Stimulation Of Medial Septum Research Articles

The impact of selective and non-selective medial septum stimulation on hippocampal neuronal oscillations: A study based on modeling and experiments

Alzheimer's disease (AD) is a neurodegenerative disorder with a rising socioeconomic impact on societies. The hippocampus (HPC), which plays an important role in AD, is affected in the early stages. The medial septum (MS) in the forebrain provides major cholinergic input to the HPC and has been shown to play a significant role in generating oscillations in hippocampal neurons. Cholinergic neurons in the basal forebrain are particularly vulnerable to neurodegeneration in AD. To better understand the role of MS neurons including the cholinergic, glutamatergic, and GABAergic subpopulations in generating the well-known brain rhythms in HPC including delta, theta, slow gamma, and fast gamma oscillations, we designed a detailed computational model of the septohippocampal pathway. We validated the results of our model, using electrophysiological recordings in HPC with and without stimulation of the cholinergic neurons in MS using designer receptors exclusively activated by designer drugs (DREADDs) in healthy male ChAT-cre rats. Then, we eliminated 75% of the MS cholinergic neurons in the model to simulate degeneration in AD. A series of selective and non-selective stimulations of the remaining MS neurons were performed to understand the dynamics of oscillation regulation in the HPC during the degenerated state. In this way, appropriate stimulation strategies able to normalize the aberrant oscillations are proposed. We found that selectively stimulating the remaining healthy cholinergic neurons was sufficient for network recovery and compare this to stimulating other subpopulations and a non-selective stimulation of all MS neurons. Our data provide valuable information for the development of new therapeutic strategies in AD and a tool to test and predict the outcome of potential theranostic manipulations.

P.0437 Memory enhancing effect after medial septum stimulation is associated with changes in hippocampal receptors expression in naturally-aged rats

P.0437 Memory enhancing effect after medial septum stimulation is associated with changes in hippocampal receptors expression in naturally-aged rats

A framework for designing data-driven optimization systems for neural modulation

Objective. Neural modulation is a fundamental tool for understanding and treating neurological and psychiatric diseases. However, due to the high-dimensional space, subject-specific responses, and variability within each subject, it is a major challenge to select the stimulation parameters that have the desired effect. Data-driven optimization provides a range of different algorithms and tools for addressing this challenge, but each of these algorithms has specific strengths and limitations, and therefore must be carefully designed for a given neural modulation problem. Here we present a framework for designing data-driven optimization algorithms for neural modulation. Approach. We develop this framework using an optogenetic medial septum stimulation model, where the goal is to find the stimulation parameters that modulate hippocampal gamma power to a desired value. This framework proceeds in four steps: (a) collecting stimulation data, (b) creating high-throughput simulation models, (c) prototyping a range of different data-driven optimization algorithms and evaluating their performance, and (d) deploying the best performing algorithm in vivo. Main results. Following this framework, we prototype and design an algorithm specifically for finding the medial septum optogenetic stimulation parameters that maximize hippocampal gamma power. Building on this, we then change our objective function to find the stimulation parameters that modulate gamma to a specific setpoint, use the framework to understand and anticipate the results before deploying in vivo. Significance. We show that this framework can be used to design an effective optimization solution for a specific neural modulation problem, and discuss how it can potentially be applied beyond the optogenetic medial septum stimulation model.

Medial septal stimulation increases seizure threshold and improves cognition in epileptic rats

BackgroundTemporal lobe epilepsy is most prevalent among focal epilepsies, and nearly one-third of patients are refractory to pharmacological intervention. Persistent cognitive and neurobehavioral comorbidities also occur due to the recurrent nature of seizures and medication-related side effects. HypothesisElectrical neuromodulation is an effective strategy to reduce seizures both in animal models and clinically, but its efficacy to modulate cognition remains unclear. We hypothesized that theta frequency stimulation of the medial septum would increase septohippocampal oscillations, increase seizure threshold, and improve spatial learning in a rat model of pilocarpine-induced epilepsy. MethodsSham and pilocarpine rats were implanted with electrodes in the medial septum, hippocampus and prefrontal cortex. EEG was assessed days prior to and following stimulation. Sham and pilocarpine-treated rats received either no stimulation, continuous (throughout each behavior), or pre-task (one minute prior to each behavior) 7.7 Hz septal stimulation during the Barnes maze spatial navigation test and also during assessment of flurothyl-induced seizures. ResultsBoth continuous and pre-task stimulation prevented epilepsy-associated reductions in theta oscillations over time. Additionally, both stimulation paradigms significantly improved spatial navigation in the Barnes maze, reducing latency and improving search strategy. Moreover, stimulation led to significant increases in seizure threshold in pilocarpine-treated rats. There was no evidence of cognitive enhancement or increased seizure threshold in stimulated sham rats. ConclusionThese findings have profound implications as theta stimulation of the septum represents a single frequency and target that has the potential to both improve cognition and reduce seizures for patients with refractory epilepsy.

Stimulation of the medial septum should benefit patients with temporal lobe epilepsy

Electrical stimulation of the septal nuclei via deep brain stimulating electrodes is proposed as a potentially beneficial therapy for medication-resistant temporal lobe epilepsy. In a multicenter study, stimulation of anterior thalamus was shown to reduce numbers of seizures, but decrease was only in the range of 40%. This might be improved with septal stimulation, which has strong and direct reciprocal connections with the hippocampal formation, the structure most involved in temporal lobe epilepsy. Medial septal neurons drive a 3–12Hz theta rhythm in hippocampus of rodents. Theta rhythm is less obvious in human hippocampus, but it is present and it varies with cognitive tasks. The hippocampal theta rhythm is disrupted by seizures. In animal models, restoration of theta by sensory stimulation, septal electrical stimulation or cholinergic drugs infused into septum ameliorates seizures. Seizure activity in hippocampus is faithfully reflected in septal nuclei, and septum sometimes leads the seizure activity. A subset of patients with temporal lobe epilepsy have structural enlargement of their septal nuclei. At high levels of intensity, septal stimulation is subjectively pleasurable and strongly reinforcing. Rats will repeatedly press a bar to stimulate their septum. Initial experience with human septal stimulation in the 1950s was not favorable, with ineffective therapy for schizophrenia and a high rate of surgical complications. Subsequent experience in 50–100 pain patients employing modern neurosurgical techniques was more favorable and demonstrated septal stimulation to be safe and tolerable. The current state of knowledge is sufficient to consider design of a clinical trial of medial septal stimulation in selected patients with medication-resistant temporal lobe epilepsy.

Deep brain stimulation of the medial septum or nucleus accumbens alleviates psychosis-relevant behavior in ketamine-treated rats

Deep brain stimulation (DBS) has been shown to be effective for relief of Parkinson's disease, depression and obsessive-compulsive disorder in humans, but the effect of DBS on psychosis is largely unknown. In previous studies, we showed that inactivation of the medial septum or nucleus accumbens normalized the hyperactive and psychosis-related behaviors induced by psychoactive drugs. We hypothesized that DBS of the medial septum or nucleus accumbens normalizes the ketamine-induced abnormal behaviors and brain activity in freely moving rats. Male Long-Evans rats were subcutaneously injected with ketamine (3 mg/kg) alone, or given ketamine and DBS, or injected with saline alone. Subcutaneous injection of ketamine resulted in loss of gating of hippocampal auditory evoked potentials (AEPs), deficit in prepulse inhibition (PPI) and hyperlocomotion, accompanied by increased hippocampal gamma oscillations of 70-100 Hz. Continuous 130-Hz stimulation of the nucleus accumbens, or 100-Hz burst stimulation of the medial septum (1s on and 5s off) significantly attenuated ketamine-induced PPI deficit and hyperlocomotion. Medial septal stimulation also prevented the loss of gating of hippocampal AEPs and the increase in hippocampal gamma waves induced by ketamine. Neither septal or accumbens DBS alone without ketamine injection affected spontaneous locomotion or PPI. The results suggest that DBS of the medial septum or nucleus accumbens may be an effective method to alleviate psychiatric symptoms of schizophrenia. The effect of medial septal DBS in suppressing both hippocampal gamma oscillations and abnormal behaviors induced by ketamine suggests that hippocampal gamma oscillations are a correlate of disrupted behaviors.

Improvements in memory after medial septum stimulation are associated with changes in hippocampal cholinergic activity and neurogenesis.

Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.

Loss of medial septal modulation of dentate gyrus physiology in young mice overexpressing human β-amyloid precursor protein

Mice overexpressing the human mutant β-amyloid precursor protein (hβAPP; PDAPP mice) show deficits in hippocampal-dependent spatial learning and hippocampal short- and long-term plasticity at ages preceding Aβ plaque deposition. We determined whether young PDAPP mice also exhibit alterations in septohippocampal function in vivo, which plays an important role in cognitive function. Electrical stimulation of the medial septum significantly increased neuronal excitability and reduced paired-pulse facilitation in the dentate gyrus. Medial septal-induced facilitation of dentate neuronal excitability was reduced in PDAPP mice. The inhibitory effects of medial septum stimulation on dentate paired-pulse facilitation were also attenuated in PDAPP mice. Young mice overexpressing hβAPP exhibit early abnormalities in neural circuits implicated in cognitive function that may play an important role in the more profound deficits observed in aged PDAPP mice.

Converging inputs to the entorhinal cortex from the piriform cortex and medial septum: facilitation and current source density analysis.

Converging inputs to the entorhinal cortex from the piriform cortex and medial septum: facilitation and current source density analysis. J. Neurophysiol. 78: 2602-2615, 1997. The entorhinal cortex receives sensory inputs from the piriform cortex and modulatory inputs from the medial septum. To examine short-term synaptic facilitation effects in these pathways, current source density (CSD) analysis was used first to localize the entorhinal cortex membrane currents, which generate field potentials evoked by stimulation of these afferents. Field potentials were recorded at 50-micron intervals through the medial entorhinal cortex in urethan-anesthetized rats and the one-dimensional CSD was calculated. Piriform cortex stimulation evoked a surface-negative, deep-positive field potential component in the entorhinal cortex with mean onset and peak latencies of 10.4 and 18.4 ms. The component followed brief 100-Hz stimulation, consistent with a monosynaptic response. CSD analysis linked the component to a current sink, which often began in layer I before peaking in layer II. A later, surface-positive field potential component peaked at latencies near 45 ms and was associated with a current source in layer II. Medial septal stimulation evoked positive and negative field potential components which peaked at latencies near 7 and 16 ms, respectively. A weaker and more prolonged surface-negative, deep-positive component peaked at latencies near 25 ms. The early components were generated by currents in the hippocampal formation, and the late surface-negative component was generated by currents in layers II to IV of the entorhinal cortex. Short-term facilitation effects in conscious animals were examined using electrodes chronically implanted near layer II of the entorhinal cortex. Paired-pulse stimulation of the piriform cortex at interpulse intervals of 30 and 40 ms caused the largest facilitation (248%) of responses evoked by the second pulse. Responses evoked by medial septal stimulation also were facilitated maximally (59%) by a piriform cortex conditioning pulse delivered 30-40 ms earlier. Paired pulse stimulation of the medial septum caused the largest facilitation (149%) at intervals of 70 ms, but piriform cortex evoked responses were facilitated maximally (46%) by a septal conditioning pulse 100-200 ms earlier. Frequency potentiation effects were maximal during 12- to 18-Hz stimulation of either the piriform cortex or medial septum. Occlusion tests suggested that piriform cortex and medial septal efferents activate the same neurons. The CSD analysis results show that evoked field potential methods can be used effectively in chronically prepared animals to examine synaptic responses in the converging inputs from the piriform cortex and medial septum to the entorhinal cortex. The short-term potentiation phenomena observed here suggest that low-frequency activity in these pathways during endogenous oscillatory states may enhance entorhinal cortex responsivity to olfactory inputs.

Piriform cortex efferents to the entorhinal cortex in vivo: kindling-induced potentiation and the enhancement of long-term potentiation by low-frequency piriform cortex or medial septal stimulation.

The entorhinal cortex receives input from many cortical areas and mediates the flow of information between these sites and the hippocampal formation. Long-term synaptic plasticity in cortical efferents to the entorhinal cortex may contribute to the transmission of neural activity to the hippocampus, as well as the storage of information, but little is known about plasticity in these pathways. We describe here the use of evoked field potential recordings from chronically implanted electrodes in the rat entorhinal cortex to investigate synaptic plasticity in the large piriform (olfactory) cortex projection to the superficial layers of the entorhinal cortex. Both kindling-induced potentiation and long-term potentiation (LTP) were tested. In addition, we attempted to modulate LTP induction by the co-induction of frequency potentiation and by the co-activation of the medial septum. Epileptogenic kindling stimulations of the piriform cortex (1-s, 60-Hz trains 3 times/day for 5 days) were found to result in a reliable potentiation of field responses evoked by piriform cortex test pulses. Non-epileptogenic tetanization of the piriform cortex with 400-Hz 16-pulse trains reliably resulted in LTP effects. These effects could be augmented by embedding brief LTP induction stimuli within 11-pulse, 15-Hz trains that alone produce only frequency potentiation. Co-activating the medial septum with 10-Hz trains, just prior to tetanization of the piriform cortex, augmented LTP of piriform cortex inputs to the entorhinal cortex in an input-specific manner. All potentiation effects were found to last for periods of weeks. These findings demonstrate that both epileptogenic and non-epileptogenic piriform cortex stimulation induces lasting potentiation of population field responses in the entorhinal cortex of the awake rat. The LTP effects were inducible in a graded manner and were sensitive to the temporal context of stimulation. The finding that low-frequency activation of the septum can enhance plasticity in the entorhinal cortex adds to a body of data indicating a role for the medial septum in contributing to theta activity and plasticity in both the entorhinal cortex and hippocampal formation.

Relationships between septo-hippocampal cholinergic activation and the improvement of long-term retention produced by medial septal electrical stimulation in two inbred strains of mice.

This experiment was designed to highlight the relationships between septo-hippocampal cholinergic activation and the processing of memory consolidation. For that purpose, we have analyzed the consequences of a medial septal electrical stimulation (100 Hz, 30 microA) applied soon after partial acquisition session of an appetitive operant conditioning task on in vivo hippocampal cholinergic activity on the one hand and on subsequent retention 24 h later on the other hand. For maximize our data base for such comparison we used two neurochemically and behaviorally distincts strains of mice, BALB/c and C57BL/6. In these conditions, our results showed that BALB/c mice evidenced better performance in retention than C57BL/6 mice after medial septal stimulation. On the other hand, the stimulation applied in resting conditions produced a moderate and similar hippocampal cholinergic activation in the two strains. Moreover, in BALB/c mice the only strain which exhibited good consolidation capacities the stimulation do not induced any additive effect on the substantial increase of the hippocampal cholinergic activity produced by the previous acquisition session. Finally, a correlative study realized in C57BL/6 mice seems to indicate that the higher the hippocampal cholinergic activity was the lower were the consolidation capacities. These results lead us to suggest that the improvement of memory consolidation induced by the medial septal stimulation is the consequence of the recruitment of non cholinergic elements located close to the electrode tip. Consequently the septo-hippocampal cholinergic activation is more likely to facilitate certain information processes prior to the consolidation mechanisms proper.

Post-training medial septal stimulation improves spatial information processing in BALB/c mice

The experiment reported here was designed to highlight the effects of medial septal nucleus electrical stimulation on memory processes. To that end, we have used a learning task carried out in a 4-hole board in which animals were successively presented with the location of 2 baited holes. Under these conditions, the consequence of a weak stimulation (30 microA peak to peak, 80 s in duration) applied 30 s after acquisition of these 2 separate spatial informations was assessed on a retention test 24 h later. The results indicated that performance of stimulated animals was improved by medial septal stimulation as shown by an increase in the time duration of exploration of the second previously baited hole. However, post-training stimulation also produced a significant avoidance of the first previously baited hole not observed in the control groups. These results suggest that medial septal stimulation improves retroactive inhibition involved in working memory processes, thus leading to better retention of this kind of learning situation.

Stimulation of the lateral septum is a more effective conditioned stimulus than stimulation of the medial septum during classical conditioning of the eye-blink response.

Eight rabbits were trained in the classically conditioned eye-blink response procedure using stimulation of the septal nuclei as the conditioned stimulus (CS). Each rabbit was trained with both medial septal stimulation and lateral septal stimulation. Stimulation of the medial septum was a far less effective CS than stimulation of the lateral septum. This effect may be due to the different roles of these two nuclei in classical conditioning. Conditioning using lateral septal stimulation as a CS is dependent on the cerebellar interpositus nucleus as is conditioning using peripheral and other brain stimulation CSs.

Chemical modulation of ephaptic activation of CA3 hippocampal pyramids

In rats under urethane anaesthesia, antidromic population spikes were evoked in CA3 pyramidal layer by fimbrial/commissural stimulation at a very low frequency (~ 0.5 Hz). Submaximal population spikes — between 20 and 90% of maximum — were enhanced by 8–38% by applications of acetylcholine and bicuculline, or by medial septal stimulation. Noradrenaline had a less pronounced and regular facilitatory action, whereas γ-aminobutyrate and glutamate only depressed population spikes. Maximal enhancement by acetylcholine or bicuculline was observed when the antidromic population spike was initially at 38–53% of maximum amplitude. A simple explanation of these results is that acetylcholine and bicuculline, by raising their excitability, facilitate the excitation of non-invaded pyramidal cells by antidromic field potentials. They are fully in keeping with previous intracellular observations on ephaptic interactions between CA3 neurons, and provide a further illustration, in situ, of the importance of increased excitability and disinhibition—whether caused by drugs or synaptic action—in promoting synchronized excitation by ephaptic currents.

Modulation of inhibition in the hippocampus in vivo.

The nature and mechanisms of septohippocampal transmission have been elucidated by taking advantage of an in situ preparation in experiments with Sprague-Dawley rats under urethane. Both extracellular field potentials and intracellular recordings were made in CA1-3 regions of the hippocampus; and the hippocampal commissure and medial septum stimulated to evoke synaptic activity. Using muscarinic and nicotinic agonists and antagonists it was shown that both acetylcholine and medial septal activity can increase the excitability of pyramidal cells, mainly through muscarinic receptors. The effect of septal stimulation was enhanced by local application of physostigmine and reduced by intraventricular injections of hemicholinium. It was also shown that acetylcholine, when applied in the stratum pyramidale, can reduce the voltage and conductance changes observed during evoked inhibitory postsynaptic potentials (IPSP) without affecting the action of gamma-aminobutyric acid on membrane conductance and voltage. It is therefore proposed that acetylcholine can reduce evoked IPSPs through presynaptic inhibition. Evidence is also presented that medial septal stimulation can reduce the efficacy of evoked IPSPs. These observations provide further support for the existence of a cholinergic septohippocampal pathway.

Medial septal projections to the dentate gyrus of the rat: electrophysiological analysis of distribution and plasticity.

Previous electrophysiological experiments in rabbits have suggested that medial septal stimulation activates dentate granule cells and evokes an associated negative field response at the granule cell layer, without an associated "dendritic" response. Anatomical studies have suggested that septal input to the granule cells may be to stratum moleculare, or close to the cell layer, or may not exist at all. The present experiments confirmed in rats anaesthetised with urethane that medial septal stimulation elicits single action potentials from cells in the granule layer. The associated negative field potential was maximal in the granule cell layer and there was no sign of a separate dendritic potential. The fibres responsible for this potential travel to the dorsal hippocampus in the fornix superior rather than the fimbria, taking the same course as the fibres which contribute to the dense cholinesterase staining just above the granule cell layer. Stimulation at 100 Hz for 1 s of either medial septal, or perforant path, input to the dentate granule cell layer produced long term potentiation of the subsequent evoked field responses to the stimulated pathway. The responses to the non-stimulated pathway were unchanged. Paired pulse stimulation produced both homosynaptic and heterosynaptic potentiation. These data suggest that medial septal input synapses close to granule cell bodies and produces a negative field potential which is a combination of dendritic and population spike potentials. Medial septal input also appeared to produce direct activation of hilar neurones, some of which may be basket cells or other interneurones. The data also show that long term potentiation is specific to this input, perhaps dependent on presynaptic mechanisms. Paired pulse potentiation, at least in the heterosynaptic case appears to depend on postsynaptic mechanisms.

Intracellular recordings from rat dorsolateral septal neurons, in vitro

We have made intracellular recordings from the dorsolateral septal nucleus (DLSN) in a rat brain slice. DLSN neurons fire short tetrodotoxin (TTX) sensitive action potentials followed by an after-hyperpolarization. The action potential is followed by either a Ca 2+-dependent depolarization or a Ca 2+-dependent after-hyperpolarization. Stimulation of medial septum results in antidromic invasion of DLSN neurons while stimulation of the fimbria/fornix results in orthodromic EPSPs or action potentials.

Inhibition of spinal dorsal horn neuronal responses to noxious skin heating by medial preoptic and septal stimulation in the cat : J. Neurophysiol., 48 (1982) 981–991

Inhibition of spinal dorsal horn neuronal responses to noxious skin heating by medial preoptic and septal stimulation in the cat : J. Neurophysiol., 48 (1982) 981–991

Differential effects of medial forebrain bundle lesions on adrenocortical responses following limbic stimulation

Adult male rats had electrolytic lesions placed bilaterally in the medial forebrain bundle and were subsequently implanted with stimulating electrodes in one of the following limbic regions: (1) dorsal hippocampus; (2) ventral hippocampus; (3) medial septal nucleus; (4) basolateral amygdala; (5) mesen cephalic reticular formation. Following electrical stimulation, blood was drawn by acute venesection, under ether, for plasma corticosterone determinations. In non-lesioned animals, electrical stimulation in all of the limbic regions led to elevated plasma corticosterone levels. In rats with lesions in the medial forebrain bundles, the adrenocortical response to stimulation in the dorsal hippocampus, the basolateral amygdala or the reticular formation was markedly attenuated. On the contrary, the same lesions were without effect upon the corticosterone secretory response to medial septal stimulation, and had only a slight inhibitory effect upon the response to electrical stimulation in the ventral hippocampus. The results demonstrate that the medial forebrain bundle plays a major role in the transmission of impulses to the mediobasal hypothalamus, originating in the dorsal hippocampus, basolateral amygdala or mesencephalic reticular formation, which activate adrenocortical secretion; its role in the transmission of cues arising in the ventral hippocampus or medial septum is, however, minor.

Inhibition of spinal dorsal horn neuronal responses to noxious skin heating by medial preoptic and septal stimulation in the cat.

1. Responses of single lumbar dorsal horn units to controlled noxious radiant heating of glabrous hindfoot skin were recorded in cats anesthetized with sodium pentobarbital and 70% N2O. The heat-evoked responses of all units studied were markedly suppressed during concomitant electrical stimulation (mean, 30 Hz; 25-300 microA) of medial preoptic and ventromedial septal areas. 2. Brain sites at which stimulation inhibited spinal neuronal heat-evoked responses were mapped by systematically varying the depth of the stimulating electrode in tracks at anteroposterior levels +14 through +18. At each stimulation site, the magnitude of the spinal neuronal response to heat (50 degrees C, 10 s, 1 per 3 min) during brain stimulation was expressed as a percentage of the control response (no brain stimulation), which was stable in size over repeated trials. Sites at which stimulation markedly reduced the heat-evoked response were located in the medial preoptic area and in the ventromedial septum (diagonal band of Broca) up to anterior level +17. 3. The magnitude of inhibition increased with graded increases in brain-stimulation intensity. For 15 units, the mean current threshold to generate inhibition was 25 microA. 4. Responses of dorsal horn neurons to a series of graded noxious heat stimuli increased linearly from threshold (40-45 degrees C) to 52 degrees C. The slopes of such linear temperature-response curves were significantly reduced, without a change in the response threshold, when the temperature series was repeated during concomitant preoptic or septal stimulation. 5. The possible relationship of the medial preoptic and septal areas to inhibitory systems in the brain stem, and their possible role in analgesic mechanisms, are discussed.