José M. R. Delgado

Free Behavior and Brain Stimulation

Publisher Summary Of the methods used to investigate the neurophysiological basis of behavior, perhaps the most direct and dramatic is electrical stimulation of the brain. Direct stimulation of the brain is considered a crude method for the exploration of cerebral functions, and the understanding of the results is limited. The chapter describes methodology for cinemanalysis, telerecording, and telestimulation to study free behavior during brain stimulation. It also demonstrates that spontaneous activities are recorded, identified and quantified, allowing the systematic study of free and evoked behavior on both individual and social levels. The chapter also discusses the types and significance of behavior evoked by brain stimulation in unrestrained subjects and presents a theory of fragmental organization of behavior. Brain stimulation evokes (1) stereotyped tonic or phasic activity without any emotional disturbance, (2) driving activity to reach an objective with a motor performance adapted to the relations between subject and purpose, (3) changes in behavioral tuning that are detected in isolated animals because of the lack of manifestations, but may modify decisively the character of response to normal stimuli, (4) inhibition of spontaneous or evoked behavior, and (5) abnormal effects such as tremor or seizures.

Cerebral Heterostimulation in a Monkey Colony

In an established colony a subordinate monkey repeatedly pr essed a lever which stimulated the caudate nucleus of the boss monkey by radio and inhibited his aggressive behavior. In other experiments, timed stimulations of the posteroventral nucleus of the thalamus of the boss monkey, paired with a tone, increased his aggressiveness and established conditioned escape responses of the whole group. Both types of experiments may be useful in neurophysiological and pharmacological investigations.

Aggression, Noxiousness, and Brain Stimulation in Unrestrained Rhesus Monkeys

Although there are numerous reports of intra- and inter-species aggression elicited by electrical brain stimulation (Adams, 1968; Akerman, 1966; Delgado, 1955, 1966, 1968; Delgado et al., 1968; Heath, Monroe, & Mickle, 1960; Hess, 1957; Holst & Paul, 1962; Phillips, 1964; Roberts, Steinberg, & Means; Wassman & Flynn, 1962), there has been little research (Adams & Flynn, 1966) on the relationship between evoked aggression and reinforcing properties of the electrical brain stimulation (EBS). By determining the reinforcing properties of EBS, it is possible to differentiate between, what we have called, primary and secondary aggression. Primary aggression could be elicited by EBS through cerebral mechanisms which are independent of aversive sensations. Secondary aggression could be elicited by EBS or peripheral stimuli which first produce noxious sensations which subsequently cause aggression. This distinction is important because secondary aggression has been elicited by peripheral shock in hamsters and several strains of rats (Ulrich, 1966; Ulrich & Azrin, 1962), cats (Ulrich, Wolff, & Azrin, 1964) pigeons (Reynolds, Catania, & Skinner, 1963), and monkeys (Azrin, Hutchison, & Hake, 1963).

PSYCHOLOGICAL RESPONSES IN THE HUMAN TO INTRACEREBRAL ELECTRICAL STIMULATION.

&NA; During interviews, intracerebral electrical stimulation of sharply localized areas in the temporal lobe of a young woman with psychomotor epilepsy consistently produced ego‐alien ideational experiences similar to those observed by Penfield. The responses were associated with considerable anxiety and with evoked electrical seizure activity. The use of the interview as the observational situation and careful study of the interview tape‐recordings made it possible to discover that the content of the ideational experiences was often a function of her prestimulation “mental content.” This finding led to an examination of Penfields formulations and to some alternative hypotheses about mechanisms that might be involved in psychic responses to temporal‐lobe stimulation.

FRAGMENTAL ORGANIZATION OF EMOTIONAL BEHAVIOR IN THE MONKEY BRAIN

The fact that emotional behavior can be evoked in animals by direct electrical stimulation of the brain was demonstrated long ago by Hess (1928) and has been confirmed by numerous investigators (see reviews by Ranson & Magoun, 1939; Hess, 1957; Akert, 1961; Sheer, 1961; Delgado, 1964). It is generally accepted that emotional responses may be elicited by excitation of cerebral structures located from the brain stem up to the forebrain, including the spinothalamic tract, reticular substance, central gray, tectal area, posteroventral nucleus of the thalamus, midline thalamus, hypothalamus, stria terminalis, amygdala, preoptic area, and septum. There is much information available on this subject, but various factors have handicapped the study of emotions. 1. Communication among scientists has been hampered by semantic and conceptual controversies, stemming partly from the lack of unanimity about the meaning of the term “emotion,” and from its intrinsic heterogeneity (Duffy, 1934; Lashley, 1938; Leeper, 1948; Young, 1961; Delgado, 1966a). In spite of these doctrinal issues, the investigation of emotions is possible because of the recurrence of typical patterns of behavioral response which can be observed, recorded, identified, analyzed in time and space, and possibly correlated with intracerebral activity. It is generally accepted that emotions are composed of two elements: individual feelings and expressive manifestations. Recently, we proposed that emotions may be identified by a series of characteristics, including lack of voluntary control, positive or negative reinforcement, motivation and driving properties, lasting modifications of the responsive state, conscious interpretation of sensory inputs, social contagiousness, feedback, nonlinearity of stimulus-response relation, disturbance of ongoing behavior, and dynamic sequences of behavioral categories. A discussion of this subject has been published elsewhere (Delgado, 1966a). 2. Most experiments have been performed in lower mammals, usually rats or cats, which have different and more limited expressive repertoires than monkeys or humans, and in which there may also be important differences in cerebral organization. 3. Most investigators have used anesthetized animals, and in other cases the animals have been either restrained or isolated in small cages. The most important manifestations of emotions, which are related to social behavior, have usually been neglected. 4. Past experiments of electrical stimulation of the brain were generally of short duration and often did not evaluate the influence of changes in the environment or investigate the possible effects of repeated, long-term stimulations.

The application of Delgado's telemetric mobility recorder for human studies.

Since the assessment of psychomotor activity and patterning has been considered of value in the diagnosis of neuropsychiatric syndromes, we have begun to test the applicability of continuous telemetric recording of mobility for clinical investigation. In eight psychiatric inpatients, all-night-sleep electroencephalographic recordings were compared to all-night telemetric counts. Wakefulness, electroencephalographic movement counts, and telemetric counts were significantly correlated to each other. Used in conjunction with all-night-sleep electroencephalographic studies, telemetric measurement of motor activity adds another dimension for assessing the quality of sleep. In addition, the technique should be useful for determining twenty-four-hour motor activity.

Sequential Behavior Induced Repeatedly by Stimulation of the Red Nucleus in Free Monkeys

Rhesus monkeys in a colony were stimulated by means of intracerebral electrodes controlled by radio, for 5 seconds every minute, day and night, for periods up to 14 days. Stimulations of the red nucleus evoked a reliable sequence of behavior including bipedal locomotion, climbing, vocalization, and social interactions. During periods of spontaneous sleep, stimulations produced only a small head movement, but the whole behavioral sequence reappeared as soon as the animal awoke. In monkeys injected with chlorpromazine, the evoked behavior was inhibited in the same way as during spontaneous sleep, while the administration of atropine, Regitine, and Indurol which blocked both sympathetic and parasympathetic systems, produced only minor modifications of the sequential response.

USE OF INTRACEREBRAL ELECTRODES TO EVALUATE DRUGS THAT ACT ON THE CENTRAL NERVOUS SYSTEM

Direct exploration of the brain before and after the administration of substances that act on the central nervous system may help in the understanding and evaluation of their pharmacological effects. Indirect methods, however, have generally been used by previous investigators. For example, in the study of antiepileptics, most of the described techniques are based upon the observation of seizures induced by injected drugs, by electricity applied to the scalp, or by a combination of both. These evoked seizures might then be modified or prevented by the administration of antiepileptic substances (BBriiny and SteinJensen, 1946; Bertrand, Gayet-Hallion, and Quivy, 1949; Chen and Ensor, 1950; Cheymol, 1950; Everett and Richards, 1944; Goodman, Toman and Swinyard, 1949; Merritt and Putnam, 1945; Putnam and Merritt, 1937; Richards and Everett, 1946; Tainter et al., 1943; Toman, 1949; Toman, Everett, and Richards, 1952; Toman and Goodman, 1948; Toman, Swinyard, and Goodman, 1946; Spiegel, 1937; Swinyard, 1949; Woodbury, 1951). These methods were useful in the study and screening of antiepileptic drugs, but they supplied no direct data about the site and mechanism of action of such drugs. I n the brain there are many anatomical structures, with varying excitability and differing pharmacological sensitivity, that may be tested independently in studies of drug action. The technique of permanent implantation of electrodes into the brain, described a few years ago (Delgado, 1949, 1952, 1955) and applied to several physiological problems (Delgado 1952b, 1955b) and psychological studies (Delgado and Rosvold, 1953; Delgado, Roberts, and Miller, 1954) has been used by us in the past 4 years to study some agents that act upon the central nervous system. The technique was useful because it allowed us to make simultaneous exploration of many different points (as many as 40) of the surface and depth of the brain of the same animal, without anesthesia, for periods of several months. In this way, cerebral functions could be explored before and after the administration of a drug, and different drugs could be tested in the same preparation. In this paper, criteria for cerebral exploration of neuropharmacological problems are discussed, and examples of drug action are presented.

Repeated stimulation of amygdala in awake monkeys.

Abstract In 11 rhesus monkeys amygdaloid and hippocampal regions were electrically stimulated for 1.5 sec every 15 sec for periods of from 3 h to 43 days. In most cases the evoked motor responses persisted reliably. Electroencephalographic disturbance were recorded in the first hours of stimulation and disappeared when the experiment was continued for longer periods. Repeated stimulation of 38 out of 53 points in the limbic system did not modify spontaneous behavior. Positive and negative reinforcement induced by sensory or by brain excitation were not affected by repeated amygdala excitation. Repeated stimulation of 15 other limbic points produced a considerable and lasting inhibition, including decrease in spontaneous mobility, in sensory reactivity, and in aggression induced by central gray excitation. In one monkey a smile-like motor response was elicited more than 400, 000 times, inducing hypertrophy of the contracting muscles, and a transitory increase of brain impedance. No histological lesions could be detected in any of the stimulated areas. Feasibility and safety of limbic stimulation for indefinite periods of time are supported by these experiments.

Limbic system and free behavior.

Publisher Summary The purposes of this chapter is to describe (1) methodology and some recent developments for radio stimulation studies, (2) to present experimental material obtained in monkey colonies—and also in monkeys under restraint—during electrical stimulation of the hypothalamus, fimbria of the fornix and amygdala, and (3) to discuss the physiological and psychological implications of these investigations. The knowledge of the limbic system has expanded considerably in the last decade due in part to bridging efforts initiated by physiologists and psychologists to further the correlation of electrical and chemical data with behavioral performance and psychological manifestation. Progress in electron microscopy, microelectrode methodology, and microchemistry has led to important discoveries concerning the submicroscopic properties of membranes, synapses and transmitters which certainly are essential for our understanding of behavioral mechanisms, but it should be remembered that the neuron is only a fraction of the whole organism, and that it is necessary to investigate and to correlate both sides of the scale: the microphysiology and also the physiology of the behaving brain, with its complex electrical, chemical and thermal reactions which are manifested as movements, emotions, worries and pleasures.