep stages are especially elevated in this period of the night. 2. Deprivation of REM sleep by partial substitution of each phase for fragments of active wakefulness, duration of which corresponds to the mean duration of deprived part of the REM sleep phases within SWC (Oniani et al., 2002). This method, like the second variant of the first method, allows sustaining general volume of REM sleep during the night, within more or less optimal range, especially in those patients in which qualitative and quantitative increase of these phases’ intensity is observed. Sustenance of REM sleep within optimal range, probably, has a special importance insofar REM sleep, being one of the major phases of SWC, has its biological function in the regulation of integrative activity of the brain and its total elimination from SWC, which is characteristic of the antidepressants application, is an undesirable event. Moreover, the second method enables acquisition of the self-awaking reaction in the patients, on the basis of conscious awareness of dream (La Berge and Rheingold, 1996), as is the case in the healthy subjects (Oniani et al., 2002). The phenomenon of self-awakening may be used for the aim of automation of given method without technical interference. 3. One of the new methods for complete selective deprivation of the REM sleep phases is partial substitution of the NREM sleep stages, just prior to the REM sleep phase onset, for fragments of active wakefulness lasting an average time of the REM sleep phase in SWC (Oniani et al.,1999; 2000). This method allows executing both total or partial deprivation of the REM sleep phases within the same night. The second variant could be realized by means of partial substitution of the NREM stages for fragments of active wakefulness either in the first half of nocturnal sleep or in the second half as well. Use of this method, along with total deprivation of the REM sleep phases, leads not to decrease of the NREM sleep volume within SWC but to its significant increase, that would be exerted a positive effect on the depressive patients.
During application of the above new non-pharmacological methods for deprivation of REM sleep on animals and healthy subjects (Oniani et al.,1988a; 1988b; Maisuradze et al., 1999; Oniani et al.,1999; Oniani et al., 2000; Oniani et al., 2001c, 2002) no such undesirable changes of the brain functional state, which are induced by the classical methods (Dement, 1960) do occur: 1. Accumulation of unsatisfied need for the REM sleep phase in deprivation period, that leads to enhancement of REM sleep phases onset; 2) Rebound of the REM sleep in the post-deprivation period; 3) Significant changes in the excitability of subcortical and cortical brain structures, etc.
In the Laboratory of Neurobiology of the SWC above-mentioned first and second new non-pharmacological methods for correction of SWC disorders have been approbated on depressive outpatients (Oniani et al., 2004a, 2004b). New non-pharmacological methods for REM sleep deprivation should possess antidepressant properties. In other words, these methods represent non-pharmacological antidepressants because they promote increased concentration of the monoamines to the optimal level characteristic of normal functioning of the brain as compared to decreased level characteristic of depressive state.
On the grounds of preliminary investigation, a suggestion has been made that a leading role in the development of depression may be played a suppressed activity of the waking system. Consequently, in the Project special attention should be drawn at the study of influence of regulations of the arousal system functional state by means of the neuropeptides of hypocretin/orexins group on the level of depressive state and SWC structure. Besides by the creation of the conditions for daytime optimal working (physical and mental) activity, it is feasible to improve quality of nocturnal sleep and, respectively, following general state and mood of the patients during daytime.
The other nonetheless important aspect of this Project is correction of those undesirable side - effects, which are characteristic of the majority of pharmacological antidepressants (for instance, total lack of REM sleep phases in the SWC). Optimization of volume and intensity of the REM sleep in the depressive patients, treated by medicines, probably could be achieved by application of threshold doses of the antidepressants and through regulation of the brain metabolism.
Considering the above-said, a Project has been prepared, which belongs to a category of basic and applied investigations. A certain part of experiments (2 tasks) in the Project implies execution of experiments in animals, which will permit creating perspective ways for further implementation of investigation results in clinical conditions. The main part (5 tasks) of the Project is dedicated to correction of deteriorated activity of the brain in depressive patients.
The Project will be carried out by personnel of the Department of Neurobiology of SWC at I.S. Beritashvili Institute of Physiology, Georgian Academy of Sciences, with participating of the clinicians and psychologists of respective qualification. Participation in carrying out the Project "linked with the tool" of scientists and specialists will give them possibility to reorientate their activity.
The final results of the study may be the following:
1. An objective implementation of three new non-pharmacological methods of REM sleep deprivation in patients with depression of different category and degree, with an aim of correction of SWC structure disorders, improvement of general mood and cognitive processes;
2. Correction of deteriorated SWC structure, improvement of general mood and cognitive processes in the subjects with diagnosed depression, after withdrawal of long-lasting intake of the antidepressants, by means of new non-pharmacological methods deprivation of REM sleep;
3. Correction of side - effects of the antidepressants in SWC on the background of their more or less long-lasting administration, by means of regulation of the brain metabolism in depressive patients;
4. Correction of altered SWC structure, general mood and cognitive processes, by means of application of threshold doses of the antidepressants, which induce only partial elimination of REM sleep from SWC in the subjects with clinically diagnosed depression of certain category;
5. Correction of deteriorated SWC structure, general mood and cognitive processes in depressive subjects, by means of administration of hypocretin/orexin group neuropeptides and by the creation of the conditions for daytime optimal working activity.
Successful fulfillment of the Project will open new vistas in the treatment of the patients with depression and in prevention of these diseases as well. New methods, developed for the correction of the psycho-neurological disorders, should be implemented in special clinics and in outpatients, which are chronically treated with different antidepressants.
The foreign collaborators consented to cooperate in research, exchange information in the course of carrying out the Project; will consider reports; make consultations. Joint discussion of the Project results, meeting at conferences and direct visits can be the form of collaboration.
The following methods of investigation will be used for the realization of the Project: on animals - under anesthesia stereotaxic implantation of electrodes in various structures of brain; polygraphic recording of SWC; tests on active and passive avoidance, open field and forced swim (Porsolt et al, 1977); pharmacological and non-pharmacological deprivation REM sleep; regulation of arousal and brain metabolism levels with the use of some drugs; in human beings - polygraphic recording of SWC; new non-pharmacologic methods for deprivation REM sleep; regulation of arousal and brain metabolism levels with the use of some drugs.
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