Technologies of Nonlinear Stimulation: Role in the Treatment of Diseases of the Brain and the Potential Applications in Healthy Individuals

In 2015, the theory was proposed that links the development and maintenance of the typical in norm complex structure of neural networks and the activity of the brain with the complexity of visual and other sensory environmental signals that affect the person during the life. Simplification of the temporal structure of environmental cues is associated with abnormal development and aging of the central nervous system. As well, the use of fractal optic stimulation and complex aperiodic stimuli of other modalities may enhance the effectiveness of strategies for a recovery in the structure and function of the retina and brain, including neurodegenerative pathology, by reactivation of neuroplasticity. In the spectrum of nonlinear stimulating therapy techniques, different variants of mono- and multimodal fractal stimulation should be used, as well as their combinations with white noise, music therapy, cognitive, and physical training. We believe that using of non-linear stimulation technologies in a healthy person may be important in a variety of situations that lead to the simplification of the networks and dynamics of the activity of the brain. Application of physiologically adequate nonlinear stimuli is promising to slow and prevent age-related cognitive impairment in the elderly, in rehabilitation and recovery programs for healthy individuals of certain professions associated with physical or psychological stress, and athletes.     

A theory of drug tolerance and dependence II: the mathematical model

The preceding paper presented a model of drug tolerance and dependence. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behaviour to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The present paper discusses the mathematical model in terms of its design. The model is a nonlinear, learning feedback system, fully satisfying control theoretical principles. It accepts any form of the stimulus-the drug intake-and describes how the physiological processes involved affect the distribution of the drug through the body and the stability of the regulation loop. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes.     

细菌药物耐受

细菌药物耐受(Drug tolerance)是指在没有发生耐药突变的情况下细菌耐受抗生素杀菌的能力,表现为细菌群体难以或不能被杀菌型药物清除。细菌药物耐受的调控机制包括群体异质性和压力应答两种途径。药物耐受性的本质是细菌通过调控或遗传突变的方式改变生理代谢状态,从而抵制药物引起的细胞死亡途径。比如,处于缓慢生长或生长停滞生理状态的细菌往往能够抵抗药物的杀菌作用。临床研究发现细菌药物耐受是导致持续性感染疾病迁延难愈、复发率高的病原学机制之一。同时,研究证明耐受性的形成是细菌耐药性(Drug resistance)产生的进化途径之一。因此,揭示细菌药物耐受的机制将有助于人们深入了解抗生素的杀菌机理,以及细菌耐药性形成的适应性进化机制,并为新型杀菌药物以及药物增效剂靶标的发现和抗生素合理使用策略的开发奠定理论基础。     

The 1985 Upjohn award lecture. Tolerance, learning, and neurochemical adaptation

Alcohol or drug tolerance has been viewed traditionally as a homeostatic response to a direct chemical action of the agent on the neuron. This concept has undergone major modification as a result of recent observations that behavioral and environmental factors can alter markedly the tolerance developed to the same drug regimen. Obligatory task performance under the influence of the drug, classical conditional stimuli in an environment habitually associated with drug administration, previous exposure to a tolerance-producing regimen, and environmental modification of the expression of the drug's effect can all influence dramatically the degree of tolerance produced by a given dosage. Attempts to identify possible cellular mechanisms of tolerance development are illustrated by a review of studies on the relations between ethanol tolerance and changes in the neuronal membrane Na+ -K+ ATPase and its interaction with ethanol and norepinephrine, hippocampal serotoninergic systems and their interaction with a vasopressin derivative, a membrane-bound calcium- and calmodulin- dependent kinase, and hypothalamic-hypophyseal endorphin-producing systems. None of these studies or other similar ones, whether correlational or interventional in nature, has yet provided full and credible explanations of the effects of behavioral and environmental factors on tolerance development. Finding such explanations is the major current challenge in the neurobiology of tolerance.     

Constraints on the tailflick assay: morphine analgesia and tolerance are dependent upon locus of tail stimulation

In three experiments, the locus of tail stimulation in the tailflick assay was found to be an important parameter in determining morphine action. Rats were intravenously infused (Experiment I), injected with morphine subcutaneously (Experiment II), or implanted subcutaneously with morphine pellets (Experiment III). Analgesia was evaluated periodically following drug administration using the tailflick test and 3 adjacent 1 in. tail areas. In all three experiments, the distal tail section was more sensitive to the analgesic effects of morphine than more proximal sections. In Experiments I and III, tolerance to the effects of morphine developed more slowly at the distal tail location. These results indicate that the locus of stimulation in the tailflick assay can profoundly affect the development of analgesia and tolerance to morphine.     

Feeding,drug abuse,and the sensitization of reward by metabolic need

The incentive-motivating effects of external stimuli are dependent, in part, upon the internal need state of the organism. The increased rewarding efficacy of food as a function of energy deficit, for example, has obvious adaptive value. The enhancement of food reward extends, however, to drugs of abuse and electrical brain stimulation, probably due to a shared neural substrate. Research reviewed in this paper uses lateral hypothalamic electrical stimulation to probe the sensitivity of the brain reward system and investigate mechanisms through which metabolic need, induced by chronic food restriction and streptozotocin-induced diabetes, sensitizes this system. Results indicate that sensitivity to rewarding brain stimulation varies inversely with declining body weight. The effect is not mimicked by pharmacological glucoprivation or lipoprivation in ad libitum fed animals; sensitization appears to depend on persistent metabolic need or adipose depletion. While the literature suggests elevated plasma corticosterone as a peripheral trigger of reward sensitization, sensitization was not reversed by meal-induced or pharmacological suppression of plasma corticosterone. Centrally, reward sensitization is mediated by opioid receptors, since the effect is reversed by intracerebroventricular (i.c.v.) infusion of naltrexone, TCTAP (μ antagonist) and nor-binaltorphimine (κ antagonist). The fact that these same treatments, as well as i.c.v. infusion of dynorphin A antiserum, block the feeding response to lateral hypothalamic stimulation suggests that feeding and reward sensitization are mediated by a common opioid mechanism. Using in vitro autoradiography, radioimmunoassays and a solution hybridization mRNA assay, brain regional μ and κ opioid receptor binding, levels of prodynorphin-derived peptides, and prodynorphin mRNA, respectively, were measured in food-restricted and diabetic rats. Changes that could plausibly be involved in reward sensitization are discussed, with emphasis on the increased dynorphin A_1–8 and prodynorphin mRNA levels in lateral hypothalamic neurons that innervate the pontine parabrachial nucleus, where μ binding decreased and κ binding increased. Finally, the possible linkage between metabolic need and activation of a brain opioid mechanism is discussed, as is evidence supporting the relevance of these findings to drug abuse. Special issue dedicated to Dr. Eric J. Simon.     

A theory of drug tolerance and dependence I: a conceptual analysis

A mathematical model of drug tolerance and its underlying theory is presented. The model extends a first approach, published previously. The model is essentially more complex than the generally used model of homeostasis, which is demonstrated to fail in describing tolerance development to repeated drug administrations. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary only in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behavior to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes. In addition, it establishes a relation between the drug dose at any moment, and the resulting drug effect and relates the magnitude of the reactions following withdrawal to the rate of tolerance and other parameters involved in the tolerance process. The present paper analyses the concept behind the model. The next paper discusses the mathematical model.     

Antagonists of NMDA glutamate receptors selectively affect synaptic mechanisms of the nociceptive sensitization in the snail

The effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists on the mechanisms of nociceptive sensitization were studied in LPl1 and RPl1 neurons of the semiintact preparation of a Helix lucorum snail. Application of sensitizing stimuli on the head part of the control preparation led to a depolarization of the membrane and increase in its excitability. A depression of responses of neurons evoked by tactile or chemical sensory stimulation during the short-term period and significant facilitation of responses during the long-term period of sensitization were observed. Sensitization performed under conditions of application of NMDA antagonists (AP5 or MK801) produced similar changes in membrane potential, membrane excitability, and neuronal responses evoked by tactile stimulation of the head or foot. However, the chemical stimulation of the head under these conditions evoked a significant depression of responses during the short- and long-term sensitization periods. The results suggest that the NMDA glutamate receptor antagonists selectively affect the plasticity induction mechanisms of the command neuron synaptic inputs, which mediate the chemical sensory stimulation from the snail's head.     

Neurobiology of addictive behavior

Addictive behavior developes after repeated substance use and it typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to the drug use than to other activities. Relapse, the resumption of drug taking after periods of abstinence, remains the major problem for the treatment of addiction. The process of drug addiction shares striking commonalities with neural plasticity associated with natural reward learning and memory and is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems that attribute incentive salience to reward-associated stimuli. The switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control. Current neurophysiologic evidence suggests that the development of addiction is to some extent due to neurochemical stimulation of the midbrain dopaminergic system that is traditionally considered as a 'common neural currency' for rewards of most kinds. Addictions are a result of the interplay of multiple genetic and environmental factors. They are characterized by phenotypic and genetic heterogeneity as well as polygenicity. Environmental factors are crucial in addiction vulnerability and resistese too.     

Critical role of intracellular calcium in plasticity mechanisms of defense behavior command neurons LPl1 and PPl1 of Helix lucorum during nociceptive sensitization

The role of intracellular calcium in changes in excitability and responses of defense behavior command neurons LP11 and PP11 of Helix lucorum to sensory stimulation was investigated in semi-intact preparation of a snail during nociceptive sensitization. It was found that application of sensitizing stimuli onto the snail's head initiated membrane depolarization, increase in its excitability as well as depression of neural responses evoked by sensory stimuli in short-term period of sensitization and significant facilitation of neural responses in long-term period of sensitization. To elucidate the contribution of LP11 and PP11 neurons in plasticity rearrangements involved in the mechanisms of sensitization, we applied sensitizing stimuli during strong hyperpolarization of the neurons or after intracellular injection of calcium chelators. Application of sensitizing stimuli during hyperpolarization of the neurons suppressed the increase in membrane excitability and depressed the neural responses evoked by chemical stimulation of snail's head i.m. short- and long-term periods of sensitization. At the same time, synaptic facilitation of neural responses evoked by tactile stimulation of snail's head and foot was observed, which was similar to synaptic facilitation in the control sensitized snail. Intracellular injection of EGTA or BARTA (calcium chelators) before sensitization suppressed synaptic facilitation in neural responses evoked by sensory stimulation. Under these conditions, the increase in excitability was more pronounced then in the control snail neurons. The experimental results suggest the changes in neural responses evoked by sensory stimulation in sensitized snails involve postsynaptic calcium-dependent mechanisms of plasticity in LP11 and PP11 neurons.     

Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways

Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.     

Plasticity of the landing response of Drosophila melanogaster

Summary Fruitflies (Drosophila melanogaster) may respond with landing reactions in tethered flight to unilateral progressive motion of single vertical dark stripes. The response frequency to repeated unilateral stimulation has a characteristic time course, a fast increase followed by a slower decrease. This behaviour is explained by the habituation of the input channels to a leaky integrator. The half-life of the integrated signal is in the range of 1 s. Contralateral sensitization (CoS) describes the sensitization of the landing response to unilateral stimuli by preceding contralateral stimulation. It acts by increasing the initial reactivity, which habituates. The effects of CoS are thus still obvious after 1 min of repetitive stimulation. CoS can effectively be mediated by movement stimuli as well as by flickering light. We also show that binocular rotation rather than unilateral back to front motion inhibits the landing response (in the monocular part of the visual field). The biological significance of the described temporal characteristics of the landing response system and their possible neuronal basis are discussed.Abbreviations CoS contralateral sensitization     

Functions of the LE sensory neurons inAplysia

Mechanosensory neurons which innervate the siphon and have their cell bodies in the LE cluster of the abdominal ganglion ofAplysia have revealed many cellular and molecular processes that may play general roles in learning and memory. It was initially suggested that these cells are largely responsible for triggering the gill-withdrawal reflex evoked by weak siphon stimulation, and that most of this effect is mediated by their monosynaptic connections to gill motor neurons. This implied a simple link between plasticity at these synapses and modifications of the reflex during learning. We review more recent studies from several laboratories showing that the LE cells are not activated by very weak tactile stimuli that elicit the gill-withdrawal reflex, and that an unidentified population of siphon sensory neurons has lower mechanosensory thresholds and produces shorter latency responses. Furthermore, the direct connections between LE cells and gill motor neurons make a minor contribution when the reflex is elicited in pinned siphon preparations by light stimuli that weakly activate the LE cells. Because weak mechanical stimulation of the unrestrained siphon causes little or no LE cell activation, it is unlikely that, under natural conditions, sensitization or conditioning of reflex responses elicited by light siphon touch depends upon plasticity of LE cell synapses onto either motor or interneurons. The LE cells appear to function as nociceptors because they are tuned to noxious stimuli and, like mammalian nociceptors, show peripheral sensitization following nociceptive activation. This sensitization and the profound activity-dependent potentiation of LE synapses indicate that LE cell contributions to defensive reflexes should be largest during and after intense activation of the LE cells by noxious stimulation (with the LE cell plasticity contributing to long-lasting memory of peripheral injury). The LE sensory neurons offer special opportunities for direct tests of this and other hypotheses about specific mnemonic functions of fundamental mechanisms of neural plasticity.     

Effect of selective protein kinase C inhibitor on synaptic plasticity of command neurons of defensive behaviour during sensitization in snails

Polymyxin B (proteinkinase C inhibitor) effects on nociceptive sensitization of semiintact preparation were investigated in LP11 and RP11 snail neurons. It was found that application of sensitizing stimuli to control snail head initiated neural membrane depolarization, increase its excitability as well as depression of neural responses evoked by sensory stimulation during short-term stage. Polymyxin B application suppressed neural responses evoked by sensitizing (nociceptive) stimuli. At the same time changes in neural membrane excitability as well as neural responses evoked by tactile stimulation of snail foot or chemical stimulation of snail head were similar with ones in control snails. Polymyxin Bdid does not change the depression of neural responses evoked by tactile stimulation of snail head during short-term stages of sensitization but significantly suppressed facilitation of neural responses evoked by tactile stimulation of snail head during long-term stage of sensitization. It was suggested that proteinkinase C is involved in regulation of nociceptive mechanisms as well as in plasticity selective induction mechanisms in command neuron synaptic inputs activated by tactile stimulation of snail head.     

United we sense, divided we fail: context-driven perception of ambiguous visual stimuli

Ambiguous visual stimuli provide the brain with sensory information that contains conflicting evidence for multiple mutually exclusive interpretations. Two distinct aspects of the phenomenological experience associated with viewing ambiguous visual stimuli are the apparent stability of perception whenever one perceptual interpretation is dominant, and the instability of perception that causes perceptual dominance to alternate between perceptual interpretations upon extended viewing. This review summarizes several ways in which contextual information can help the brain resolve visual ambiguities and construct temporarily stable perceptual experiences. Temporal context through prior stimulation or internal brain states brought about by feedback from higher cortical processing levels may alter the response characteristics of specific neurons involved in rivalry resolution. Furthermore, spatial or crossmodal context may strengthen the neuronal representation of one of the possible perceptual interpretations and consequently bias the rivalry process towards it. We suggest that contextual influences on perceptual choices with ambiguous visual stimuli can be highly informative about the neuronal mechanisms of context-driven inference in the general processes of perceptual decision-making.     

Potentiation by cocaine of relaxations of the guinea-pig colon caused by noradrenaline and by stimulation of adrenergic nerves.

The distal colon of the guinea-pig is relaxed by noradrenaline, by isoprenaline and by the stimulation of fibres running with the colonic nerves or intramurally. The relaxations in response to stimulation of the colonic nerves have a guanethidine-sensitive (adrenergic) and a guanethidine-insensitive (non-adrenergic) component. Cocaine causes a three-fold sensitization of the muscle to noradrenaline but no sensitization to isoprenaline. Cocaine increases the duration, but does not affect the amplitude, of the relaxation observed when adrenergic nerves are stimulated, and affects neither duration nor amplitude of the non-adrenergic response. The adrenergic nerve terminals lie in Auerbach's plexus, not in the longitudinal muscle. It is concluded that the sensitization to noradrenaline and the increases in durations of responses to adrenergic nerve stimulation are due to inhibition of catecholamine uptake into adrenergic nerves by cocaine. It appears that, even where the neuromuscular separation is large as it is in the colon, the concentration of exogenous noradrenaline at the receptors can be decreased by neuronal uptake, and the uptake mechanism can modify responses to nerve stimulation in vitro.     

Selective involvement of opioids in mechanisms of synapse-specific plasticity in Helix lucorum snail during sensitization acquisition

Effects of met-enkephalin (opioid peptide) and naloxone (opioid antagonist) on nociceptive sensitization were studied in L-RP11 Helix neurons. In control snails sensitizing stimulation produced reversible membrane depolarization and depression of neural responses evoked by sensory stimuli during the short-term stage of sensitization and facilitation of these responses at the long-term stage. Met-enkephalin (10 but not 0.1 microM) suppressed the neural responses evoked by nociceptive stimuli. Sensitizing stimulation during metenkephalin application prevented the facilitation of neural responses evoked by tactile stimulation of snail head, whereas facilitation of neural responses evoked by chemical stimulation of head or tactile stimulation of foot were similar to that in control sensitized snails. Sensitizing stimulation during met-enkephalin and/or naloxone application prevented the facilitation of neural responses evoked by chemical stimulation of snail head, whereas responses evoked by tactile stimulation of snail head or foot were facilitated (as in neurons of control sensitized snails). Opioids are suggested to be involved in regulation of nociceptive mechanisms and selective induction of long-term plasticity in L-RP11 neural inputs activated by tactile of chemical stimulation of snail head.     

Effect of morphine and acetylcholine on contractile activity and cyclic AMP in guinea-pig ileum

Neither acute nor prolonged exposure to morphine altered cAMP content or spontaneous movements of longitudinal muscle-myenteric plexus strips of the guinea-pig ileum. By contrast, exogenous acetylcholine or electrical stimulation of the strips elicited both a decrease of cAMP concentration and a twitch response. Atropine blocked the effects of stimulation on these parameters. Addition of morphine to electrically stimulated strips inhibited the twitch response but did not affect cAMP levels. Incubation with morphine led to the development of tolerance to the inhibitory effect on twitch activity and prevented the fall in cAMP normally elicited by electrical stimulation. These results suggest that muscarinic activation is associated with a reduction of cAMP content, an effect which would be impaired in opiate-tolerant tissues.     

γ-Glutamyltransferase-dependent resistance to arsenic trioxide in melanoma cells and cellular sensitization by ascorbic acid

The cell ability of tumor cells to tolerate stress conditions is a typical feature of solid tumors. In particular, the resistance to oxidative stress of melanoma cells likely contributes to their intrinsic drug resistance. In an attempt to develop novel strategies for overcoming the mechanisms of cellular protection against oxidative stress, in this study we have explored the efficacy of the combination of two prooxidant agents in two human melanoma cell clones. The selected clones are characterized by a marked difference in expression of γ-glutamyltransferase, which is known to produce a persistent low level of oxidative stress resulting in the stimulation of protective systems. The γ-glutamyltransferase-overexpressing clone exhibited a low susceptibility to arsenic trioxide-induced apoptosis, associated with low reactive oxygen species induction and increased catalase activity. The combination of arsenic trioxide with subtoxic concentrations of ascorbic acid resulted in a sensitization to apoptotic cell death. The expression of protective mechanisms, in particular catalase activity, accounted for the behavior of the resistant clone. The sensitization achieved by the combination was associated with a cellular response involving the ASK1/p38 axis, which is implicated in the regulation of catalase expression and the activation of apoptotic signals. In conclusion, the results of our study provide evidence that a rational combination of prooxidant agents may be effective in overcoming cellular tolerance to oxidative stress.