Chronic pain as a reticular formation syndrome

Evidence was previously presented to support the thesis that chronic pain is activated by neuronal elements that make up the multisynaptic short axon core of the reticular system (Andy and Peeler 1985). The present thesis, that chronic pain is a reticular formation syndrome, is based on a retrospective analysis of four patients with chronic pain who were successfully treated with a lesion in the anterior thalamus and stimulation electrode implants in the posterior thalamus and pontomesencephalic brain stem. The reticular formation was the common underlying anatomic substrate at those three sites. In addition to chronic pain, all the patients had other symptoms attributable to other body organs and systems. The number and type of symptoms that made up the syndrome differed between patients. Symptoms making up the core of the syndrome were pain, anxiety, nervousness, insomnia, and depression. Experimental and clinical findings are briefly presented to demonstrate the various reticular formation sites, pragmatically considered "reticular functional systems," from which symptoms may arise. It is hypothesized that the symptoms are recruited by a low threshold "pain oscillator" that is generated at one reticular site and subsequently permeates the rest of the reticular system. Therapeutic stimulation inactivates the low threshold system by "jamming" it.     

Changes in seizure activity thresholds of the cat brain in various stages of sleep and wakefulness

Changes in seizure activity of the brain evoked by electrical stimulation of the dorsal hippocampus in various stages of sleep and wakefulness were studied in adult cats. During slow sleep, when the EEG is dominated by high-voltage slow waves, near-threshold epileptogenic hippocampal stimulation evokes well-marked paroxysmal discharges. During wakefulness or the paradoxical phase of sleep, when the EEG is desynchronized, this hippocampal stimulation is less effective: either no seizure discharges are produced or they are weak. Activation of the mesencephalic reticular formation before epileptogenic hippocampal stimulation hinders the appearance of seizure activity whereas activation after hippocampal stimulation does not inhibit paroxysmal discharges already in progress; on the contrary, in some cases they are actually strengthened a little. One of the main factors limiting the appearance and spread of seizure activity is considered to be the tonic inhibitory influence of the neocortex on other parts of the brain.     

Alterations of spectral parameters of rat brain electrical activity after sciatic nerve section

Changes in electrophysiological brain characteristics accompanying the development of neurogenic pain syndrome induced by transsection of sciatic nerve were analyzed. At the maximum pain syndrome 3 weeks after the deafferentation, a reorganization of the brain electrical activity was observed in the limbic structures (hippocampus, amygdale, and nucleus accumbens), frontal cortex, and the caudate putamen. An increase in the relative spectral power of the delta and alpha bands and a decrease in the relative power of the beta2 band (as compared to baseline activity) took place. Alteration of the electrical activity in the limbic structures did not depend on manifestations of the neurogenic pain syndrome (autotomy). The increase in the relative spectral power of the alpha-band activity in all the structures under study suggests the involvement of the reticular thalamic nucleus in pathogenesis of neurogenic pain syndrome.     

Thalamic stimulation for control of movement disorders

Chronic recurrent thalamic stimulation has been effective in alleviating a variety of movement disorders. In contrast to thalamic lesions, it is preferred for the treatment of intractable motor disorders in low-risk elderly patients and patients with diffuse brain lesions secondary to trauma. Abnormal diencephalic electrical discharges have been observed and thought to be associated, in some way, with either generating or sustaining the movement abnormalities. The beneficial effects are ascribed to an electrophysiologic functional ablation of the discharging systems. This interpretation is based on the observation that the diencephalic discharges are attenuated by the applied stimulation and that the beneficial effects are reversible even after several months of applied therapeutic stimulation.     

Chronic pain syndromes

Brainstem-scalp discharge propagation was evaluated in 20 patients with chronic pain, of which 10 were ranked according to the frequency of involved systems making up the chronic pain syndrome. It is concluded that brainstem discharges alone were sufficient to generate the chronic pain syndrome.     

Changes in the neuronal activity in the dorsolateral pontine region caused by electrical stimulation of the brainstem regions inhibiting movement and the muscle tone

Activity of 44 mesencephalic locomotor area's (MLR) units and 38 pontine inhibitory area's (PIA) units was recorded during stimulation of the giganto-cellular reticular nucleus and oral pontine reticular nucleus inducing the hindlimb muscle tone inhibition in decerebrated rats. The muscle tone suppression was always accompanied by a decrease in the MLR and an increase in the PIA unit discharges. Stimulation of the brainstem inhibitory area seems to activate reticulospinal inhibitory system and suppress some MLR units relating to locomotion and muscle tone.     

Change in reactions of visual cortex neurons to light flash upon hypothalamic and reticular stimulation

The effect of electrical stimulation of the hypothalamic positive reinforcement zone (PRZ), the neutral hypothalamic zone (NZ), and the reticular formation (RF), of the midbrain on the impulse activity of single neurons of the visual cortex evoked by light flashes was studied in unanesthetized and uncurarized white rats. Poststimulus histograms of the neurons's responses were compared. Under the influence of stimulation the evoked activity of the neurons which responded to light changed in a majority of them (from 63% for the NZ to 82% for the RF). Qualitative differences were found in the effects of PRZ and RF stimulation. The effects of PRZ stimulation consisted in the invariability or in a decrease in the frequency of the neuron's discharge comprising the short-latent response, and an increase in the frequency of the discharges in the long-latent response ("positive-motivation" type). The effects of RF stimulation were manifested in intensification of the neuronal discharges in the short-latent and a decrease in the discharges in the long-latent response ("reticular" type). The responses of a considerable number of the neurons changed to the "combined" type. The data obtained indicates the different natures and mechanisms of the ascending activating effects caused by stimulation of the PRZ and the RF and which brings about positive nonspecific reinforcements. These effects, which are manifested differently in different periods of the neuron's working cycle cannot be explained by "energizing" or "tonus" concepts; their explanation must be sought for in informational (systemic) concepts.N. I. Grashchenkov Laboratory of Problems of Functional Control in the Human and Animal Organism, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 3, No. 4, pp. 359–368, July–August, 1971.     

Changes in the activity of plasma beta-endorphin-like-immunoreactivity induced by transcutaneous stimulation of the brain

A newly devised technique of electrical transcutaneous brain stimulation has been applied to a population of cephalalgic patients in order to assess its proficiency in pain relieving and in increasing the concentration of serum endorphins. A significant pain relief associated with an increase in serum endorphins has been obtained only in those patients in which clinical and instrumental evaluations had identified the headache as one of "organic" origin. By contrast both in "non organic" and in control subjects the technique has proved to be effectiveless. Our results suggest that transcutaneous electrical brain stimulation can affect the release of endogenous opioids relieving pain at least in selected patients.     

回苏灵引起家兔膈神经和胫神经痉挛性放电的机制分析

本工作在28例局部麻醉、肌肉麻痹的家兔上进行。实验观察到静脉注射大剂量回苏灵(1.5mg/ kg)后,在胫神经、膈神经及脑干孤束核(NTS)区与网状结构等部位均可记录到痉挛性放电。其中胫神经上先出现紧张性高频放电,后转为阵挛性排放,一般在50—100min 后恢复。膈神经也可出现类似放电,但其排放节律比胫神经快,两者不完全同步;在恢复期,吸气放电与痉挛性排放可交替出现。高位离断脊髓后,胫、膈神经的痉挛性放电即消失。NTS 区的吸气相关单位所出现的痉挛性排放,其频率与膈神经的不完全同步;但在脑干网状结构可找到与胫神经、膈神经痉挛性排放基本同步的放电单位,且孤立脑干,仍可见该单位的痉挛性放电。以上结果提示,回苏灵痉挛性放电的发源部位主要在脑干网状结构。切断脊髓背束及外侧束的大部,保留网状脊髓束和脊髓网状束,不影响胫,膈神经的痉挛性放电;脊髓半横切后,同侧胫、膈神经的痉挛性放电则消失。     

Combined electrical stimulation of the periaqueductal gray matter and sensory thalamus

11 patients with chronic intractable pain of at least 3 years' duration underwent a morphine infusion test, the results of which suggested a syndrome of superimposed somatogenic and neurogenic pain components. They then underwent stereotactic implantation of a dual-channel brain stimulation system with two brain electrodes, one in the left periaqueductal gray matter (PAG) and the other in the sensory thalamus contralateral to the neurogenic pain. Using this system, all patients have obtained excellent simultaneous relief of both pain components (follow-up 12-36 months). The findings support a notion of two separate sensory modulating systems. They indicate that combined electrical stimulation of the PAG and sensory thalamus is a technically feasible and clinically satisfactory modality for the control of pain in humans, and they appear to indicate that better pain control is obtained by continuous, cycled stimulation of the PAG than by the conventional mode of stimulation.     

Absence attacks controlled by thalamic stimulation

Thalamic electrical stimulation in 3 patients alleviated chronic pain, absence attacks and spontaneously occurring delta and theta EEG discharges. It is suggested that diencephalic discharges may activate and/or lower the threshold for pain at the level of the diencephalon.     

Study of neuronal structures of the brain stem which produce rapid reactions in reticulo-spinal pathways

The total electrical discharges of the ventral and ventrolateral funiculi of the 11th thoracic segment of the spinal cord in response to stimulation of different points of the pons varolii and the medulla oblongata between frontal planes P-2 and P-12 were investigated in decerebrated cats. Regions were found corresponding to the location of the oral and caudal reticular nuclei of the pons and the rostral section of the reticular giant cell nucleus whose stimulation caused a short-latent discharge in the ventral funiculus (latent period 1.6–1.9 msec) with maximum amplitude. It was concluded that such a discharge is due to the direct stimulation of a rather homogeneous group of fast-conducting reticulo-spinal fibers which terminate mainly in the ventral funiculus and which have an average rate of conduction of 131 m /sec. When the same regions were stimulated, the short-latet discharge of the ventro-lateral funiculus had a considerably lower amplitude and was accompanied by a powerful, late discharge with a latent period of about 3.3 msec. It was assumed that this funiculus consists mainly of fibers with a lower rate of conduction which originate in a broader region of the medial RF of the brain stem. Stimulation of contralateral regions of the reticular formation of the medulla oblongata evoked only a weak short-latent discharge in the ventral funiculus; the late component of the discharge in this case was considerably stronger.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 3, No. 3, pp. 274–283, May–June, 1971.     

Effects of morphine on visual evoked responses recorded in five brain sites.

The effects of morphine on averaged evoked responses to visual stimulation were examined in specific brain structures relevant to pain, analgesia, tolerance and motor disturbances. Permanent electrodes (60 μ in diameter) were implanted stereotaxically in the central gray, mesencephalic reticular formation, caudate nucleus, parafasicular-centromedian complex and the lateral geniculate body as a control site. Visual evoked responses were obtained in unanesthetized, unrestrained rats prior to and following the administration of morphine in successive doses of 1, 5, 10 and 30 mg/kg and 1 mg/kg of naloxone (a morphine antagonist). The parafasicular-centromedian complex and the reticular formation exibited a progressive increase in response amplitude to increased dose of morphine. These effects were reversed by naloxone. In this study the parafasicular-centromedian complex was found to be the most sensitive structure to morphine, displaying the largest changes in response amplitude as a result of morphine administration.     

Effect of pentobarbital on unit activity of reticular and ventrolateral thalamic nuclei in cats

Responses of single units in the reticular and ventrolateral thalamic nuclei were studied in acute experiments on curarized cats before and after intravenous injection of small doses (0.5–15 mg/kg) of pentobarbital, with simultaneous derivation of activity by two electrodes. After injection of pentobarbital, unit activity in the reticular nucleus consisted of high-frequency grouped (52.5% of 40 neurons) or continuous (30%) discharges as long as barbiturate spindles were present in the electrocorticogram. Activity of only four neurons (10%) of this nucleus was inhibited during the presence of spindles. In all other neurons of the reticular nucleus (7.5%) the character of discharges was unchanged after injection of pentobarbital. The appearance of grouped discharges, repeated several times (66.5% of 40 neurons), or blocking of activity (30%) throughout the period of spindle recording was observed in neurons of the ventrolateral nucleus. The remaining neurons of that nucleus (3.5%) did not respond to intravenous pentobarbital. The appearance of high-frequency discharges in neurons of the reticular nucleus while spindles were recorded coincided with a period of silence in neurons of the ventrolateral nucleus (58.5% of 34 pairs of neurons). High-frequency electrical stimulation of the mesencephalic reticular formation led to asynchronous activation of neurons of the ventrolateral nucleus (82%) and inhibition of unit activity in the reticular nucleus (88%).I. S. Beritashvili Institute of Physiology, Academy of Sciences of the Georgian SSR, Tbilisi. Translated from Neirofiziologiya, Vol. 14, No. 5, pp. 517–524, September–October, 1982.     

Brainstem discharge sites: therapeutic targets for chronic pain

Optimum mesothalamic targets for therapeutic electrode implants are characterized by (1) spontaneously occurring focal discharges, (2) attenuation of the discharges by electrical stimulation, and (3) stimulation-induced pain relief.     

Study of the role of the right and left orbitofrontal cortex in compensatory cerebral reactions after acute brainstem damage

Significance of the right and left orbitofrontal cortex (OFC) in recovery after acute brainstem lesion (at the level of n. Deiters) was investigated using rat model of complex brainstem-orbitofrontal cerebral damage. It was found that the right-side lesion of the OFC combined with isolated brainstem damage resulted in aggravation of the animal condition and highly probable lethal outcome within the first two weeks after surgery (because of the brain circulation disorder of hemorrhagic type). It may be associated with sympathetic activation. It is suggested that a certain "stimulation" of the left OFC (as the effect of its incomplete destruction) involves a parasympathetic compensatory reaction that allows animals with a severe brainstem pathology to survive. It is shown that, with the general nonspecific tendency to postoperative increase in emotionality, the greatest shifts in the emotional sphere take place under conditions of a combined damage of the brainstem and left OFC.     

Effect of adrenalin and adrenal desympathization on brain-seizure activity

The effect of adrenalin and bilateral adrenal desympathization on brain-seizure activity evoked by electrical stimulation of the dorsal hippocampus was studied in adult cats. A few days after bilateral adrenal desympathization the threshold of epileptogenic hippocampal stimulation was lowered and the duration of the evoked seizure response increased. Intravenously injected adrenalin raised the threshold of epileptogenic hippocampal stimulation. After injection of small doses of adrenalin directly into the mesencephalic reticular formation the evoked seizure activity was inhibited: The threshold of epileptogenic hippocampal stimulation was raised and the total duration of the seizure discharges reduced. It is postulated that one of the important factors limiting brain-seizure activity is an increase in the circulating blood adrenalin level.     

Postnatal changes in functional activities of the pig's brain: a combined functional magnetic resonance imaging and immunohistochemical study

Developmental changes in brain activation after pain stimulation and after passive movement of the hind paw were assessed by functional magnetic resonance imaging (fMRI) in pigs of postnatal ages 2, 4 and 6 months. Response patterns were correlated with histological maturation parameters. At 2 months, fMRI failed to detect brain activation after pain stimulation and revealed weak, but widespread activation after passive movement. At 4 months, strong reaction of numerous cortical areas on the contralateral side was seen after pain stimulation. Following passive movement, activation was weaker but more widespread, and the brainstem was also involved. By 6 months, cortical activation became more restricted to the contralateral sensory cortex and brainstem after pain stimulation and to the contralateral sensory and ipsilateral premotor and motor cortices after passive movement. Neocortical synaptophysin immunoreaction increased significantly between 2 and 4 months and slightly decreased by 6 months. The density of GABA-immunoreactive neurons and fibers significantly increased, reaching a maximum at 6 months. Our studies indicate that remodeling of synapses and development of inhibitory GABA neurons last until 6 months postnatally, when the fMRI response of the pig's brain also attains its mature adult pattern.     

Nociceptive reactions during stimulation of immunity in rats with various individual resistance to stress

Various behavioural nociceptive reactions and individual resistance against stress were studied under conditions of stimulation of the immune processes by various techniques. The research problems included a study of influence of the immune stimulation with preparation "Imunofan" upon pain responses depending on individual resistance of animals to a stress, and the obtained results were compared with similar data in natural model of immune activation. To reveal central immune regulation of nociceptive reactions, imunofan was injected into brain ventricles. The work was carried out in 43 "Wistar" adult male rats. Free "open field" behaviour of animals was recorded to define a stress-resistance. Following nociceptive reactions, tail-flick to thermal stimuli; start, escape, jumping and vocalization to electrical skin stimulation, were studied. It was shown that intramuscular injection of imunofan (0.01 ml, 0.005% solution) depressed an active behaviour of animals in open field and reduced pain thresholds. This hyperalgesia was much higher in non-resistant rats in comparison to the resistant ones. Similar results were obtained in natural activation of immunity caused by operative procedure necessary for injection of imunofan into ventricles. Intracerebroventricular injections were accompanied by stronger and more complex changes of pain sensitivity.     

Analysis of the effects of electrical stimulation of certain limbic structures

It has been established that stimulation of the structures of the limbic system (hippocampus, amygdaloid complex, septum) and the medial nucleic of the thalamus of rabbits in conditions of free behavior elicits four basic types of behavioral reactions: arousal, orientation-investigatory, aggressive-defensive and various epileptiform (convulsive) reactions. Activation of behavior, i.e., arousal and the orientation-investigatory reaction, constantly appear on stimulation of the unspecific thalamic nuclei. The aggressive-defense reaction is elicited by stimulating the nuclei of the amygdaloid complex of the ventral part of the hippocampus and the ventromedial nuclei of the thalamus. The epileptiform reactions are most readily reproduced on stimulation of the amygdaloid complex and the ventral part of the hippocampus. The threshold for the appearance of discharges of the aftereffect is very low. The latter are more sustained on stimulation of the basolateral part of the amygdala and the ventral part of the hippocampus. In rabbits as compared with higher animals the discharges on stimulation rapidly spread not only to the limbic system but also to the reticular formation and the neocortex.Kharkov Medical Institute. Translated from Neirofiziologiya, Vol. 1, No. 2, pp. 194–201, September–October, 1969.