T.N. Majkova, S.N. Lukashev, M.A. Piradov, M.V. Danilova
Headache Clinic, Dnepropetrovsk; National University of Dnepropetrovsk; Institute of Neurology Russian Acad. Med. Sci., Moscow; Dnepropetrovsk Clinical Hospital
Central synaptic neurotransmission: universal self-regulation theory
Objective assessment of physiological and pathological mechanisms of the development of various abnormalities in CNS is the basis for diagnostics and efficient correction of various cerebral diseases. Unfortunately, modern diagnostic methods do not meet these requirements, so the progress in understanding pathogenesis of these diseases and elaboration of therapeutic prescriptions often result from empirical findings .
Three basic features of central synaptic transmission may help to widen the theoretical basis in the treatment of cerebral diseases: first, the strength of post-synaptic response depends on the amount of a transmitter released in the synaptic cleft (the concept of gradual generation of postsynaptic membrane response ; second, postsynaptic inhibition an d excitation depend on the type of postsynaptic receptors but do not depend on the type of the transmitter [1, 3]; and third, there are two forms of synaptic transmission — fast and slow .
Our aim was to reveal the peculiarities of central neurotransmission in clinical practice on the basis of EEG recording, which is the most adequate modern method binding the available theoretical and experimental data with clinical practice . It is known that EEG reflects the total bioelectrical activity of the brain resulting from the transmitter-induced depolarization and hyperpolarization of postsynaptic membranes of all active synapses. However, the nature of various bioelectrical rhythms in EEG is still not disclosed. We believe that the tools, which relate the bioelectrical phenomena to their synaptic origin, are the drugs exerting the specific effects on CNS. Comparison of neurochemical alterations produced by drugs with the corresponding amplitude and frequency changes in EEG may explain the neurotransmitter-receptor relations.
Our experience based on observations of more than 5000 patients with various CNS disorders, in whom EEG were recorded during monotherapeutic treatment with all known groups of central neurotropic drugs made it possible to advance some questions. The answers to them lead to universal concept, which helps to understand the mechanisms of brain function. Specifically, this approach may explain how one drug may produce the opposite clinical effects or transform the positive effects into the negative ones in the patients with the same form of the disease; why the drugs with different action mechanisms produce similar changes in EEG; or why treatment of the same nosological forms can be performed with the drugs affecting different sites of the brain. We carried out a prospective study, which revealed the interrelations between the pharmacologic effects and encephalographic data for the major groups of neurotropic preparations with established mechanisms of action. Analysis of the obtained data explained the nature of EEG rhythms and made it possible to use this method to reveal the major trends in the changes of central synaptic neurotransmission in the total neural activity of the brain.
Purpose of the study. Objective assessment of functional status of human brain by reasonable experimental approach. Theoretical basis of universal self-regulation of central synaptic neurotransmission.
Groups. Inclusion criteria: after informed consent, the patients of both sex aging 18 to 55 years were enrolled in the study. During 1 to 8 years, they suffered from chronic tension-type headache (CTTH)  and were not treated with central neurotropic drugs for the last 3 months prior to the study. CTTH was diagnosed according to International Classification of Headache . Exclusion criteria: the study did not enroll the patients with arterial hypertension or structural cerebral lesions, pregnant or nursing women, and the patients with depressive disorders. Therapeutic efficiency criteria: incidence of headache (during one month before the study and during the first and second treatment months), EEG parameters, and quality of life index .
Methods. EEG mapping was performed with 17-channel computerized DX-4000 EEG-system (Ukraine). EEG was recorded with the scalp electrodes positioned according to Young's modification of the international 10-20 EEG system. EEG was recorded in relaxed wakeful state during the first half of the day according to the following protocol: probe 1, baseline; probe 2, eye opening; probes 3-5, hyperventilation for 3 minutes; probe 6, low-frequency background photostimulation; and probe 7, high-frequency background photostimulation. The power and incidence of basic rhythms were analyzed together with paroxysmal activity and synchronization events.
Quality of life index . The patients of experimental group (n=91) were treated with central neurotropic drugs in combination with peripheral beta-blocker atenolol (12,5-50 mg/day). The control group patients (n=90) received atenolol alone. The neurotropic drugs were amitriptyline — 0,0125-0,05 g/day, mirtazapine — 0,0075-0,030 g/day, selegiline — 0,01 g/day, levodopa preparations — 0,25-0,5 g/day, clozapine - 0,0125 g/day, chlorpromazine - 0,025-0,05 g/day, thioridazine — 0,025-0,05 g/day, sulpiride — 0,2-0,4 g/day, metoclopramide — 0,01-0,03 g/day, carbamazepine — 0,4-0,6 g/day, sodium valproate — 0,5-1 g/day, and lamotrigine, up to 0,1 g/day. Taking into consideration our experience and literature data , we divided the drugs into two groups according to their effects on EEG. The first group consisted of "synchronizing" drugs, which elevated the power of alpha-rhythm: antipsychotics, antidepressants, and MAO-B inhibitors. The second group of "desynchronizing" drugs comprised the anticonvulsants, which decreased the power of alpha-rhythm. The treatment was administered depending on EEG parameters. The patients with low-power alpha rhythm (less than 30 uV2/Hz), desynchronized basic rhythm, or prevalence of the slow rhythms (n=44) were given the drugs, which increased the power of alpha-rhythm. The patients with middje- or high-power alpha-rhythm (30-100 uVyHz, n=47) were treated with anticonvulsants, which decreased the power of major rhythms and desynchronized EEG. Inclusion of the patients in certain groups according to EEG parameters resulted from specific individual and efficient treatment of them, because the examined persons were not volunteers, but needed medical help. The examination data and the treatment efficiency were analyzed with parametric statistics (MS-EXCEL-2000 for Windows).
Results. Significant neurophysiologic and clinical changes were revealed in the "synchronized" group: they increased the power and incidence of alpha-rhythm as well as the number of synchronized fragments in EEG. The therapeutic effects of the administered drugs were manifested by significant rise of the quality of life accompanied by almost complete relief of headache in all the patients.
In the "desynchronized" group, the significant drop of alpha- and theta-rhythms was observed together with a decrease in the incidence of synchronized fragments and paroxysmal activity in EEG. After treatment, the patients felt better, which was attested by significant rise in the quality of life index and by decrease in the incidence of headache.
The treatment did not change the neurophysiologic parameters in the control group of patients, which did not receive the central neurotropic drugs. The treatment efficiency assessed by the number of headache days and the quality of life index did not differ from the initial data. The results of our study are given in table.
Comments. The study revealed the certain regular changes in EEG caused by the selected groups of drugs. Evidently, the antidepressants, antipsychotics, MAO inhibitors, and levodopa drugs elevate the power and incidence of alpha-rhythm. In addition, they enhance synchronization and the incidence of paroxysmal episodes in EEG. Although these drugs exert different effects on synaptic transmission, they produce the same result — an increase of transmitter content in the synaptic cleft. This increase results from blockade of presynaptic uptake by antidepressants  or postsynaptic binding by antipsychotics. The same aim is also achieved by MAO inhibitors, which decelerate degradation of the transmitters in synapses or by the levodopa drugs, which promote dopamine neurotransmission .
Thus, elevation of power and incidence of alpha-rhythm in EEG as well as its synchronization are the neurophysiologic phenomena reflecting an increase of neurotransmitter content in the synaptic cleft. Probably, this content determines alpha-rhythm. This hypothesis is corroborated by a drop in alpha-rhythm power and by desynchronization of EEG during the treatment with anticonvulsants, which block the release of neurotransmitter.
The disclosed relations between EEG indices and administered drugs were identical for various nosological forms of CNS diseases. They reflect triggering pathological mechanisms, which cause specific effectors systems.
Our data agree with gradual excitation of postsynaptic membrane in dependence on the amount of transmitter . According to these data, the degree of presynaptic depolarization and the corresponding amount of released transmitter determine the number of depolarized sites in the postsynaptic membrane, where the shifts of membrane potential partially overlapped in time and space. This postsynaptic reaction develops in parallel with presynaptic depolarization .
Analysis of the revealed dependence of alpha-rhythm on transmitter content in the synaptic cleft shows that the power of this rhythm reflects the duration C)f depolarizing shifts in the local sites Of the postsynaptic membrane and the density of these depolarized sites. The power of alpha-rhythm is determined i>y the sum of simultaneously triggered receptor reactions. The range of postsynaptic responses varies from low-amplitude high-frequency reactions observed during transmitter deficiency to the high-amplitude low-frequency reactions reflecting the massive release of the transmitter. This fact explains shortening of the refractory period in the excitable sites of postsynaptic membrane during local reaction in the first case, and widening of this period under the conditions of maximal involvement of the receptors in generation of the postsynaptic response. From phenom-enological viewpoint, deficient or excessive neurotransmission is reflected by desynchronized low-amplitude or synchronized high-amplitude patterns of the total neural activity, correspondingly. Taking into consideration a short duration of neurotransmission (0,5 msec), we suggest that presynaptic depolarization and postsynaptic response are reflected in EEG as a common event, while the total synchronized or desynchronized postsynaptic responses reflect the amount of acting neurotransmitter. Probably, not only the amount of neurotransmitter, but also the frequency pattern of presynaptic firing plays an important physiological role, although it is impossible to assess the individual contribution of these factors into EEG. The useful models demonstrating the discussed neurochemical modulation of EEG are potentiation the firing of noradrenergic neurons by blocking the autoreceptors with tricyclic antidepres-sants  and synchronization of EEG in patients treated with these drugs.
Our experience based on EEG recording in 5000 patients over 10 years showed that the reported regularities of neurotransmission revealed in EEG are individual and rather persistent. While treating the vegetative or emotional dysfunctions with neurotropic preparations, we were guided by the clinical criteria of efficiency. To this end, EEG was employed to assess the state of central transmission and to control the neurotropic effects of pharmacological preparations. The positive clinical effects correlated with alpha-rhythm prevalence, minimal incidence of focal or slow diffuse rhythms, and the episodes of paroxysmal activity. The physiological range of power spectrum parameters of alpha-rhythm is rather broad. It reflects the constitutive peculiarities in the functional and anatomical organization of the brain. It should be noted that under physiological conditions of neurotransmission, elevation of alpha-rhythm power is accompanied by the development of inhibitory clinical reactions (decrease of the headache in our study) and by neurophysiologic manifestations such as potentiation of parasympathetic influences on the heart . In this case, transmitter overload in the effector neurons is probably compensated by modulation of excitation and refractoriness by inhibitory amino acids (IAA) such as GAB A or glycine.
During the development of pathological processes in CNS caused by the disturbances in neurotransmission, two types of decompensation are possible. First, some pathogenic factor or medication promotes the development of persistent hy-permediatory presynaptic and postsynaptic depolarization or hyperpolarization. The type of membrane polarization depends on the character of the receptor response. This process is characterized by the involvement of maximum receptor surface and hypersynchronization of EEG, which under the deficiency of compensatory influences IAA is transformed into paroxysmal activity accompanied by pathological clinical manifestations . Thus, in the case of hypermediatory overexcitation of the brain, IAA play the role of the protective modulating factors, whose deficiency promotes the development of various pathologic dysfunctions of CNS.
Second, the opposite situation can take place, when disturbances in neurotransmission results from transmitter deficiency caused by therapeutic or pathologic hyperpolarization of the presynaptic neurons. In this case, to restore transmission in the poorly excitable effector neurons in order to meet the physiological requirements, the modulator influences should elevate the initially positive level of postsynaptic potential and augment the receptor excitability. Probably, the role of such modulators can be played by excitatory amino acids (EAA) glutamate and aspartate. In EEG, transmitter deficiency is manifested by greatly desynchronized low-amplitude activity characterized by paroxysmal episodes. In these cases, the signs of overexcitation are frequently observed, such as psychotic complications during compulsive therapeutic desynchronization of EEG in epileptic patients.
Elimination of inhibitory modulation results in hypermediatory overexcitation of the postsynaptic membrane of the effector neurons reflected by paroxysmal activity in EEG. By contrast, elimination of excitatory modulation in the case of hypornediatory inhibition of neurotransmission (for example, in narcosis coma) results in spontaneous firing of postsynaptic neurons. In both cases, EEG demonstrates degraded slow-wave theta- and delta-rhythms indicating the pronounced changes in excitability of postsynaptic neurons.
Therefore, the interrelations between clinical and EEG data revealed with the use of pharmacological preparations showed that physiological neurotransmission is performed by neurotransmitters within the limits of constitutional anatomic and physiological peculiarities of the brain, and it is determined by the amount of the transmitters producing postsynaptic activation in the genetically set limits of physiologic excitability and refractoriness of CNS neurons. The objective criterion and instrumental correlation of physiologic neurotransmission is alpha-rhythm in EEG. During pathological abundance or deficiency of the transmitter in the synaptic cleft, the neurotransmitter disorders are clinically manifested and reflected in EEG by hypersynchronization of alpha-rhythm in the first case, and its greatest desynchronization in the latter one. Probably, during progressive hyper- or hypomediatory disease, the physiological correction of the disturbed neurotransmission is effected by inhibitory or excitatory aminoacids, correspondingly. In these cases, EEG demonstrates the respective changes in alpha-rhythm power up to the paroxysmal activity. Elimination of modulatory influenced of IAA or EAA results in dramatic inhibition of neurotransmission, which is manifested in EEG by theta- and delta-rhythms reflecting isolated firing of the neurons. These concepts consider the disturbances of neurotransmission as an important pathoge-netic mechanism underlying a wide range of the diseases and impart the clinical meaning to EEG. The use of pharmacologic preparations for the directed influence on the basic EEG rhythms makes it possible to develop differential individual approach to pharmacologic correction of various cerebral dysfunctions.
- BeriramG. Katzung. Basic & Clinical Pharmacology. — Prentice — Hall International Inc., 1994. — 612 p.
- Emkart J., Toussaint M., Simon C. et al. Alpha activity and cardiac correlates: three types of relationships during nocturnal sleep // Clin. Neurophysiol. — 2000. — Vol. 111, N 5. — P. 940-946.
- Gordon M. Shepherd. Neurobiology. — Oxford University Press, 1983. — 454 p.
- Oreengard P. Neuroscience — The neurobiology of slow synaptic transmission // Science. — 2001. — Vol. 294, N5544. - P. 1024-1030.
- International Headache Society Classification Subcommittee. International classification of headache disorders, 2nd edition//Cephalalgia. - 2004. - Vol. 24 (Suppl 1). - P. 1-160.
- Mezzich J. E., Cohen N., Liu J. et al. Validation of an efficient quality of life index: Abstract of the XI World Congress of Psychiatry "Psychiatry on New Thresholds". — Hamburg, Germany, 6-11 August, 1999. - P. 427-428.
- Mirtovskaya V. N., Majkova T. N., Poltavets D. V., Chekmareva T. I. Epidemiological studies of headache in patients with epileptic EEG // Functional neurology. — 1996. — Vol. XI, N 2-3. — P. 131.
- B. Philip G. Janicak, John M. Davis, Sheldon H. Preskorn, Frank J. Ayd. Principles and practice of psychopharmacotherapy. — Williams&Wilkins, 1997. — 728 p.
Опубликовано в издании Врачебное дело