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The role of the basal ganglia in procedural memory
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THE NEUROSCIENCES, Vol 8, 1996: pp 39–46
The role of the basal ganglia in procedural memory Steven P. Wise
knowledge.7 Notwithstanding the many problems in defining these terms8 and the circularity inherent in their application to nonhuman animals,7,9-11 many behaviors thus characterized survive extensive damage to the ‘medial temporal lobe’ (see E.A. Murray, W. Suzuki, D. Gaffan, this issue, pp. 13-22, 3-12, 33-38, respectively). Therefore, some other structures must support these relatively automatic and subconsciously mediated behaviors, and it is only natural to speculate that the basal ganglia and its corticostriatal inputs might be important in that regard. The almost immediate acceptance12 and level of enthusiasm for the habit hypothesis is noteworthy. For example, Webster et al (ref 13, p. 87) repeat without reservation the idea that ‘the pathway from inferior temporal cortex to the striatum is part of a circuit that underlies the formation of visuomotor associations, or visual ‘habits’’. Somewhat less definitively, Squire et al (ref 7, p. 475) conclude that ‘recent work suggests that the brain structures important for acquiring skills and habits involve the corticostriatal system’. And Bachevalier (ref 14, p. 468) asserts unequivocally the existence of an ‘early developing cortico-striatal habit system’. One might suppose that such enthusiasm stems from a wealth of empirical data and that the habit hypothesis had, being well and rigorously tested, withstood an onslaught of skeptical experimentation and testing. Examination of the published literature, however, reveals a less convincing body of data.
A common conjecture about the basal ganglia holds that these nuclei and their cortical inputs subserve relatively automatic stimulus–response behavior (habits) and other procedural memories. This speculative hypothesis warrants critical reassessment. No unequivocal evidence supports the assignment of this information-processing specialization to the basal ganglia or its cortical afferents. Key words: striatum / habit / procedure / skill / motor system ©1996 Academic Press Ltd
THE ROLE OF the basal ganglia remains enigmatic despite decades of intensive investigation, partly inspired by interest in such maladies as Parkinson’s (PD) and Huntington’s disease (HD). The principal components of the basal ganglia — the pallidum, the striatum (including the caudate nucleus and putamen), and its catecholaminergic input from the midbrain — appear to be among the oldest and most conservative features of the vertebrate brain.1 Their antiquity, alone, suggests that these nuclei perform functions fundamental to vertebrate behavior. One common speculation is that the basal ganglia subserve relatively automatic responses to sensory inputs, learned or innate.2,3 In this seminar, I will term this conjecture the habit hypothesis of basal ganglia function. Mishkin and his colleagues4-6 first proposed that the basal ganglia and its corticostriatal inputs subserve what they termed ‘habits’. The key features of habitual behavior include a stored association between a stimulus and a response, information that is: (a) slowly learned, (b) relatively stable over time, except under extinction conditions, (c) transferred poorly among effector systems and behavioral contexts, and (d) unavailable to the mechanisms of consciousness. In humans, for whom it is possible to assess conscious awareness through verbal reports and other means, this form of memory has been considered one among many forms of nondeclarative, implicit or procedural
Experimental evidence from nonhuman primates Visual discrimination learning and retention have been reported to be impaired by damage to the tail of the caudate nucleus,15 by lesions of the ventroposterior putamen and environs16 or by disruption of temporal lobe white matter,17,18 which is thought to eliminate corticostriatal (among other) pathways. Deficits in visual pattern discrimination can be due to an inability to learn a response to a stimulus, as assumed for the sake of the habit hypothesis. However, even when problems in perception and visual
From the Laboratory of Neurophysiology, National Institute of Mental Health, P.O. Box 608, Poolesville, MD 20837, USA 1044-5765/96/010039 + 08 $12.00/0
39
S. P. Wise this task, subjects are shown 20 pairs of objects each day. One member of the pair is baited with reinforcement, the other is not. Remarkably, in as few as 10 sessions or so, monkeys can learn to select the baited object on over 90% (of 100) trials (which must be spread, by necessity, over 5 days). Ablation of the medial temporal cortex and subcortex20 does not retard either learning rate or performance on this task. Wang et al19 attempted to lesion the tail of the caudate nucleus because it is the main recipient of visual information from the nonprimary (extrastriate) visual cortex.21,22 According to their abstract, after an attempt to place ibotenic acid into the tail of the caudate bilaterally, monkeys that had learned to discriminate one set of 20 object pairs before the lesions were trained on two additional sets of 20 object pairs. Wang et al report that ‘for each animal, the number of trials required to reach criterion was more than twice that for the initial set of objects’, but that there was no deficit on a standard test of visual recognition memory. At first glance, the report of Wang et al seems to verify the habit hypothesis by establishing a double dissociation: lesions of amygdala, hippocampus and underlying perirhinal cortex cause deficits in recognition memory but not in their test of habit formation; by contrast, striatal lesions cause deficits in habit formation but not in recognition memory. However, closer examination reveals serious flaws in this summary. When viewed from a falsificationist perspective, what Wang et al19 report is, at most, a modest retardation in the rate of acquisition of a very demanding task. Their preliminary findings suggest that there is no deficit in task performance once the discriminations have been learned. Assuming, for the sake of discussion, that the lesions are as intended, the results suggest an interpretation opposite to that reached by Wang et al. What the results reveal, in my opinion, is the dramatic capability in learning object discriminations in monkeys with (presumably) extensive damage to the tail of the caudate nucleus. The brain-damaged subjects reach 90%-correct task performance about half as fast as usual and perform nearly perfectly thereafter, thus demonstrating relatively intact learning and completely intact memory capability. It is interesting to note that the result on the 24-hour concurrent discrimination task appears to be roughly equal to that on the simpler discrimination tasks mentioned above: approximately halving the learning rate. The subtlety of the deficit on the concurrent
recognition memory can be ruled out, several alternative interpretations remain possible. In these tasks, approach or contact of one and only one of two stimuli is rewarded. Accordingly, discrimination deficits could result from a deficiency in learning stimulus-reward associations. Among several nonspecific factors, attentional deficits, especially defects in shifting attentional set (see below) could cause poor performance on visual discrimination tasks. The published studies to date have failed to consider these possibilities. Further, and notwithstanding the assertions of the authors, there has been no systematic effort to make a control lesion interrupting the white matter fiber tracts surrounding the lesion sites, nor any useful histological analysis of the lesions. The impairments, therefore, can be accurately attributed to the tail of the caudate nucleus15 or ventroposterior putamen16 only with difficulty. In addition to the interpretational difficulties noted above, the reported visual discrimination deficits have been modest. Buerger et al16 reported deficits in retrieval of a preoperatively learned visual discrimination. Monkeys with large putamen lesions involving the adjacent white matter showed little postoperative savings of the learned discrimination, but they relearned to a criterion of 90% (of 100 trials) with just 141 errors. Monkeys with smaller lesions showed even less impairment. Divac et al15 attempted to lesion the tail of the caudate nucleus and studied new postoperative learning of a simple visual discrimination. Subjects with tail of caudate lesions learned the discrimination to a criterion of 90% (also of 100 trials) in 492 trials, making 234 errors in the process. There were no control subjects, but lesions involving different parts of the striatum were associated with learning to criterion in about half (44%) that number of trials with about half (also 44%) that number of errors to criterion performance. Thus, the rate of task acquisition, on these visual discriminations at least, appears to be approximately halved after extensive damage to the posterior striatum. All of the lesioned monkeys were able to learn the task and to perform the behavior once learned. The most direct examination of the habit hypothesis appears in a 1990 abstract of unpublished data by Wang et al.19 That abstract contains the claim that lesions of the tail of the caudate nucleus cause deficits in the ‘24-hour concurrent discrimination learning task’, a variant of visual discrimination tasks mentioned above. The study was designed to verify the central prediction of the habit hypothesis: striatal lesions should cause selective deficits on such tasks. In 40
The role of the basal ganglia in procedural memory context of the clinical data, such deficits appear to reflect the persistence of habits (e.g. direct reaching to a visible target), rather than a disruption of them. Accordingly, evidence that basal ganglia dysfunction leads to such perseverative behavior stands against the habit hypothesis, as presently construed.
learning task raises several issues. One concerns whether such a slight deficit should be lumped with a more dramatic one under the rubric of ‘double dissociation’. On one side of the dissociation, medial temporal lobe lesions devastate performance on visual recognition tasks (see E.A. Murray, this issue, pp 13-22). After certain of these ablations, monkeys perform near chance levels when just one minute intervenes between the sample presentation and the choice test. On the other side of the dissociation, after striatal lesions monkeys perform a highly demanding task nearly flawlessly, although they take about twice as long to learn the discrimination. Notwithstanding the difficulties inherent in comparing results across different sets of subjects and tasks, some consideration of the magnitude of the lesion effects seems warranted. Rather than considering such a pattern of results simply as a double dissociation, it seems better to recognize the asymmetry of the deficits. In so doing, one might consider the effect of eliminating some of the visual information that flows through the basal ganglia to the frontal lobe. Regions of frontal cortex usually receive visual information from the posterior striatum through multisynaptic pallidal, nigral and thalamic pathways.23 One might speculate that disruption of these pathways, especially in the context of relatively intact corticocortical visual information flow to the same areas of cortex, somehow causes a mild retardation in discrimination learning rates. In summary, the results reported in abstract form by Wang et al19 suggest that the tail of the caudate nucleus is unnecessary for either the acquisition or performance of the 24-hour concurrent discrimination task, their presumed test of habit formation. Their results appear little different than those obtained earlier with standard tests of visual discrimination learning.15-18 Although the rate of learning is retarded, by about a factor of two, the eventual mastery of visual discrimination and subsequent task performance shows that the lesioned parts of the striatum cannot alone subserve such behavior. The finding of deficits in detour reaching after moderate depletions of striatal dopamine24,25 has also been cited in support for the habit hypothesis, but it fails to provide much. These studies show, as do similar ones involving either prefrontal or premotor cortical lesions,26 that monkeys with localized brain damage persist in reaching directly for a visible reward, even though the movement is blocked by a transparent barrier. Normal monkeys reach around the barrier to obtain a reward. As noted below in the
Clinical observation in Huntington’s and Parkinson’s disease In humans, the evidence most pertinent to the habit hypothesis comes from clinical studies. To summarize the most often cited results, HD and/or PD patients have been reported to have deficits in: reading words projected as mirror images,27 contacting a rotating target with a hand-held stylus,28 solving certain puzzles,29 and speeding reactions based on repeated movement sequences.30,31 These tasks, termed mirror reading, rotary pursuit, Tower of Hanoi (London and Toronto), and serial reaction-time tasks, respectively, are performed relatively normally by amnesics.7,10,11 Accordingly, the behavioral deficiencies of HD and PD patients have been taken to support the habit hypothesis of basal ganglia function.
Procedural tasks In the major clinical papers one can find evidence of procedural learning that has often been neglected in favor of emphasizing statistically significant deficits. I do not mean to imply that the deficits in HD or PD patients are unreliable, but rather that, in addition to significant deficits, it seems likely that significant learning also can be observed. As an outsider in this field, my reading of the published data on HD suggests that the initial procedural learning in these patients is relatively intact or, at least, substantially intact. What distinguishes the procedural learning of HD patients from that of controls is a rapid plateau in acquisition rate; i.e. HD patients begin by learning procedural tasks fairly well, if not completely normally, but level off much more quickly than control subjects. This pattern of deficit might suggest a failure in consolidation rather than in learning or performance abilities per se. Alternatively, patients may learn the tasks in a different way, one that only supports a lower level of performance. Martone et al 27 reported that patients with HD showed deficits in mirror reading. The deficit consisted of a slowing in the time taken to read horizontally inverted text. Over three days of testing 41
S. P. Wise gests a somewhat different summary: the advanced HD patients improved from block-to-block within a testing day, but performed at an inferior level overall. One advanced HD patient, presumably with extensive degeneration of the striatum, improved performance 94%, i.e. the patient approached perfect performance on a task that, according to the habit hypothesis, requires striatal information processing. In the serial reaction-time task, subjects are instructed, by a visual display, to press one of several keys for a series of movements. If the sequence is random, e.g. a random selection among four possible movement targets, reaction time remains fairly constant over the series. If, unbeknownst to the subject, some repetitive sequence structures the order of movements, a speeding of reaction can be observed as the series progresses. Although somewhat controversial, it is generally believed that the speeding of reaction time precedes the explicit recognition of the sequence or even the awareness that there is a sequence. HD patients show less benefit of the sequence structure than normal controls.30,31 In my view, the clinical data cited above do not provide strong support for the habit hypothesis of basal ganglia function or the allied view that the basal ganglia mediate procedural memory. While the prevailing interpretation remains attractive, it has certain problems. If, as hypothesized, the basal ganglia subserve performance based on habits or procedural memory, then one would predict the most automatic and well-learned behavior to be most disrupted by basal ganglia disease. This prediction follows whether the well-learned behavior is a stimulus-response habit, a motor or cognitive skill, or some other reflection of procedural knowledge. Contrary to the prediction of the habit hypothesis, the deficits in mirror reading, rotary pursuit and serial reaction-time tasks can be viewed as resulting from the persistence of automatic behavioral routines rather than a deficiency in them. A deficit in mirror reading could result from the persistence of reading strategies developed from years of experience with noninverted letters. Impaired rotary pursuit performance could represent a persistence of old motor skills (i.e. an inability to adopt new, or modify old, motor programs). The tower-puzzle deficits, likewise, might reflect the perpetuation of poor strategies. And the serial reaction-time deficit might be construed as the persistence of a default response to visual instructions, which built of experience without sequences, is based upon a reaction-time mechanism that HD patients cannot change to take advantage of sequence structure. On this view, the
with unique word triads, HD patients did improve in mirror reading speed, by 11%, but not as much as a control group, which improved by 18%. The deficit in reading unique word triads appeared to result from the HD patients reaching an early performance plateau. In the initial phases of learning this cognitive skill, their performance appeared to parallel that of the controls. Harrington et al32 found no deficits in mirror reading in PD patients. Heindel et al28 reported deficits in HD patients on a rotary pursuit task. As with mirror reading, HD patients show some initial improvement followed by a rapid plateau in performance. It is difficult to determine, since the authors do not report it explicitly, whether that initial improvement is significant. The HD group improved the time-on-target from ~ 27 s in the first block to ~ 32 s (a 19% improvement), whereas the control group stayed on target ~ 41 s (a 51% improvement). These comparisons are compromized by the fact that the investigators had to adjust the target rotation rate to equalize initial performance. In a related study of Heindel et al,33 HD patients showed almost as much initial improvement as elderly control subjects, but reached an earlier performance plateau. The elderly control group improved from ~ 20 s on target to ~ 30 s (a 50% improvement), whereas the HD patients held the stylus on target for ~ 26 s (a 30% improvement) in the second block of trials. In both studies of Heindel et al the concentration on comparing the first blocks of trials to the last block obscured the improvement in performance that had occurred between the first and second blocks. As for PD patients, they showed some deficits in rotary pursuit, but those deficits were much more subtle than in the HD group. In fact, the nondemented PD patients outperformed the elderly control group,33 barely failing to match the middleaged control group (28 s versus 35 s on-target improvement over six blocks). Harrington et al (ref 32, p. 328) found that whereas PD patients and controls ‘showed a similar amount of rotary pursuit learning across blocks [within a day]…, the PD group showed less learning across days’. Butters et al 34 tested HD patients on the Tower of Hanoi puzzle, a test that in one form or another (e.g. the Tower of London or the Tower of Toronto) has been repeated in PD patients with both positive29 and negative results.35 As for HD patients, Butters et al (ref 34, p. 729) reported that early HD patients showed normal learning and retention of the puzzle solution, but advanced HD patients showed ‘little improvement’. However, examination of their Figure 5 sug42
The role of the basal ganglia in procedural memory most automatic behaviors are the most intact in HD and PD, in accordance with the effects of striatal dopamine depletions in monkeys,24,25 mentioned above. Of course, one might argue that any residual procedural ability could be due to incomplete degeneration, leaving the habit hypothesis otherwise intact. However, the case of the ‘advanced’ HD patient who solved the Tower of Hanoi puzzle34 and the relatively preserved initial rates of procedural learning cited above seem inconsistent with such a view. The data are as consistent with an alternative, one stressing the role of basal ganglia in mediating changes from prevailing response rules, i.e. with breaking down automatic behavior rather than its perpetuation or mediation.36,37 In accordance with these ideas, Heindel et al38 reported an inability in HD patients to use experience with weight lifting to influence their perception about weight. That deficit was attributed to an inability to modify programmed movement parameters.
to controls) when a secondary, distracting task must be performed along with the primary one. A typical distracting task demands counting backward by threes from 100. These findings can be construed as supporting the habit hypothesis on the assumption that, in the presence of a secondary task demanding attention, subjects must rely on relatively automatic behavioral schema. Augmented deficits in primary task performance in PD or HD patients, on this account, support the habit hypothesis. However, dual-task effects can be equally attributed to the well-studied difficulties of such patients in shifting attentional set.48-51 Recently, for example, a study of HD patients has led Sprengelmeyer et al (ref 52, p. 145) to the conclusion that ‘a number of ‘higher’ cognitive deficits described in Huntington’s disease might, at least partly, be due to basic attentional disturbances’. Impairments on assessing the probability of success53 may similarly reflect attentional deficits rather than primary problems in procedural learning.
Attentional set shifting tasks
Ancillary arguments
Deficits in problem solving have been examined not only with the puzzle tasks29,35,39 outlined above, but also by other tests of cognitive skill. Results from studies of PD patients employing the Wisconsin Card Sorting Task,40 and tests of forward planning,41 mental flexibility and generalization,42 like those using the tower puzzles, have been interpreted by some authors as being consistent with the habit hypothesis. However, most of those results were originally interpreted in terms of frontal lobe dysfunction rather than with respect to the corticostriatal system or basal ganglia per se, which limits their applicability to the hypothesis in question. In accord with the habit hypothesis, there are reports that PD patients sometimes perform better (at walking, for example) when they attend to what they are doing.43,44 Taking the anecdote at face value, it appears to support the notion that these patients substitute nonautomatic processes for deficient, automatic ones. However, the neurophysiology of PD suggests a different explanation. It is well known that responses to attended stimuli are enhanced throughout the sensory and motor system.45 This enhancement in sensorimotor signal strength could overcome the blockade to motor output that is thought to retard movement in PD.46,47 Finally, there are number of ‘dual-task’ effects in PD, in which task performance deteriorates (relative
In this section, I will examine several ancillary arguments that have been put forward in support of the habit hypothesis. Not all of the arguments have strong bearing on the hypothesis, and some are outdated, but all have been advanced at one time or another in its support, and therefore deserve consideration. One such contention involves the concept of the ‘extrapyramidal system’ and the identification of the basal ganglia as principal structures operating in that system. According to Mishkin and Petri (ref 5, p. 288), the habit system ‘is likely to involve connections of the cortex with the striatum…and associated structures within the extrapyramidal system’. The basal ganglia were once thought to direct their output, through the thalamus, primarily if not exclusively to premotor and motor cortical areas. Since the striatum receives input from a variety of visual, auditory, somatosensory and polysensory cortical areas, it seemed a likely site for sensorimotor associations to form. Current neuroanatomical thought is inconsistent with that view.54,55 Much of the basal ganglia system, especially those parts that receive the most direct inputs from nonprimary (extrastriate) visual areas,13,22 is thought to lack direct access to motor or premotor cortical areas and to send its output instead to the prefrontal cortex. Thus, the basal ganglia would not appear to be privileged sites for sensorimotor associations. 43
S. P. Wise habit hypothesis, although both have been cited as doing so. The reader is referred to the recent reviews by Brooks58 on the brain-imaging literature and by Marsden and Obeso36 on the human brain-lesion literature.
Two other arguments that have been advanced to support the habit hypothesis are, broadly stated, evolutionary. Mishkin et al (ref 4, p. 73) refer to the existence of habit formation ‘across the entire phyletic scale’. They argue (ref 4, p. 74) that since habits evolved early, candidates for the structure underlying habit learning should have evolved early as well:
Conclusion
The striatal complex or basal ganglia is an obvious candidate from an evolutionary standpoint in that it antedates both the cerebral cortex and the limbic system in phylogenesis.
The habit hypothesis finds only weak and equivocal support from the existing neurobiological literature. In both clinical and experimental studies, evidence for the acquisition of procedural memories or habit formation tasks have been neglected while subtle deficits have been emphasized as ‘consistent’ with the hypothesis. In reviewing this problem, students might note that the quest for double dissociations can lead to an overemphasis on subtle behavioral deficits, while ignoring dramatic capabilities. The evidence indicates that relatively automatic behaviors remain possible to perform and to learn, albeit at a somewhat slower rate, after extensive damage to the basal ganglia. Accordingly, much more direct and convincing data is needed before the habit hypothesis of basal ganglia function deserves the broad acceptance it has received. Among many alternatives, one might consider the role of corticocortical interactions in mediating sensorimotor learning. For example, in a model proposed by Houk and Wise,59 motor outputs are determined by the input–output processing of a number of distributed neural modules, many of which involve the corticortical connections of the frontal cortex. They proposed that learning in frontal networks may be guided by forcing functions provided by its main subcortical inputs, in particular those from basal ganglia and the cerebellum, as those signals are transmitted through thalamic relays. By forcing function, Houk and Wise refer to the idea that basal ganglia and cerebellar inputs would alter synaptic weights in the frontal cortical network to gradually promote a cortical output consistent with a particular input–output function. The frontal cortex would thus become slowly trained to become efficient and automatic at the function being forced on it by pallidal or cerebellar inputs. In a sense, the model of Houk and Wise presents the mirror-image of the habit hypothesis, which supposes that higher order cortical areas train the basal ganglia as behavior becomes habitual. In their model, automatic sensorimotor behavior relies on corticocortical connections and the basal ganglia, along with the cerebellum, gradually train the frontal cortex.
As attractive as the notion may be, there is no sound basis for believing the striatum to be phylogenetically older than either the cerebral cortex or the limbic system, as either is usually defined. Mishkin et al probably meant to compare the striatum to neocortex, that part of the cerebral cortex which appeared with the advent of mammals or their immediate ancestors about 180 million years ago. If one relies solely on estimated phylogenetic age, there is no support for assigning habit formation to the basal ganglia as opposed to certain parts of the cortex, including the archicortex and paleocortex, that probably have as long an evolutionary history. Mishkin et al4 further argued that since the striatal complex evolved before the cerebral cortex, habit learning should emerge before visual recognition learning in individual development, as well. Thus, Bachevalier’s finding of early learning of a habit formation task has been taken to support the habit hypothesis of basal ganglia function.14 However, even if one accepts the dubious proposition that the basal ganglia evolved earlier than the cerebral cortex (or limbic system), and one further accepts that habit learning precedes visual recognition learning, the conclusion that the basal ganglia subserve habit formation does not follow except by invocation of Haeckel’s discredited doctrine of recapitulation. Although the problems with Haeckel’s doctrine are covered in most introductory biology texts and in a comprehensive monograph,56 I recommend that students from fields other than biology consult the erudite and authoritative work, Aristotle to Zoos, by Medawar and Medawar.57
Concurring reviews In this critique, I have neglected the data from noninvasive brain imaging or the effects of focal basal ganglia lesions. Neither line of evidence supports the 44
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S. P. Wise 44. Marsden CD (1982) The mysterious motor function of the basal ganglia: the Robert Wartenberg lecture. Neurology 514-539 45. Desimone R, Duncan J (1995) Neural mechanisms of selective visual attention. Annu Rev Neurosci 18:193-222 46. Bergman H, Wichmann T, DeLong MR (1990) Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249:1436-1438 47. Wichmann T, Bergman H, DeLong MR (1994) The primate subthalamic nucleus. 3. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of Parkinsonism. J Neurophysiol 72:521-530 48. Brown RG, Marsden CD (1991) Dual task performance and processing resources in normal subjects and patients with Parkinson’s disease. Brain 114:215-231 49. Brown RG, Marsden CD (1988) Internal versus external cue and the control of attention in Parkinson’s disease. Brain 111:323-345 50. Owen AM, Roberts AC, Hodges JR, Summers BA, Polkey CE, Robbins TW (1993) Contrasting mechanisms of impaired attentional set-shifting in patients with frontal lobe damage or Parkinson’s disease. Brain 116:1159-1175 51. Cronin-Golomb A, Corkin S, Growdon JH (1994) Impaired problem solving in Parkinson’s disease: Impact of a set-shifting deficit. Neuropsychologia 32:579-593 52. Sprenglemeyer R, Lange H, Homberg V (1995) The pattern of attentional deficits in Huntington’s disease. Brain 118:145-152
53. Knowlton BJ, Paulsen JS, Squire LR (1995) Impaired probabilistic classification learning in Huntington’s disease. Soc Neurosci Abstr 21:1493 54. Alexander GE, Crutcher MD, DeLong MR (1991) Basal gangliathalamocortical circuits: Parallel substrates for motor, oculomotion, ‘Prefrontal’ and ‘Limbic’ functions, in Progress in Brain Research (Uylings HBM, Van Eden CG, DeBruin JPC, Corner MA, Freenstra MPG, eds) pp 119-145. Elsevier Science Publishers, Amsterdam 55. Strick PL, Dum RP, Picard N (1995) Macro-organization of the circuits connecting the basal ganglia with the cortical motor areas, in Models of Information Processing in the Basal Ganglia (Houk JC, Davis JL, Beiser DG, eds) pp 117-130. MIT Press, Cambridge 56. Gould SJ (1977) Ontogeny and Phylogeny, Belknap, Cambridge 57. Medawar PB, Medawar JS (1983) Aristotle to Zoos. A Philosophical Dictionary of Biology, Harvard University Press, Cambridge 58. Brooks DJ (1995) The role of the basal ganglia in motor control: contributions from PET. J Neurol Sci 128:1-13 59. Houk JC, Wise SP (1995) Distributed modular architectures linking basal ganglia, cerebellum, and cerebral cortex: Their role in planning and controlling action. Cerebral Cortex 5:95-110
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THE NEUROSCIENCES, Vol 8, 1996: pp 39–46
The role of the basal ganglia in procedural memory Steven P. Wise
knowledge.7 Notwithstanding the many problems in defining these terms8 and the circularity inherent in their application to nonhuman animals,7,9-11 many behaviors thus characterized survive extensive damage to the ‘medial temporal lobe’ (see E.A. Murray, W. Suzuki, D. Gaffan, this issue, pp. 13-22, 3-12, 33-38, respectively). Therefore, some other structures must support these relatively automatic and subconsciously mediated behaviors, and it is only natural to speculate that the basal ganglia and its corticostriatal inputs might be important in that regard. The almost immediate acceptance12 and level of enthusiasm for the habit hypothesis is noteworthy. For example, Webster et al (ref 13, p. 87) repeat without reservation the idea that ‘the pathway from inferior temporal cortex to the striatum is part of a circuit that underlies the formation of visuomotor associations, or visual ‘habits’’. Somewhat less definitively, Squire et al (ref 7, p. 475) conclude that ‘recent work suggests that the brain structures important for acquiring skills and habits involve the corticostriatal system’. And Bachevalier (ref 14, p. 468) asserts unequivocally the existence of an ‘early developing cortico-striatal habit system’. One might suppose that such enthusiasm stems from a wealth of empirical data and that the habit hypothesis had, being well and rigorously tested, withstood an onslaught of skeptical experimentation and testing. Examination of the published literature, however, reveals a less convincing body of data.
A common conjecture about the basal ganglia holds that these nuclei and their cortical inputs subserve relatively automatic stimulus–response behavior (habits) and other procedural memories. This speculative hypothesis warrants critical reassessment. No unequivocal evidence supports the assignment of this information-processing specialization to the basal ganglia or its cortical afferents. Key words: striatum / habit / procedure / skill / motor system ©1996 Academic Press Ltd
THE ROLE OF the basal ganglia remains enigmatic despite decades of intensive investigation, partly inspired by interest in such maladies as Parkinson’s (PD) and Huntington’s disease (HD). The principal components of the basal ganglia — the pallidum, the striatum (including the caudate nucleus and putamen), and its catecholaminergic input from the midbrain — appear to be among the oldest and most conservative features of the vertebrate brain.1 Their antiquity, alone, suggests that these nuclei perform functions fundamental to vertebrate behavior. One common speculation is that the basal ganglia subserve relatively automatic responses to sensory inputs, learned or innate.2,3 In this seminar, I will term this conjecture the habit hypothesis of basal ganglia function. Mishkin and his colleagues4-6 first proposed that the basal ganglia and its corticostriatal inputs subserve what they termed ‘habits’. The key features of habitual behavior include a stored association between a stimulus and a response, information that is: (a) slowly learned, (b) relatively stable over time, except under extinction conditions, (c) transferred poorly among effector systems and behavioral contexts, and (d) unavailable to the mechanisms of consciousness. In humans, for whom it is possible to assess conscious awareness through verbal reports and other means, this form of memory has been considered one among many forms of nondeclarative, implicit or procedural
Experimental evidence from nonhuman primates Visual discrimination learning and retention have been reported to be impaired by damage to the tail of the caudate nucleus,15 by lesions of the ventroposterior putamen and environs16 or by disruption of temporal lobe white matter,17,18 which is thought to eliminate corticostriatal (among other) pathways. Deficits in visual pattern discrimination can be due to an inability to learn a response to a stimulus, as assumed for the sake of the habit hypothesis. However, even when problems in perception and visual
From the Laboratory of Neurophysiology, National Institute of Mental Health, P.O. Box 608, Poolesville, MD 20837, USA 1044-5765/96/010039 + 08 $12.00/0
39
S. P. Wise this task, subjects are shown 20 pairs of objects each day. One member of the pair is baited with reinforcement, the other is not. Remarkably, in as few as 10 sessions or so, monkeys can learn to select the baited object on over 90% (of 100) trials (which must be spread, by necessity, over 5 days). Ablation of the medial temporal cortex and subcortex20 does not retard either learning rate or performance on this task. Wang et al19 attempted to lesion the tail of the caudate nucleus because it is the main recipient of visual information from the nonprimary (extrastriate) visual cortex.21,22 According to their abstract, after an attempt to place ibotenic acid into the tail of the caudate bilaterally, monkeys that had learned to discriminate one set of 20 object pairs before the lesions were trained on two additional sets of 20 object pairs. Wang et al report that ‘for each animal, the number of trials required to reach criterion was more than twice that for the initial set of objects’, but that there was no deficit on a standard test of visual recognition memory. At first glance, the report of Wang et al seems to verify the habit hypothesis by establishing a double dissociation: lesions of amygdala, hippocampus and underlying perirhinal cortex cause deficits in recognition memory but not in their test of habit formation; by contrast, striatal lesions cause deficits in habit formation but not in recognition memory. However, closer examination reveals serious flaws in this summary. When viewed from a falsificationist perspective, what Wang et al19 report is, at most, a modest retardation in the rate of acquisition of a very demanding task. Their preliminary findings suggest that there is no deficit in task performance once the discriminations have been learned. Assuming, for the sake of discussion, that the lesions are as intended, the results suggest an interpretation opposite to that reached by Wang et al. What the results reveal, in my opinion, is the dramatic capability in learning object discriminations in monkeys with (presumably) extensive damage to the tail of the caudate nucleus. The brain-damaged subjects reach 90%-correct task performance about half as fast as usual and perform nearly perfectly thereafter, thus demonstrating relatively intact learning and completely intact memory capability. It is interesting to note that the result on the 24-hour concurrent discrimination task appears to be roughly equal to that on the simpler discrimination tasks mentioned above: approximately halving the learning rate. The subtlety of the deficit on the concurrent
recognition memory can be ruled out, several alternative interpretations remain possible. In these tasks, approach or contact of one and only one of two stimuli is rewarded. Accordingly, discrimination deficits could result from a deficiency in learning stimulus-reward associations. Among several nonspecific factors, attentional deficits, especially defects in shifting attentional set (see below) could cause poor performance on visual discrimination tasks. The published studies to date have failed to consider these possibilities. Further, and notwithstanding the assertions of the authors, there has been no systematic effort to make a control lesion interrupting the white matter fiber tracts surrounding the lesion sites, nor any useful histological analysis of the lesions. The impairments, therefore, can be accurately attributed to the tail of the caudate nucleus15 or ventroposterior putamen16 only with difficulty. In addition to the interpretational difficulties noted above, the reported visual discrimination deficits have been modest. Buerger et al16 reported deficits in retrieval of a preoperatively learned visual discrimination. Monkeys with large putamen lesions involving the adjacent white matter showed little postoperative savings of the learned discrimination, but they relearned to a criterion of 90% (of 100 trials) with just 141 errors. Monkeys with smaller lesions showed even less impairment. Divac et al15 attempted to lesion the tail of the caudate nucleus and studied new postoperative learning of a simple visual discrimination. Subjects with tail of caudate lesions learned the discrimination to a criterion of 90% (also of 100 trials) in 492 trials, making 234 errors in the process. There were no control subjects, but lesions involving different parts of the striatum were associated with learning to criterion in about half (44%) that number of trials with about half (also 44%) that number of errors to criterion performance. Thus, the rate of task acquisition, on these visual discriminations at least, appears to be approximately halved after extensive damage to the posterior striatum. All of the lesioned monkeys were able to learn the task and to perform the behavior once learned. The most direct examination of the habit hypothesis appears in a 1990 abstract of unpublished data by Wang et al.19 That abstract contains the claim that lesions of the tail of the caudate nucleus cause deficits in the ‘24-hour concurrent discrimination learning task’, a variant of visual discrimination tasks mentioned above. The study was designed to verify the central prediction of the habit hypothesis: striatal lesions should cause selective deficits on such tasks. In 40
The role of the basal ganglia in procedural memory context of the clinical data, such deficits appear to reflect the persistence of habits (e.g. direct reaching to a visible target), rather than a disruption of them. Accordingly, evidence that basal ganglia dysfunction leads to such perseverative behavior stands against the habit hypothesis, as presently construed.
learning task raises several issues. One concerns whether such a slight deficit should be lumped with a more dramatic one under the rubric of ‘double dissociation’. On one side of the dissociation, medial temporal lobe lesions devastate performance on visual recognition tasks (see E.A. Murray, this issue, pp 13-22). After certain of these ablations, monkeys perform near chance levels when just one minute intervenes between the sample presentation and the choice test. On the other side of the dissociation, after striatal lesions monkeys perform a highly demanding task nearly flawlessly, although they take about twice as long to learn the discrimination. Notwithstanding the difficulties inherent in comparing results across different sets of subjects and tasks, some consideration of the magnitude of the lesion effects seems warranted. Rather than considering such a pattern of results simply as a double dissociation, it seems better to recognize the asymmetry of the deficits. In so doing, one might consider the effect of eliminating some of the visual information that flows through the basal ganglia to the frontal lobe. Regions of frontal cortex usually receive visual information from the posterior striatum through multisynaptic pallidal, nigral and thalamic pathways.23 One might speculate that disruption of these pathways, especially in the context of relatively intact corticocortical visual information flow to the same areas of cortex, somehow causes a mild retardation in discrimination learning rates. In summary, the results reported in abstract form by Wang et al19 suggest that the tail of the caudate nucleus is unnecessary for either the acquisition or performance of the 24-hour concurrent discrimination task, their presumed test of habit formation. Their results appear little different than those obtained earlier with standard tests of visual discrimination learning.15-18 Although the rate of learning is retarded, by about a factor of two, the eventual mastery of visual discrimination and subsequent task performance shows that the lesioned parts of the striatum cannot alone subserve such behavior. The finding of deficits in detour reaching after moderate depletions of striatal dopamine24,25 has also been cited in support for the habit hypothesis, but it fails to provide much. These studies show, as do similar ones involving either prefrontal or premotor cortical lesions,26 that monkeys with localized brain damage persist in reaching directly for a visible reward, even though the movement is blocked by a transparent barrier. Normal monkeys reach around the barrier to obtain a reward. As noted below in the
Clinical observation in Huntington’s and Parkinson’s disease In humans, the evidence most pertinent to the habit hypothesis comes from clinical studies. To summarize the most often cited results, HD and/or PD patients have been reported to have deficits in: reading words projected as mirror images,27 contacting a rotating target with a hand-held stylus,28 solving certain puzzles,29 and speeding reactions based on repeated movement sequences.30,31 These tasks, termed mirror reading, rotary pursuit, Tower of Hanoi (London and Toronto), and serial reaction-time tasks, respectively, are performed relatively normally by amnesics.7,10,11 Accordingly, the behavioral deficiencies of HD and PD patients have been taken to support the habit hypothesis of basal ganglia function.
Procedural tasks In the major clinical papers one can find evidence of procedural learning that has often been neglected in favor of emphasizing statistically significant deficits. I do not mean to imply that the deficits in HD or PD patients are unreliable, but rather that, in addition to significant deficits, it seems likely that significant learning also can be observed. As an outsider in this field, my reading of the published data on HD suggests that the initial procedural learning in these patients is relatively intact or, at least, substantially intact. What distinguishes the procedural learning of HD patients from that of controls is a rapid plateau in acquisition rate; i.e. HD patients begin by learning procedural tasks fairly well, if not completely normally, but level off much more quickly than control subjects. This pattern of deficit might suggest a failure in consolidation rather than in learning or performance abilities per se. Alternatively, patients may learn the tasks in a different way, one that only supports a lower level of performance. Martone et al 27 reported that patients with HD showed deficits in mirror reading. The deficit consisted of a slowing in the time taken to read horizontally inverted text. Over three days of testing 41
S. P. Wise gests a somewhat different summary: the advanced HD patients improved from block-to-block within a testing day, but performed at an inferior level overall. One advanced HD patient, presumably with extensive degeneration of the striatum, improved performance 94%, i.e. the patient approached perfect performance on a task that, according to the habit hypothesis, requires striatal information processing. In the serial reaction-time task, subjects are instructed, by a visual display, to press one of several keys for a series of movements. If the sequence is random, e.g. a random selection among four possible movement targets, reaction time remains fairly constant over the series. If, unbeknownst to the subject, some repetitive sequence structures the order of movements, a speeding of reaction can be observed as the series progresses. Although somewhat controversial, it is generally believed that the speeding of reaction time precedes the explicit recognition of the sequence or even the awareness that there is a sequence. HD patients show less benefit of the sequence structure than normal controls.30,31 In my view, the clinical data cited above do not provide strong support for the habit hypothesis of basal ganglia function or the allied view that the basal ganglia mediate procedural memory. While the prevailing interpretation remains attractive, it has certain problems. If, as hypothesized, the basal ganglia subserve performance based on habits or procedural memory, then one would predict the most automatic and well-learned behavior to be most disrupted by basal ganglia disease. This prediction follows whether the well-learned behavior is a stimulus-response habit, a motor or cognitive skill, or some other reflection of procedural knowledge. Contrary to the prediction of the habit hypothesis, the deficits in mirror reading, rotary pursuit and serial reaction-time tasks can be viewed as resulting from the persistence of automatic behavioral routines rather than a deficiency in them. A deficit in mirror reading could result from the persistence of reading strategies developed from years of experience with noninverted letters. Impaired rotary pursuit performance could represent a persistence of old motor skills (i.e. an inability to adopt new, or modify old, motor programs). The tower-puzzle deficits, likewise, might reflect the perpetuation of poor strategies. And the serial reaction-time deficit might be construed as the persistence of a default response to visual instructions, which built of experience without sequences, is based upon a reaction-time mechanism that HD patients cannot change to take advantage of sequence structure. On this view, the
with unique word triads, HD patients did improve in mirror reading speed, by 11%, but not as much as a control group, which improved by 18%. The deficit in reading unique word triads appeared to result from the HD patients reaching an early performance plateau. In the initial phases of learning this cognitive skill, their performance appeared to parallel that of the controls. Harrington et al32 found no deficits in mirror reading in PD patients. Heindel et al28 reported deficits in HD patients on a rotary pursuit task. As with mirror reading, HD patients show some initial improvement followed by a rapid plateau in performance. It is difficult to determine, since the authors do not report it explicitly, whether that initial improvement is significant. The HD group improved the time-on-target from ~ 27 s in the first block to ~ 32 s (a 19% improvement), whereas the control group stayed on target ~ 41 s (a 51% improvement). These comparisons are compromized by the fact that the investigators had to adjust the target rotation rate to equalize initial performance. In a related study of Heindel et al,33 HD patients showed almost as much initial improvement as elderly control subjects, but reached an earlier performance plateau. The elderly control group improved from ~ 20 s on target to ~ 30 s (a 50% improvement), whereas the HD patients held the stylus on target for ~ 26 s (a 30% improvement) in the second block of trials. In both studies of Heindel et al the concentration on comparing the first blocks of trials to the last block obscured the improvement in performance that had occurred between the first and second blocks. As for PD patients, they showed some deficits in rotary pursuit, but those deficits were much more subtle than in the HD group. In fact, the nondemented PD patients outperformed the elderly control group,33 barely failing to match the middleaged control group (28 s versus 35 s on-target improvement over six blocks). Harrington et al (ref 32, p. 328) found that whereas PD patients and controls ‘showed a similar amount of rotary pursuit learning across blocks [within a day]…, the PD group showed less learning across days’. Butters et al 34 tested HD patients on the Tower of Hanoi puzzle, a test that in one form or another (e.g. the Tower of London or the Tower of Toronto) has been repeated in PD patients with both positive29 and negative results.35 As for HD patients, Butters et al (ref 34, p. 729) reported that early HD patients showed normal learning and retention of the puzzle solution, but advanced HD patients showed ‘little improvement’. However, examination of their Figure 5 sug42
The role of the basal ganglia in procedural memory most automatic behaviors are the most intact in HD and PD, in accordance with the effects of striatal dopamine depletions in monkeys,24,25 mentioned above. Of course, one might argue that any residual procedural ability could be due to incomplete degeneration, leaving the habit hypothesis otherwise intact. However, the case of the ‘advanced’ HD patient who solved the Tower of Hanoi puzzle34 and the relatively preserved initial rates of procedural learning cited above seem inconsistent with such a view. The data are as consistent with an alternative, one stressing the role of basal ganglia in mediating changes from prevailing response rules, i.e. with breaking down automatic behavior rather than its perpetuation or mediation.36,37 In accordance with these ideas, Heindel et al38 reported an inability in HD patients to use experience with weight lifting to influence their perception about weight. That deficit was attributed to an inability to modify programmed movement parameters.
to controls) when a secondary, distracting task must be performed along with the primary one. A typical distracting task demands counting backward by threes from 100. These findings can be construed as supporting the habit hypothesis on the assumption that, in the presence of a secondary task demanding attention, subjects must rely on relatively automatic behavioral schema. Augmented deficits in primary task performance in PD or HD patients, on this account, support the habit hypothesis. However, dual-task effects can be equally attributed to the well-studied difficulties of such patients in shifting attentional set.48-51 Recently, for example, a study of HD patients has led Sprengelmeyer et al (ref 52, p. 145) to the conclusion that ‘a number of ‘higher’ cognitive deficits described in Huntington’s disease might, at least partly, be due to basic attentional disturbances’. Impairments on assessing the probability of success53 may similarly reflect attentional deficits rather than primary problems in procedural learning.
Attentional set shifting tasks
Ancillary arguments
Deficits in problem solving have been examined not only with the puzzle tasks29,35,39 outlined above, but also by other tests of cognitive skill. Results from studies of PD patients employing the Wisconsin Card Sorting Task,40 and tests of forward planning,41 mental flexibility and generalization,42 like those using the tower puzzles, have been interpreted by some authors as being consistent with the habit hypothesis. However, most of those results were originally interpreted in terms of frontal lobe dysfunction rather than with respect to the corticostriatal system or basal ganglia per se, which limits their applicability to the hypothesis in question. In accord with the habit hypothesis, there are reports that PD patients sometimes perform better (at walking, for example) when they attend to what they are doing.43,44 Taking the anecdote at face value, it appears to support the notion that these patients substitute nonautomatic processes for deficient, automatic ones. However, the neurophysiology of PD suggests a different explanation. It is well known that responses to attended stimuli are enhanced throughout the sensory and motor system.45 This enhancement in sensorimotor signal strength could overcome the blockade to motor output that is thought to retard movement in PD.46,47 Finally, there are number of ‘dual-task’ effects in PD, in which task performance deteriorates (relative
In this section, I will examine several ancillary arguments that have been put forward in support of the habit hypothesis. Not all of the arguments have strong bearing on the hypothesis, and some are outdated, but all have been advanced at one time or another in its support, and therefore deserve consideration. One such contention involves the concept of the ‘extrapyramidal system’ and the identification of the basal ganglia as principal structures operating in that system. According to Mishkin and Petri (ref 5, p. 288), the habit system ‘is likely to involve connections of the cortex with the striatum…and associated structures within the extrapyramidal system’. The basal ganglia were once thought to direct their output, through the thalamus, primarily if not exclusively to premotor and motor cortical areas. Since the striatum receives input from a variety of visual, auditory, somatosensory and polysensory cortical areas, it seemed a likely site for sensorimotor associations to form. Current neuroanatomical thought is inconsistent with that view.54,55 Much of the basal ganglia system, especially those parts that receive the most direct inputs from nonprimary (extrastriate) visual areas,13,22 is thought to lack direct access to motor or premotor cortical areas and to send its output instead to the prefrontal cortex. Thus, the basal ganglia would not appear to be privileged sites for sensorimotor associations. 43
S. P. Wise habit hypothesis, although both have been cited as doing so. The reader is referred to the recent reviews by Brooks58 on the brain-imaging literature and by Marsden and Obeso36 on the human brain-lesion literature.
Two other arguments that have been advanced to support the habit hypothesis are, broadly stated, evolutionary. Mishkin et al (ref 4, p. 73) refer to the existence of habit formation ‘across the entire phyletic scale’. They argue (ref 4, p. 74) that since habits evolved early, candidates for the structure underlying habit learning should have evolved early as well:
Conclusion
The striatal complex or basal ganglia is an obvious candidate from an evolutionary standpoint in that it antedates both the cerebral cortex and the limbic system in phylogenesis.
The habit hypothesis finds only weak and equivocal support from the existing neurobiological literature. In both clinical and experimental studies, evidence for the acquisition of procedural memories or habit formation tasks have been neglected while subtle deficits have been emphasized as ‘consistent’ with the hypothesis. In reviewing this problem, students might note that the quest for double dissociations can lead to an overemphasis on subtle behavioral deficits, while ignoring dramatic capabilities. The evidence indicates that relatively automatic behaviors remain possible to perform and to learn, albeit at a somewhat slower rate, after extensive damage to the basal ganglia. Accordingly, much more direct and convincing data is needed before the habit hypothesis of basal ganglia function deserves the broad acceptance it has received. Among many alternatives, one might consider the role of corticocortical interactions in mediating sensorimotor learning. For example, in a model proposed by Houk and Wise,59 motor outputs are determined by the input–output processing of a number of distributed neural modules, many of which involve the corticortical connections of the frontal cortex. They proposed that learning in frontal networks may be guided by forcing functions provided by its main subcortical inputs, in particular those from basal ganglia and the cerebellum, as those signals are transmitted through thalamic relays. By forcing function, Houk and Wise refer to the idea that basal ganglia and cerebellar inputs would alter synaptic weights in the frontal cortical network to gradually promote a cortical output consistent with a particular input–output function. The frontal cortex would thus become slowly trained to become efficient and automatic at the function being forced on it by pallidal or cerebellar inputs. In a sense, the model of Houk and Wise presents the mirror-image of the habit hypothesis, which supposes that higher order cortical areas train the basal ganglia as behavior becomes habitual. In their model, automatic sensorimotor behavior relies on corticocortical connections and the basal ganglia, along with the cerebellum, gradually train the frontal cortex.
As attractive as the notion may be, there is no sound basis for believing the striatum to be phylogenetically older than either the cerebral cortex or the limbic system, as either is usually defined. Mishkin et al probably meant to compare the striatum to neocortex, that part of the cerebral cortex which appeared with the advent of mammals or their immediate ancestors about 180 million years ago. If one relies solely on estimated phylogenetic age, there is no support for assigning habit formation to the basal ganglia as opposed to certain parts of the cortex, including the archicortex and paleocortex, that probably have as long an evolutionary history. Mishkin et al4 further argued that since the striatal complex evolved before the cerebral cortex, habit learning should emerge before visual recognition learning in individual development, as well. Thus, Bachevalier’s finding of early learning of a habit formation task has been taken to support the habit hypothesis of basal ganglia function.14 However, even if one accepts the dubious proposition that the basal ganglia evolved earlier than the cerebral cortex (or limbic system), and one further accepts that habit learning precedes visual recognition learning, the conclusion that the basal ganglia subserve habit formation does not follow except by invocation of Haeckel’s discredited doctrine of recapitulation. Although the problems with Haeckel’s doctrine are covered in most introductory biology texts and in a comprehensive monograph,56 I recommend that students from fields other than biology consult the erudite and authoritative work, Aristotle to Zoos, by Medawar and Medawar.57
Concurring reviews In this critique, I have neglected the data from noninvasive brain imaging or the effects of focal basal ganglia lesions. Neither line of evidence supports the 44
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