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One of the earliest and most frequently employed experimental research methods used to investigate how the brain is involved in controlling behavior and behavioral processes involves ablation (removing) or lesion (destruction or functional disruption) of brain structures or areas. While considerable information has been obtained regarding brain-behavior relations from clinical cases where the damage is a result of either head injury, tumor, vascular problems, brain surgery, or disease, the nature and extent of the damaged and aﬀected areas in humans are diﬃcult to determine and often are not known. By employing laboratory animals and experimental lesion approaches, it is possible to obtain more precise and localized damage to the brain. Further, with the use of animal-testing techniques any changes in behavior can be carefully determined, the brains can then be obtained for detailed histological analysis, and the actual damage to the brain can be subsequently correlated with changes in behavior. Thus, by using the lesion approach together with experimental animals to study brain function, meaningful conclusions can be drawn regarding the relationship that exists between speciﬁc areas of the brain and how they are involved in behavior (e.g., localization of function).
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1. Localization Of Function
Issues surrounding the extent to which control of various behaviors is localized in speciﬁc brain areas have been around for many centuries (see Corse 1991). It was the work of Franz Josef Gall (1758–1828) and Johann Casper Spurzheim (1776–1832) that established the theory of phrenology, i.e., the theory that particular parts of the brain controlled separate mental faculties. Speciﬁcally, these early investigators proposed that personality types are related to bumps located in speciﬁc places on the skull. Phrenological theory was spelled out in suﬃcient detail that some components of the theory could be tested experimentally, and not many years passed before Pierre Flourens (1794–1867) developed the technique of damaging the brains of animals to study the changes produced in their behavior. The result was not only the refutation of phrenology, but justiﬁcation for the use of the experimental lesion method in studying and attempting to understand brain function. Localization of function continued to receive considerable attention during the nineteenth century with the discovery by Paul Broca (1824–1880) that a discrete area of damaged cortex interfered with speech, and the demonstration by Gustav Theodor Fritsch (1838–1929) and Eduard Hitzig (1838–1907) that movements of particular parts of the body could be elicited by applying electrical stimulation to speciﬁc regions of the animal and human brain.
One of the most systematic early attempts to use a lesion approach to determine where in the brain a complex behavioral process is controlled can be found in the research of Karl Lashley (1890–1958). Lashley devoted a lifetime of research to what he described as ‘the search for the engram,’ that is, the physical representation of learning or the site in the brain where the trace of the memory of a learned thing is stored. The approach he used involved the training and testing of rats to perform tasks of various levels of diﬃculty, and ablating or using knife cuts to various parts of the cortex either before or after learning. Rather than ﬁnding that memory for learned tasks is localized in speciﬁc areas, Lashley found that the amount of damage to the cortex was more important than which part was removed (Lashley 1950).
2. Lesion Techniques And Procedures
A variety of techniques and procedures have been used to produce selective damage to the brain. In studying the functions of the cortex, early researchers removed large areas on the external surface of the brain by ﬁrst removing a ﬂap of skull, directly exposing the brain, and then excising brain tissue with a knife or with vacuum suction. A similar technique is often used in current research, especially research involving nonhuman primates. While this approach is feasible for the cortex, damaging structures and/or areas that are deep within the brain creates special problems. Systematic exploration of subcortical areas had to wait until 1908, when Sir Victor Horsley and Robert H. Clarke developed the stereotaxic instrument, a device that permits the precise positioning of electrodes deep within the brain. Thus, by carefully implanting electrodes in known locations, investigators could for the ﬁrst time damage, stimulate, or record from areas below the external surface of the brain. One lesion technique that is still used in research involves passing direct current through an electrode that is insulated except at the tip, thus creating a localized area of damaged tissue. A similar technique involves electro-cauterization using high frequency current (e.g., radiofrequency).
A major problem associated with the use of conventional lesions (aspiration, electrolytic, radiofrequency) is that the resulting damage is nonspeciﬁc. Thus, there is frequently loss of cells in adjacent areas, axons that pass through the area of the lesion are interrupted, and the vasculature can be compromised. For this reason, there has been an increase in recent years in the use of intracerebral injections of neurotoxins. By employing stereotaxically placed focal injections, and procedures that minimize the spread of the toxin to adjacent areas, one can limit the damage to the intended structure. Further, most neurotoxins do not damage ﬁbers of passage, aﬀerents that terminate in the area are minimally aﬀected, and the vasculature is spared. Since the resulting damage is speciﬁc, the investigator is in a better position to attribute changes in behavior to damage to a speciﬁc structure.
It is especially helpful that some chemicals are selectively toxic to speciﬁc kinds of neurons. For example, 6-hydroxydopamine is a chemical that resembles the catecholamine neurotransmitters dopamine and norepinephrine. Because of this resemblance, when the toxin is injected into an area it is selectively taken up by the axons and the result is death of the cell. Investigators have used this approach to produce an animal model of Parkinson’s disease.
It was discovered in 1971 by Olney and his colleagues that glutamate, a putative excitatory neurotransmitter, had an excitatory eﬀect on neurons and that high concentrations caused cell death. Several analogues of glutamate have been found that are especially toxic to speciﬁc types of cells. For example, when kainic acid is injected peripherally, the result is behavioral convulsions accompanied by the loss of speciﬁc cell populations within the brain. Focal injections of kainic acid directly into some brain structures also result in a loss of cells, not only of neurons at the site of injection, but distant damage that is thought to be mediated by seizure Activity. Because one population of cells that is especially sensitive to kainate damage is found in the hippocampus, the toxin has been used in a number of behavioral experiments concerned with learning and memory.
A number of other glutamate analogues have been found that produce restricted damage when injected directly into brain structures. Foremost among these is ibotenic acid, a toxin extracted from the mushroom Amanita muscara. This toxin not only produces discrete and circumscribed lesions at the site of injection, but it does this in most structures without causing seizures and without damaging either axons of passage or aﬀerents that terminate in the area (Jarrard 1991). Because of the axon-sparing properties, both ibotenic acid, and a similar analogue n-methyl-d-aspartate, have been used to produce restricted damage in a number of experiments involving both rodents and monkeys.
A recent approach used to produce brain lesions with greater selectivity involves suicide transport and immunolesioning techniques (Wiley 1992). In both of these techniques cytotoxins are targeted to restricted groups of neurons. Suicide transport involves the axonal retrograde transport of toxic lectins from the site of injection back to the cell body with the resulting destruction of the neuron. Monoclonal antineuronal antibodies are used in immunolesioning techniques to deliver cytotoxins selectively to only those neurons that have surface characteristics recognized by the antibodies. An advantage of immunolesioning is that the toxins not only destroy a speciﬁc type of neuron at the site of injection but the toxin is transported in a retrograde direction back to the cell body from the injection site. While these newer approaches oﬀer considerable promise, there are a number of potential problems associated with using these extremely toxic chemicals in the laboratory.
Still another lesion approach that has been developed only recently involves the gene-knockout approach. By using biochemical methods to direct a mutation at a particular gene, one can destroy or alter widespread systems of cells or subsystems within cells.
All of the lesion approaches described above produce permanent damage to the brain. A technique that oﬀers considerable promise is the focal injection of drugs that temporarily inactivate brain cells. The most direct way to produce a temporary, reversible brain lesion is to inject a local anesthetic (such as lidocaine) into the area of interest. However, local anesthetics not only inactivate brain cells at the point of injection but they also disrupt the Activity of axons passing through the area. Thus, the overall eﬀect is similar to that found with the use of conventional lesion techniques, except that the eﬀect with local anesthetics is reversible. It was reported recently that injection of a newly-developed glutamate receptor antagonist temporarily inactivated the cells at the point of injection without disrupting ﬁbers of passage (Riedel et al. 1999). With the development of new drugs that have temporary eﬀects on speciﬁc transmitter systems the use of temporary inactivation as a reversible lesion will no doubt increase.
3. On Interpreting The Behavioral Eﬀects Of Lesions
Correctly interpreting the eﬀects on behavior of damage to speciﬁc brain structures requires an understanding and appreciation of a number of potential problems. Since a change in behavior following damage to the brain can be caused by unwanted eﬀects on sensory system functioning (e.g., vision or olfaction), the motor system, attention, motivation, etc. it is important to eliminate as many of these explanations as possible by carefully designing the experiment. Over the years, scientists have devised a number of control procedures that take into account these interpretative problems. Thus, the typical lesion experiment includes not only a group of unoperated animals to serve as controls, but also a group of animals that have sham lesions, e.g., that undergo the same surgical intervention as animals in the experimental lesion group except the structure of interest is not damaged. If it is observed in subsequent testing that the behavior of the animals with the brain lesion is diﬀerent from that of the sham-operated and control animals, then one can be more conﬁdent that the structure of interest caused the observed behavioral deﬁcit.
In order to eliminate other possible explanations for an observed behavioral change following brain damage, investigators often employ an experimental design to test for double dissociation of function. In this type of design lesion 1 impairs behavior A but not behavior B, while lesion 2 (in a diﬀerent region of the brain) impairs behavior B but not behavior A. An example of a double dissociation is when lesion 1 impairs an animal in learning a spatial task (say, learning to swim to a safe platform consistently located just under the surface of the water in a circular tank) but has no eﬀect on learning to discriminate between two visual stimuli, whereas, lesion 2 impairs discrimination learning but has no eﬀect on learning the location of the safe platform. With this type of ﬁnding, it can be concluded that the impairment in learning the spatial task is not caused by changes in attention, visual processes, motor performance, motivation, or several other behavioral processes.
Interpretation of lesion studies is also complicated by the fact that many regions of the brain are interconnected, so that damage in one area may result in morphological, biochemical, and/or physiological changes in areas of the brain not damaged directly by the lesion. Further, following damage to the brain there is often sprouting (or new growth), sparing of function, spontaneous recovery, and indirect eﬀects on other behaviors (see Kolb and Whishaw 1996) that can complicate any interpretation.
While there are potential problems in interpreting the results of lesion studies, there are several advantages that this approach has over other available procedures. First, by developing animal models using lesions, one can attempt to understand better the nature and extent of the brain damage found with various diseases and injury in humans. Second, the speciﬁcs of the lesion can be determined by careful histological study, thus, there is a permanent record of the actual brain damage. Third, by using diﬀerent procedures to study the brain (e.g., recording, functional MRI) one can often determine that several diﬀerent regions seem to be involved in a particular behavior but the question arises regarding whether the structures operate serially or whether they provide separate inputs to a common structure. In this case, lesion studies are required to determine which of these structures are actually necessary for the behavior in question.
4. Behavioral Assay Of Brain Function
Since the brain is designed to produce and control behavior, a careful analysis of changes in behavior following brain lesions is the ultimate assay of brain function. Early investigators, using lesion techniques and behavioral testing procedures available at the time, made important discoveries regarding regions of the brain that are involved in controlling such important behaviors as emotions, motivation, and learning and memory. For example, it was discovered in 1939 that bilateral ablation of the anterior temporal lobes in monkeys led to dramatic behavioral changes where previously wild and aggressive monkeys failed to display normal fears and anxieties. It is now known that the amygdala plays a crucial role in such emotions, especially fear and anxiety. By using more sophisticated lesion techniques it has been possible to identify the underlying brain circuitry. In 1940 Hetherington and Ranson showed that destruction of a region of the hypothalamus using electrolytic lesions produced animals that ate voraciously until they become extremely obese. With the use of selective lesion techniques, it is now known that the hypothalamus is not as crucially involved in the control of eating as these early ﬁndings indicated.
The lesion approach has been used frequently to attack the most basic and challenging problem in the neurosciences, e.g., an understanding of the neural bases of learning and memory. Since the early research of Karl Lashley and ‘the search for the engram,’ the development of more sophisticated lesion and behavioral testing procedures has permitted major advances in this important area of research. In a recent search for the location of the engram, Richard F. Thompson and colleagues (Thompson and Krupa 1994) used a simple behavioral task (Eyelid Classical Conditioning) and a combination of recording and lesion techniques (both conventional lesions and temporary inactivation). By determining which structures changed Activity during learning, then selectively damaging or temporarily inactivating inputs and outputs of the suspected crucial structure, the investigators were able to show that the learning (engram) occurred in a single nucleus within the cerebellum.
Following a report in 1957 of a case of severe anterograde amnesia (e.g., inability to new material and events) following ablation of structures deep within the medial temporal lobes, investigators attempted to understand the neural bases by developing animal models (monkeys, rats). Using monkeys, it was found that aspiration of medial temporal structures resulted in a severe memory problem that was similar in many ways to that found in the clinical case. The structure that was suspected of being responsible for the deﬁcit in both human and monkey was the hippocampus. Research using the rat model generally failed to provide support for a global memory problem that encompassed all types of material, especially when an axon-sparing lesion technique was employed to remove the hippocampus (Jarrard 1993). Subs-equent research with monkeys employing more selective lesions has indicated that the major impairment that was attributed to the hippocampus is, in fact, a result of damage to cortical areas that are adjacent to the hippocampus that were inadvertently damaged during surgery.
5. Future Directions
With the development of new procedures that permit more selective lesions limited to particular structures, types of neurons, or speciﬁc proteins, it is now possible to have a level of lesion control that has been lacking in the past. A similar increase in the level of sophistication in the analysis of behavior and understanding behavioral processes has occurred. While a more complete understanding of brain-behavior relations will necessarily depend on a convergence of results obtained from a variety of approaches used to study the brain, the careful use and interpretation of lesion studies combined with sophisticated behavioral testing procedures will make major contributions to this understanding.
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