Electrical Stimulation Of The Brain Research Paper

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Direct electrical stimulation of brain tissue, in both animals and humans, has proven over more than a century of experimentation to be a truly powerful tool for revealing functional relations between brain and behavior as well as connections within the brain. Various sorts of current have been delivered through electrodes that are either applied acutely to localized brain regions or chronically implanted deep within the brain or on its surface. This research paper will describe experimental studies that have used animal models in laboratory settings, and clinical studies in which human patients have received electrical stimulation of the brain (ESB) in order to observe its effects, including especially possible therapeutic effects.

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1. Brain Stimulation And The Elicitation Of Motor Responses

In the late nineteenth century, pioneering experiments mapped motor functions of mammalian cerebral cortex using ESB (e.g., Fritsch and Hitzig 1870). These investigators, using dogs, were able to elicit discrete motor responses of specific muscles and muscle groups by applying brief electrical stimuli directly upon the exposed cortical surface. These studies laid the empirical foundation for our current understanding of topographic motor maps on the brain’s surface; later work filled in the outline provided by these early investigations. Central concepts began to emerge that eventually shaped current thinking about brain function and guided much later research. These include the notion of functional localization within brain structures, an idea originally set forth in the pseudoscientific ideas of phrenology. With the contributions of Fritsch and Hitzig (and others), however, a valid basis was afforded for specific types of localization. Not only was the frontal region of mammalian cortex recognized as a major source of neural output controlling responses of the striate musculature, but this region was observed to contain a map which was topographic in nature; that is, adjacent muscle groups are represented in adjacent groups of neurons. Furthermore the principles of both proportional and contralateral representation became apparent. Muscle groups capable of relatively finely calibrated, skilled movements (e.g., digital and some facial muscles) are represented by very much larger populations of neurons than muscles capable only of grosser movements, so that there is a topological distortion within the topographical map (proportional representation); also, cortical motor neurons in each of the brain’s hemispheres exert their influence over muscles on the opposite side of the body (contralateral representation).

2. Brain Stimulation And Perceptual Prostheses

Analogous concepts have been developed for the cortical representation of somatosensory responses originating at the skin: topographical maps exist on each cortical hemisphere representing the contralateral side of the body’s surface, with topological distortions similar to those of motor cortex, but corresponding instead to differences in sensory acuity, with the digits and some facial areas over-represented in terms of quantity of neural tissue involved. The somatosensory maps have been localized to the central and posterior parts of the cortex (in humans, the parietal lobe). Auditory and visual maps have also been studied in detail; the two halves of the visual field (left and right), for instance, are mapped onto the contralateral cortical hemispheres in the most posterior part of the cortex (in humans, the occipital lobe). Although multiple maps exist, the principle of proportional representation is clearly evident in the primary map, where the areas of greatest acuity (at and near the fixation point) are greatly over-represented compared to peripheral parts of the visual field.

Since it is widely accepted that all sensory responses are due to some unique pattern of electrical activity in the corresponding sensory cortex, it has been evident for some time that, in theory at least, an appropriate pattern of ESB within any sensory region of cortex might be arranged to mimic any specific normal, exteroceptive pattern of sensory stimuli in the corresponding modality. The possibility thus exists of developing prostheses for artificial vision or hearing, for example, using brain stimulation to evoke perceptual responses in persons lacking functional peripheral receptors or even sensory nerves.

Considerable exploratory work has been done on these problems, although practical prostheses based on ESB are not at the moment close to realization. A promising approach developed recently involves the implantation of relatively large (30–100) arrays of microelectrodes arranged to deliver ESB to the auditory or visual parts of cortex. For instance, cats trained to lever-press to an external auditory stimulus will respond similarly to very modest levels of ESB delivered over an array of microelectrodes implanted within auditory cortex (Rousche and Normann 1999); furthermore, patients with profound or total bilateral hearing loss may receive acoustic information through stimulation of electrodes implanted in the auditory regions of the brainstem (Laszig and Aschendorff 1999). By the same token, visual responses have been demonstrated in a blind patient receiving intracortical ESB over an array of electrodes implanted in the occipital lobe (Schmidt et al. 1996).

3. Brain Stimulation And Associative Learning

Since the 1980s a major neuronal network has been delineated, responsible for much of what memory theorists call ‘procedural learning’ (e.g., Thompson and Kim 1996). The elements of this network specifically responsible for plasticity and associative learning are located within the cerebellum, and include the mossy and climbing fiber systems afferent to (providing information for) intracerebellar structures; the cerebellar cortex, especially its Purkinje cells and their inputs and output; and the deep cerebellar nuclei, especially the anterior interpositus nucleus. A useful model that has frequently been used to study this network is the classical conditioning of eyeblink and other discrete motor responses in the rabbit: a neutral or conditioned stimulus, the CS, which does not initially elicit a response, is paired repeatedly with an eyeblink eliciting stimulus (the unconditioned stimulus or US), usually a brief airpuff delivered to the cornea. After 100–200 trials the CS acquires the property of eliciting the eyeblink (associative learning or acquisition). If the rabbit is subsequently exposed to repeated CS presentations in the absence of the US, the conditioned response weakens and eventually disappears, in a process referred to as extinction. An appealing feature of this preparation involves the similarities seen here between human and animal learning. The form of the response, the curves of both learning and extinction, and certain more detailed aspects such the timing of the response within each trial and the changes in timing that are seen as conditioning proceeds, are all quite similar when comparing rabbits and humans. It is generally accepted that this particular form of conditioning, which is simple and readily adapted for well-controlled laboratory studies, shares many features with human learning of motor skills, including both simple and complex motor learning and performance.

Validation of the role of these cerebellar network elements and circuits in associative learning has involved the application of numerous neurobiological approaches in both animals and humans. The use of ESB to selectively activate the specific cerebellar neuronal networks involved in procedural learning has been particularly fruitful (e.g., Thompson et al. 2000). The earliest use of brain stimulation to demonstrate the direct involvement of the cerebellum in learning was reported by Brogden and Gantt, who showed that a variety of motor responses, including eyelid closure, forelimb and hindlimb flexion, head turn, and pinna movement elicited by electrical stimulation of cerebellar white matter (chiefly in lobule HVI) were readily conditioned to auditory and visual CSs, using conventional stimulus pairing procedures of classical (Pavlovian) conditioning (Brogden and Gantt 1937, 1942). Recent experiments have been aimed at identifying and characterizing more closely the relevant pathways, using electrical microstimulation delivered over chronically implanted semimicroelectrodes in the awake, behaving rabbit during conditioning. For instance, ESB of the inferior olive, which elicits specific motor responses, substitutes effectively for the unconditioned stimulus when paired with a CS in classical conditioning, thereby lending support to the role of olivary efferent pathways (climbing fibers) in providing information about the unconditioned stimulus. By the same token, studies of the conditioned stimulus pathway have established that ESB delivered to either the pontine nuclei or the middle cerebellar peduncle, activating the mossy fiber projections to cerebellum, serves the same function as the tone that has long been used in conventional eyeblink classical conditioning. Steinmetz et al. (1989) combined these effects in a single preparation, and showed that conditioning is reliably obtained using pontine ESB as the CS and olivary ESB as the US, dispensing altogether with exteroceptive stimulation.

In subsequent experiments associative learning has been shown in a preparation in which both CS and US are delivered directly to, and confined within, the cerebellum. Four chronic stimulating electrodes are implanted in rabbit cerebellum, one bipolar pair in cerebellar cortex, providing an electrical CS activating cortical parallel fibers and thence Purkinje cells, and another bipolar pair in underlying white matter of lobule HVI, delivering an electrical US that elicits unconditioned responses. Paired CS–US presentations lead reliably to the development of conditioned responses; after conditioning is established, repeated presentations of the CS alone lead to extinction as in conventional conditioning. Also, increased local excitability is observed in cerebellar cortex following conditioning; that is, the threshold for eliciting responses to ESB delivered over the CS electrode is significantly decreased after conditioned responding is well established. Pseudorandom unpaired presentation of CS and US does not produce any CRs, indicating that true associative learning, and not sensitization, is responsible for these results (Shinkman et al. 1996).

Furthermore, associative learning that is localized within the cerebellar cortex has been demonstrated in exploratory studies, discussed in Thompson et al. 2000). These investigators delivered ESB over a single bipolar electrode implanted in the Purkinje cell layer of cerebellar cortex and used this stimulation both as the CS (very low-level stimulation that does not elicit any response) and as the US (higher-level stimulation through the same electrode that reliably elicits a discrete unconditioned motor response). When paired CS–US trials are followed by CS-alone trials, in a paradigm formally identical to a standard classical conditioning protocol, both acquisition and extinction of conditioned responses is observed, and following conditioning there is increased local excitability in cerebellar cortex (the threshold for response elicitation decreases). The effects of highly localized blocking of neuronal activity have also been studied in this preparation, using intracerebellar injections of muscimol, a substance that reversibly inactivates the firing of neurons in the immediate vicinity of the injection. The expression of previously established conditioned responses is blocked by injection of muscimol into the region surrounding the electrodes, but occurs normally in the absence of muscimol. Because muscimol affects only neuronal cell bodies, and does not influence fibers of passage, it can safely be concluded that its presence has no remote effects other than those attributable to the lack of output from the region of inactivation. These results suggest that the observed plasticity involved in classical conditioning depends upon changes in the interaction between neuronal elements in cerebellar cortex, especially parallel fibers and Purkinje cells, and in the deep cerebellar nuclei.

4. Brain Stimulation As Reward: ‘Pleasure Centers’ In The Brain

In 1953 James Olds, a postdoctoral fellow at McGill University in Montreal, was studying behaviors elicited in rats by the application of ESB. He was using a relatively new technique in which stimulating electrodes are chronically implanted under surgical anesthesia so that stimuli can be delivered at specified locations in the brain while the subject is awake, relatively unencumbered, and engaging in ongoing behaviors. Although the focus of these experiments was on behaviors directly elicited by the stimulus, Olds had the remarkable insight, based upon some of his subjects’ behaviors, that the stimulus was in some cases apparently rewarding (or, more technically, reinforcing) whatever behavior immediately preceded the application of the stimulus. That is, in B. F. Skinner’s terminology, the stimulus was serving a ‘reinforcing’ rather than an ‘eliciting’ function. Olds quickly undertook a series of experiments to verify this intuition, and ascertained that in specific subcortical regions (e.g., lateral hypothalamus, septal area), ESB can exert powerful reinforcing effects (Olds and Milner 1954).

In terms of potency, the reinforcing effects of ESB delivered using appropriately placed electrodes far outweigh those of conventional (i.e., biological or adaptive) reinforcers. To establish that this was so, Olds unearthed a long-forgotten apparatus called the Columbia Obstruction Box, which had been used in the 1930s at Columbia University in an ill-conceived attempt to ‘compare motives.’ Rats were placed on a platform separated by an electrified grid from a goal. In the original experiments, the amount of footshock the subject would tolerate to reach the goal was compared for deprived rats responding for, e.g., water, food, or sex (the flaw here, of course, is that deprivation levels for different goals do not fall on the same metric). Nevertheless, levels of footshock absorbed by implanted rats to reach rewarding ESB far exceeded those for all other reinforcers, including the previously top-ranked one—access for a mother rat to her newborn pups.

An enormous literature on various aspects of this extraordinary finding emerged over subsequent decades. A particularly intriguing line of experimentation has linked rewarding ESB with the reinforcing properties of addictive substances such as cocaine and opiates. It has now been established that the rewarding effects of ESB may be augmented or potentiated in the presence of such substances. Indeed, it appears likely that addictive substances and rewarding ESB may both exert their reinforcing effects upon a variety of behaviors by activating the same neural circuits involved in the brain’s response to conventional or natural reinforcers (e.g., Wise 1996).

5. Brain Stimulation In Human Patients

Electrical stimulation of the brain through chronically implanted electrodes, with the aim of alleviating various symptoms in human patients, has been used infrequently but to considerable effect since the 1950s. Early studies (e.g., Heath and Mickle 1960, Mark and Ervin 1970) focused on very severe affective disorders. In at least some patients, it was shown that symptoms including violent or inappropriately aggressive behavior could be triggered by stimulation of certain limbic structures, notably the amygdala, and abolished or prevented by ablation (removal) of these structures or by stimulation of regions (e.g., the septal area) whose activity is mutually antagonistic to amygdaloid excitation.

Recent studies have concerned a variety of other disorders, including conditions as diverse as Parkinson’s disease, multiple sclerosis, intractable epilepsy, and chronic pain. It is now well established, for instance, that stimulation of certain parts of the human motor nervous system, collectively designated as the extrapyramidal system, can lead to dramatic improvement in the motor disorders experienced by patients suffering from Parkinson’s disease. In this case the stimulation serves to functionally block the abnormal activity of these brain regions; although similar effects can be achieved by ablation, the use of ESB is clinically preferable (e.g., Montgomery 1999), because it is reversible, readily calibrated and adjusted, and may avoid such side effects as cognitive impairment.

While studies of the clinical efficacy of ESB in reducing or abolishing chronic pain have yielded conflicting results, the most common finding has been an impressive reduction of symptoms and a corresponding increase in patients’ quality of life (e.g., Young et al. 1985). This particular application, like many others, has its origins in the animal experimental literature. It is interesting to note that some of the most effective electrode placements in human pain patients (e.g., brainstem periaqueductal and periventricular gray matter) correspond to regions where stimulation had been shown much earlier to be both rewarding and analgesia-producing in rats.

Newer stereotaxic techniques allow for guided, precise electrode placement; at the same time, advances in electrode technology permit the application of highly localized, parametrically controlled stimulation. It seems reasonable to expect that clinical applications for ESB will continue to expand, and that directions for such expansion will continue to be informed by basic experimentation on the effects of ESB in laboratory animals.


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