26 B~sler, U. (1983) Neural Basis of Elementary Behavior in Wendler, G., eds), pp. 27-32, Parey Stick Insects Springer-Verlag 6 Weiland, G. and Koch, U. T. (1987) J. Exp. Biol. 133, 27 Clarac, F. (1984) Trends Neurosci. 7, 293-298 137-156 28 Clarac, F. and Barnes, W. J. P. (1985) in Coordination of 7 BEssler, U. (1988) J. Exp. Biol. 136, 125-147 Motor Behaviour (Bush, B. M. H. and Clarac, F., eds), pp. 8 B~ssler, U. (1977) BioL Cybern. 25, 61-72 249-269, Cambridge University Press 9 Cruse, H. (1985)J. Exp. Biol. 116, 357-362 10 Cruse, H. (1985) in Insect Locomotion (Gewecke, M. and 29 B~ssler,U. and Wegner, U. (1983) J. Exp. Biol. 105, 127-145 30 Pearson, K. G. and lies, F. J. (1973)./. Exp. Biol. 58, 725-744 Wendler, G., eds), pp. 19-26, Parey 31 Reingold, S. C. and Camhi, J. M. (1977)J. Insect Physiol. 23, 11 Land, M. F. (1972) J. Exp. Biol. 57, 15-40 1407-1420 12 B~ssler, U. (1986) Biol. Cybern. 54, 65-69 32 Zill, S. N. (1986) J. NeurobioL 17, 317-328 13 Cruse, H. and M011er, U. (1986) J. Exp. Biol. 121,349-369 14 Cruse, H. and Schwarze, W. (1988) J. Exp. Biol. 138, 33 B~ssler, U. (1987) Biol. Cybem. 55, 397-401 34 Laurent, G. and Burrows, M. (1988) J. Comp. NeuroL 275, 455-469 15 Cruse, H. and Knauth, A. (1989) J. Exp. Biol. 145, 199-213 1-12 16 Warnecke, H. and Cruse, H. (1989) Verb. Dtsch. Zool. Ges. 35 Ritzmann, R. E. and Pollack, A. J. (1988) J. Neurobiol. 19, 589-611 81,148 17 von Hoist, E. (1943) PflOgers Arch. Ges. Physiol. 246, 36 Greene, S. and Spirito, C. (1979) J. Exp. Biol. 78, 245--253 37 Dean, J. J. Exp. Biol. (in press) 846-865 38 Cruse, H. (1976) Biol. Cybern. 24, 25-33 18 Cruse, H. and Epstein, S. (1982) J. Exp. BioL 101,161-170 19 Dean, J. and Wendler, G. (1982) J. Comp. Physiol. 148, 39 Cruse, H., Riemenschneider,D. and Stammer, W. (1989) Biol. Cybern. 61, 71-77 195-207 40 Cruse, H. and Saxler, G. (1980) Biol. Cybern. 36, 159-163 20 Foth, E. and B~issler, U. (1985) Biol. Cybern. 51,313-318 21 BAssler, U. D0bner, C. and Fahrig, T. (1987) Zool. Jahrb. 41 Cruse, H. and Graham, D. (1985) in Coordination of Motor Behaviour (Bush, B. M. H. and Clarac, F., eds), pp. 283-301, Physiol. 91,393-401 22 Cruse, H. (1979) Physiol. Entomol. 4, 121-124 Cambridge University Press 42 Clarac, F. (1985) in Feedback and Motor Control in 23 Dean, J. and Wendler, G. (1983) J. Exp. Biol. 103, 75-94 Invertebratesand Vertebrates(Barnes, W. J. P. and Gladden, 24 B~sler, U. (1979) Physiol. Entomol. 4, 193-199 25 Cruse, H. (1985) J. Exp. Biol. 114, 513-519 M. H., eds), pp. 379-400, Croom Helm

Cognitive function in Parkinson's disease: from description to theory R. G. Brown and C. D. Marsden From the large body of empirical evidence on cognitive function in Parkinson's disease, a number of attempts have been made to describe the characteristics of the deficits and the conditions under which they are observed. This review considers descriptions limited to specific domains of cognition such as visuospatial function, memory and "frontal' function, and more general descriptions relating to 'set-shifting', sequencing, temporal ordering and recency discrimination, the locus of cognitive control and bradyphrenia. Later in the paper an attempt is made to provide some theoretical framework for the various descriptions. Two theories are discussed representing contrasting, but complementary approaches. The first is a 'psychological' theory in which the concept of depleted processing resources is suggested as a possible mechanism to explain the observable deficits. The second is a neurobiological model that attempts to integrate information from diverse sources to provide a model for the neuroanatomical and neurochemical substrate that may underlie some of the behavioural deficits.

were administered to largely unselected groups of subjects. From this research, certain patterns of impaired and intact performance became evident. The second stage has been an attempt to define these deficits more precisely, the conditions under which they occur, and occasionally, whether particular subgroups of patients are more susceptible. These studies, although guided by previous empirical evidence, have been largely descriptive (see Box 1)1-7. Some have been limited to deficits affecting a single domain of cognitive function such as memory or visuospatial function, or an anatomically defined region such as in the 'frontal' deficit. Others have sought to define a broader range of deficits that cross the classic boundaries of neuropsychological function, including bradyphrenia, 'set-shifting', internal attenfional control, deficits in sequencing, temporal organization and recency discrimination. These two categories should not be seen as mutually exclusive. In some cases they overlap, while in others they may be hierarchically organized. It should be noted that this paper does not aim to be an exhaustive review of the The number of publications on cognition in Parkin- literature on cognitive function in PD. One major area son's disease (PD) has grown exponentially in the past not included in the present article is that of dementia three decades. This reflects not only great interest in in PD and its relationship to other neurodegenerative this aspect of PD itself, but also the belief that the disorders. The reader is referred to a recent review cognitive abnormalities may give some clue as to that covers this area in details. normal cognitive function. In particular, the studies may hint at the role of the basal ganglia and their Descriptions of cognitive function in cortical connections in cognition. The research can be Parkinson's disease considered at three levels. First, particularly in the The visuospatial deficit. An earlier review 9, early days, research took a pragmatic 'look and see' considered the proposal that patients with PD had a approach, in which individual tests or groups of tests generalized visuospatial deficit. A number of studies TINS, Vol. 13, No. 1, 1990

© 1990,Elsevier$ciencePublishersLtd,(UK) 0166-2236/90/$02.00

R. 6. Brown and C D Marsden are at the MRC Human Movement and Balance Unit, National Hospital, and Departmentof ClinicalNeurology, Institute of Neurology, Queen Square, London W C IN 3BG, UK.

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• • • • • • • • •

Box 1. Operational descriptions of cognitive dysfunction in Parkinson's disease Impairment on tasks of visuospatial function (e.g. Ref. 1). Impaired recall memory but intact recognition memory (e.g. Ref. 2). Impaired performanceon 'active' memory tasks but intact performanceon 'passive' memory tasks 2. Impairment on effort-demanding tasks but intact performance on 'automatic' tasks 3. Impairment on tasks requiring 'set-shifting' (e.g. Ref. 4). Impairment on tasks requiring 'internal' control of attention but intact performance on tasks where 'external' control is provided 5. Impairment on tasks requiring 'self-directed taskspecific planning' but intact performance on tasks providing 'external stimulus control 's . Impairment on tasks requiring sequencing, temporal ordering and recency discrimination (e.g. Ref. 7). Impairment on tasks of 'frontal' function (e.g. Ref. 6).

since then have challenged this idea. Brown and Marsden 1° failed to find a deficit on the test of leftright discrimination and 'mental rotation', and Dela Salla et al. 11 found no impairment on a test requiring the subject to calculate rebound angles and extrapolate intersections between a target and a baseline. Taylor et al. 6 administered a range of visuoperceptual and visuospatial tests. No significant difference was found for any of the tests in terms of accuracy, and time-to-completion was significantly slower only for a block-counting task. Finally, Ransmayr et al. 12 administered two visuospatial tasks. The first involved line drawings of angular figures. If divided into two portions, each figure could form a square. The subject's task was to draw a line to indicate where the division should take place. The patients with PD were impaired on this task. The second task involved line drawings of cubes with three faces showing. On each face was a different geometric design. The subject's task was to match this cube with one of five others, the correct solution being a rotated version of the same cube. The patients were unimpaired on this task. The authors of that study noted that a major difference between the two tasks was that in the latter, subjects chose the correct solution from a number of alternatives, while in the former, the subject's response was completely self-generated. As discussed below, this distinction forms the basis for another general operational description of cognitive dysfunction in PD. Together, the results from these studies argue against a generalized visuospatial deficit in patients with PD. Results, such as those of Ransmayr et al. z2, in which dissociations are found between apparently similar tests, are important as they may allow more accurate operational descriptions to be formulated of the conditions under which deficits are found. Memory: recognition and recall. In group studies, patients with PD tend to be impaired on tests of recall but not on tests of recognition. In addition to the studies reviewed by Brown and Marsden 9, the results of Taylor et al. 6'13 and EI-Awar et al. 14 generally support this dissociation. The terms recognition and recall, however, refer only to paradigms used to 22

assess memory. Flowers et al. z suggested that 'In contrast to recall and learning tests, recognition is a "passive" memory situation. Subjects do not have to manipulate the material, nor mentally "scan" i t . . . nor do they have to organise actively a r e s p o n s e . . . A simple decision between fixed alternatives is all that is required.' Therefore, retrieval deficits in PD can be seen as occurring in tasks that require more active participation by the subjects. Essentially the same distinction was made by Weingartner et al. 3 when they referred to 'automatic' and 'effort-demanding' cognitive processes. Tasks such as free recall are seen as requiring sustained effort and cognitive capacity. Although retrieval in recognition paradigms is not necessarily automatic, it is seen as less effortdemanding than free recall. Weingartner et aL 3 assessed a range of tasks and showed a group of patients with PD to be impaired on those assumed to be most effort-demanding. The descriptions of both Flowers z and Weingartner et al. 3 were confined to the domain of memory, but the distinction between automatic/passive and effort-demanding/active processing can be applied to a wider range of tasks (see below). In conclusion, most studies have shown patients with PD to be impaired in tests of recall but not recognition. This could be considered to reflect a specific deficit within the memory system or a more generalized impairment. Opinion tends to favour the latter interpretation. The 'frontal' deficit. In neuropsychology, observable behavioural deficits are generally labelled in functional terms, e.g. visuospatial, language. One exception is the label 'frontal deficit', where a class of behavioural impairments is defined by the region of the brain involved. This is due to difficulty in ascribing a single function to the frontal cortex and its underlying brain structures. Many deficits have been observed (see Table I), and they form the basis for a number of descriptions of frontal lobe function. Attempts to localize function within the prefrontal cortex in man have not, as yet, produced any consistent results, although research in animals suggests that dissociable deficits can be produced with selective lesions (see Ref. 15 ). Table II illustrates the considerable overlap that exists between the cognitive deficits observed following damage to the frontal lobes and those described in at least some patients with PD. While many 'frontal-type' deficits have been reported in PD, it can be seen from the more recent studies that impairment was often observed only in subgroups of patients, or under specific conditions. The behavioural parallels are, nevertheless, impressive. Care is necessary, however. There is always a danger that a body of information will build up if people seek only to confirm a hypothesis. The 'frontal deficit' description is so broad that it may accommodate data from many sources and is probably best avoided in preference to more precise, and therefore testable, definitions. Some of these are considered below. Deficit in sequencing, temporal ordering and recency discrimination. Sagar and c o l l e a g u e27s '51' , 52 described a broadly defined deficit in sequencing, temporal ordering and recency discrimination. Dating an event often involves a temporal judgement, placing TINS, Vol. 13, No. 1, 1990

it in relation to other events TABLE I. Impairments observed following damage to the frontal lobes: examples of studies on occurring before or after, for which patients with Parkinson's disease the date is known. Dating thus Deficit observed following damage Deficit present in Deficit absent in involves a combination of temporal to the frontal lobe PD (Refs) PD (Refs) ordering and recency discrimi17 nation. In one study 51, subjects Impaired judgement of visual-vertical under conditions of body tilt TM were asked to recall the content of 19 a series of remote personal and Decreased control of Necker cube alternationsTM Impaired performance on 'mental rotation' tasks2° 12 1,10 public events together with the Impaired 'personal orientation '21,22 23 dates. Patients with PD were Impaired subject-ordered pointing24 25 a 25 a relatively impaired in their capacity Impaired recency discrimination 26 27 to date events compared with their Impaired performance on Reitan Trail Making 13 b 13 b ability to remember their content. Test28 29 c 29 c 31 d In a parallel study 27, subjects were Impaired performance on Stroop task3° 31d 29 c 29 c shown a series of words or 33 designs. At varying intervals Anomia (tip-of-the-tongue phenomenon) 32,33 35 e 35 e during the series the subjects were Impaired response on delayed-response task34 25 a 25 a required to make either a recency Impaired conditional associative learning36 37 discrimination or a content recog4f 4f Impaired verbal fluency (e.g. Ref. 38) nition. The patients with PD were 39 f 39 f impaired on the former but not the 35 40 latter task. To assess sequencing 6 41 ability in the absence of memory 3 43 f requirements, Sullivan et al. $2 Impaired problem solving42 44 administered the 'picture arrange45 g 39 h 39 h ment' subtest of the Wechsler Increased perseverative errors on the Wisconsin Card Sorting Test46,47 5,31 48 Adult Intelligence Scale (WAIS) 53. 25 49 This test involves placing a series 50 6 of cartoon-like pictures into an order that tells a sensible story. a Deficit present when patients off but not when on levodopa. Deficit present only in patients with poor response to treatment (see text). The test assesses, among other c Deficit present in early-onset but not in late-onset patients (see text). things, the ability to place discrete d Deficit present in uncued condition but not in cued condition (see text). events into a logical, sequential e Deficit present in demented but not in non-demented patients. order. The patients with PD were f Deficit present only on some aspects of the task. significantly impaired on this task g Deficit interpreted as one of procedural learning rather than problem solving. despite normal scores in the vo- h Deficit according to Nelson's 47 criteria, but not Milner's 46 criteria. cabulary subtest. Sequencing is important in other tasks; results, behaviour, and the pattern of behaviour observed in however, have been inconsistent. In subject-ordered patients with PD. pointing 24, subjects are shown a page containing sets Impaired 'set-shifting' ability. Another 'frontal-type' of stimuli such as words, pictures or designs. After deficit attributed to patients with PD, has been that pointing to any one stimulus, they are then shown they are impaired on tasks that require them to another page bearing the same stimuli in different 'switch set'. Bowen et al. 23,56 described a deficit in PD positions and must point to another item. This on two visuospafial tasks. Rather than attributing this continues with the subject having to point to a to a visuospatial deficit, the authors proposed that the different stimulus on each trial. Gotham et al. 25 found impaired performance was due to the need for an impairment on this task in patients with PD on subjects to shift their perspective repeatedly between normal levodopa treatment, but the same patients two spatial orientations. It was this 'shifting' comwere unimpaired relative to controls when assessed ponent, they proposed, which was crucial to the after withdrawal of their medication. In memory-span impaired performance. Brown and Marsden 5'1°, tasks such as the 'digit-span' subtest of the WAIS 53 however, also administered visuospafial tasks in and the 'Corsi block-span' test 54, subjects must which the subjects were required to shift between reproduce the target series in the same temporal two mental perspectives. Patients and controls order as it was presented. Canavan et al. 55 assessed a showed the same performance decrements when group of recently diagnosed patients with PD, not yet required to make the shift. Impaired set-shifting, receiving levodopa treatment. No deficits were found therefore, does not seem to be an inevitable feature of on either of these tasks, nor on a parallel test of cognitive performace in patients with PD. However, gesture span. Normal digit span (see Ref. 8) and block in the second study 5, the patients showed a significant s p a n 43 have been reported in p!:eyious studies. Sh0~- ' impairment on the Wisconsin Card Sorting Test term recall of sequential material within the subject's (WCST) 47, including the number of perseverafive available span does not appear to be impaired in errors, often taken to imply a difficulty in shifting set. patients with PD. The WCST is a test of categorization and behavioural Thus, concepts such as sequencing and recency regulation. Subjects must sort cards bearing stimuli discrimination have been applied to a wide variety of that differ along three physical dimensions: colour, different tasks with mixed results. It is likely that, for shape and number. The subject must use feedback to the concepts to be useful, precise definitions are switch, at intervals, between the three dimensions as required for this possibly heterogeneous class of the basis for sorting the cards. TINS, Vol. 13, No. 1, 1990

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TABLE II. Neuropsychologicalstudies offering evidence on cognitive slowing in Parkinson'sdisease Study Test Evidence of Note cognitive slowing? Hietanen and Reitan Trail Making Yes/No Slowing found for Ter~v~inen 29 Testsa (TMT Time for patients with age of part B-Time for part onset of PD < 60 years old but not for A) Stroop Test 59 (Time Yes/No patients with onset Ill-Time II) > 60 years, despite equivalent duration of illness Taylor et aL 6 Reitan Trail Making Test No (TMT Time B-Time A) Taylor et aL 13 Slowing found only in a Reitan Trail Making Test Yes/No (TMT Time B-Time A) subgroup of patients who had developed a poor responseto levodopa despite initial good response Talland and Schwab 6° Letter cancellation Yes Horne 61 Letter cancellation No Rogers et aL62 Slowing found only in a WAIS digit-symbol test 53 Yes/No subgroup of patients (adapted version) with CT evidence of structural brain damage Wilson et aL63 Memory scanning 64 No Slowing found in a group of 'old' patients (mean age 69 years) but not in a group of 'young' patients (mean age 58 years) Gamsu 65 Object-naming No latency66 Brown and Marsden I° 'Mental rotation' No

Cools et al. 4 assessed a group of patients with PD using tests that they classified as being either verbal (fluency), figural (sorting and categorization) or motor (finger-tapping sequence). All of the tasks had two sections. The crucial index of shifting ability was the subject's level of performance on the second part of the test relative to the first. For all of the tests the patients were impaired on both parts, but, compared with controls, showed a differential impairment on the second part relative to the first. Lichter et al. 48 used a Colour Match Reversal Task in which subjects were required to press a button to one side for a red screen target and to another side for a green target. After a number of trials the background colour changed. This was a signal for the subject to reverse the previous relationship between stimulus colour and side of response. As with the results of Cools et al. 4, the patients' accuracy was impaired in the reversal phase. Any conclusions, however, were complicated by the finding that the patients were normal in a further phase that required them to alternate, repeatedly and at random, between the two conditions. A shifting-deficit thus seems to be present in many but not all tasks. As discussed above, such dissociations are of value in refining the definition of the deficit. All the tasks employed by Cools et al. 4 were described by those authors as involving 'behaviour not directed by currently available sensory information'. The same was true of the WCST employed by Brown and Marsden 5 but not of their visuospatial alternation task, where the test stimuli on each trial provided explicit information regarding the nature of the task, and no switching deficit was seen in the oatients. Internal versus external control of attention. From 24

such evidence, Brown and Marsden 5 proposed that patients with PD were impaired in switching set where they had to rely on internal cues and strategies for performing the task, but that performance was normal where external cues were provided. While this operational definition was arrived at in relation to tasks involving a specific class of cognitive test, the distinction can be applied to any tasks where cognitive control has to come primarily from the subject (e.g. recall memory) or where a cue or guidance is provided by the experimenter or the stimulus configuration (e.g. recognition memory). Our conclusions echoed those of Taylor et al. 6 who had administered a wide range of other tests to a group of patients with PD. The patients were impaired on only a proportion of the tests, defined as those that required the 'spontaneous generation of task-specific planning'. Later, in relation to the pattern of performance on the memory tasks, the authors stated that, 'the presence or absence of impaired perform a n c e . . , appeared to hinge on the degree to which internally, that is, subjectively organised guidelines, are required for success. Patients performed adequately on the vast majority of memory tests where material was organised at presentation or presented in a recognition format.' These conclusions bear obvious parallels to those of Brown and Marsden 5, as well as those of Flowers et al. 2, Weingarmer et al. 3 and Ransmayr et al. 12 described above. A distinction is drawn between internal/active/ effort-demanding tasks and passive/automatic tasks, where external cues are provided or where the stimuli are organized at input. Brown and Marsden 31 tested this hypothesis with a version of the Stroop test (see Fig. 1). The PD group was impaired only in the condition without external cues. Further, the impairment was greatest for the first trial in each block where they had to switch from processing one attribute of the stimulus to the other. As predicted, the switching deficit was present only when internal cues or strategies were required. There thus appears to be increasing agreement that the internal-external distinction, or its many close relatives, may be the most useful, general description of the pattern of impaired and intact cognitive function in patients with PD. Brad~hrenia. Naville57 provided one of the first descriptions of cognitive dysfunction in patients with PD. He described a syndrome of 'bradyphrenia', characterized by a diminution of voluntary attention, spontaneous interest, initiative and the capacity for effort and work, with subjective and objective fatiguability, and a slight diminution of memory. Subsequently, this syndrome has become associated with the concept of 'subcortical dementia' (see Ref. 8) in conditions such as Huntington's disease and progressive supranuclear palsy, in addition to PD. TINS, Vol. 13, No. 1, 1990

1.5 The validity of subcortical deControls Parkinson's Disease mentia as a general syndrome has been criticized8. However, the concept of bradyphrenia in PD has not been restricted to those 1.0 patients with a clinically significant dementia, nor necessarily linked to (9 E a syndrome of apathy and inertia. tThe question to address here is O how well the idea of 'cognitive (9 slowing' fits the observable deficits 0.5 in PD. How can this putative slowing be assessed? Most studies to date have inferred the timing of cognition by measuring the time to 0 I I I I I I 1 I produce the overt behaviour. It 1 2-4 5-8 9-10 1 2-4 5-8 9-10 is, of course, essential to demonstrate that the overall response slowing is greater than that ex- Fig. 1. Subjects were presented with a series of stimuli, either 'red' written in green or 'green' pected from motor slowing alone. written in red. Subjects had to identify the meaning of the word for ten trials, then the colour of the ink for ten trials, and so on, switching between the two attributes twelve times. In one condition, The approach is to administer two the subject was given an explicit visual cue before each trial, which signalled whether the relevant or more tasks that have identical attribute was the colour of the ink or the meaning of the word. In the second condition, the motor components, but that differ subjects received only a warning signal prior to each trial, and had to provide their own intemal in the level of cognitive processing cues or strategies for focusing attention. The figure shows the mean reaction times (s) for required. Increased cognitive performance on the Stroop task after subtracting performance on a comparable non-Stroop control complexity leads, in many tasks, to task. Data are averaged across within-block positions for the cued task (squares) and non-cued task increased response time. It is (circles), for the PD group (filled symbols) and control group (open symbols). necessary to demonstrate, in PD, a slowing with increasing cognitive complexity above tics of cognitive dysfunction observed in PD. Apparand beyond that shown by a control group. A number ent slowing may be found on some tasks, but this may of examples will be considered. The results of studies imply a deficit relating to the tasks themselves, rather that have used this approach are summarized in Table than reflect a non-specific slowing in cognition. ii6, ]0,13,29,6o-63,65. A variety of tasks have been given, but none have The theories The discussion, so far, has dealt only with the demonstrated consistent slowing. Some studies demonstrated deficits in specific subgroups, but no descriptions that have been applied to the cognitive consistent pattern emerges from the data to deter- deficits observed in PD. Concepts such as sequencing, internal and external cues, and set-switching mine which patients are most likely to be affected. It is important to note that all of the tests assessed have been used. However, it is a mistake to assume relatively simple aspects of cognitive function. It may that having a label for a deficit is the same as be that slowing will be found only in tasks that place explaining the nature of the underlying processes. greater demands on the subject's cognitive capacity. Similarly, to say that patients with PD show a 'frontal Morris et al. 43 used a computerized version of the deficit' tells us little unless we understand the Tower of London task42, which involves relatively functions of the frontal cortex. The descriptions, complex problem-solving skills. This is an adaptation therefore, serve a useful, but limited, function. of the Tower of Hanoi puzzle, widely used in studies Theory-driven, rather than data-driven investigation of human and artificial intelligence problem solving. It would be more useful. Two theories will be involves moving a series of beads from a start position considered to illustrate two contrasting approaches. to a goal position in the minimum number of moves, The first uses an abstract construct (processing constrained by simple rules. Forward planning is resources) to explain the processes responsible for essential for optimum performance. A control con- some aspects of cognitive impairment in PD. The dition with the same motor component but without second is concerned with the neurobiological basis of any problem-solving skills was also used. The the cognitive impairment. members of the PD group were able to solve the The 'black box' approach: the theory of processing puzzles in the same number of moves as the control resources. All animals are subject to more information subjects, but were slower to make the first move. at any moment than their processing system can cope This could be seen as an index of initial planning. The with. One approach to explaining this assumed that time to make subsequent moves, however, was not there is a general limit on an organism's capacity to longer than in controls, suggesting that once a plan perform 'mental work'. It was also assumed that this had been formed, the patients could access it and use limited capacity could be allocated with considerable it just as quickly as the control group. Such apparent freedom among concurrent activities67. The concept slowing is a valid topic for further study and may of a limited-capacity central processor providing a reveal some interesting results about problem-solving supervisory role in cognitive function is fundamental behaviour in PD. to some contemporary theories in cognitive psycholIt seems clear, then, that 'cognitive slowing' is not a ogy, e.g. the 'Central Executive' in the Worldng useful or valid general description of the characteris- Memory Model68 and the supervisory attentional TINS, VoL 13, No. 1, 1990

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system (SAS) in the attentional model of Norman and Shallice69. The SAS, for instance, is seen as being called upon in situations that involve planning and decision making, in novel or poorly learned tasks, or in situations where some habitual response has to be overcome as may occur in switching set. Shallice4z'7° suggests that dysfunction of this supervisory system may underlie the cognitive dysfunctions observed following damage to the frontal lobes. It is only a small step to extend the theory to patients with PD. Brown and Marsden3~ observed that patients with PD were unimpaired on a version of the Stroop task in which external cues were provided, but were impaired on a parallel task in which they had to rely on their own, internal cues or strategies to perform the task (see Fig. 1). Control subjects, in contrast, showed no difference in performance between the two conditions. These results were interpreted in terms of a deficit in the SAS, and more spec~cally, in terms of reduced processing resources. The equivalent performance of the control group on the two Stroop tasks was not taken as evidence that they required identical processing resources, only that the resource demands of both tasks were within the limit of available resources. Indeed, the non-cued task was seen as likely to make greater demands on the SAS than the cued task. The dissociation of performance of the patient group on the two tasks could be explained if their level of processing resources was depleted. Provided the demands of the task were still within this level, as in the cued task, performance would be normal. If the resource demands exceeded those available, as in the non-cued task, a performance deficit would be observed. A theory based on depleted central processing resources, therefore, can account for the observed dissociation. However, invoking an abstract construct such as processing resources is not, in itself, of particular additional value over the operational distinction of internal and external cues. It simply moves the level at which the deficit is defined. Furthermore, it could be argued that any task on which the patients are impaired is, by definition, resource demanding. The logic becomes circular and the theory lacks value. Fortunately, the resource model allows us to generate further testable hypotheses that would not necessarily have emerged from considering only the operational nature of the task. If the pattern of impaired and intact performance in patients with PD is due to depleted central processing resources, then it should be possible to replicate that pattern in normal subjects by removing some of their available resources. If a resourcedemanding secondary task such as mental arithmetic or random number generation is performed at the same time, less resources will be available for the primary task. Although demonstrating a comparable deficit in patients and normal subjects with a manipulation of a simple task parameter does not prove that the mechanism underlying the deficit is the same in both cases, the modelling of abnormal cognition in normal individuals has considerable practical appeal as well as heuristic power. If, as a result of experiments on normal subjects, new deficits or patterns of performance can be induced that can then be found in patients, the power of the theory is greatly increased. One approach, therefore, may be to conduct parallel experiments in normal subjects and patient groups to 26

determine the validity and predictive power of the theory.

The 'anatomical' approach: the frontal caudate loop theory. The 'frontal' picture of PD can be considered from two perspectives. We have already seen how some patients with PD share many of the characteristic cognitive deficits observed in patients with damage to the frontal lobes. However, the behavioural data are of limited value on their own, but when integrated with information from other sources, they become most interesting and form the basis of a functional neurobiological model. No attempt is made to explain the cause of the deficits in terms of underlying psychological processes, only to provide the neurochemical and anatomical substrate for the behaviour change. The evidence upon which the frontal theory is based comes from several sources in addition to the neuropsychological data. These include (1) the pathological and neurochemical changes found in the brains of patients with PD, (2) the organization of neuronal systems in the intact brain, mainly from work in animals, and (3) the functional significance of these pathways and systems through the use of selective lesions and physiological recording in animals. In the 1970s the basal ganglia were generally thought to 'funnel' diverse cortical inputs via the ventrolateral thalamus to the motor cortex n, using processed sensory information in the initiation and control of movement. In 1981, DeLong and Georgopolis 72 suggested that this view was oversimplified. They suggested that there were two functionally and anatomically segregated loops through the basal ganglia. The first, the 'motor' loop involved mainly the putamen. Information received from sensorimotor cortex was relayed, via ventrolateral thalamus, back to certain premotor areas. The second, called the 'complex' loop, passed mainly through the caudate and projected, via anteroventral thalamus, to areas of prefrontal cortex. Subsequently, this scheme was revised in favour of one involving multiple basal ganglia-thalamocortical circuits 73. Five such circuits were suggested, with each receiving 'multiple, partially overlapping corticostriate input.s, which are progressively integrated in their subsequent passage through pallidum and nigra to a restricted portion of the thalamus, and from there back to a single cortical area.' The two circuits of primary interest here, functional subdivisions of the earlier 'complex' loop involving the caudate, are labelled anatomically by their ultimate projection sites, namely the 'dorsolateral prefrontal', 'lateral orbitofrontal' and 'anterior cingulate' circuits. While the functional significance of these circuits is not well understood, evidence is available from animal studies to suggest that lesions to dorsolateral prefrontal and lateral orbitofrontal cortex may have differential effects on tasks such as 'delayed response' and 'delayed alternation'7¢-76. One implication of the concept of a basal gangliathalamocortical circuit, regardless of the function subserved, is that disruption at different points within a circuit might be expected to have similar behavioural consequences. This has, in fact, been demonstrated in primates 75'77. In PD, depletion of striatal dopamine is the major consequence of the degeneration of the substantia nigra (pars compacta). Post-mortem studies reveal at least 80% depletion in the putamen, TINS, Vol. 13, No. I, 1990

but much less in the caudate nucleus (see Ref. 78). While dopamine depletion in the putamen is implicated in the motor symptoms of PD, particularly akinesia, attention has focused on the caudate depletion as playing a role in the pattern of cognitive impairment found in the disease. Disruption of caudate 'outflow' would be expected to influence the functioning of the various prefrontal projection sites 6. A further factor to consider is the depletion of dopamine within the frontal cortex itself, caused by degeneration of cells within the ventral tegmental area 79. However, average cortical dopamine loss is in the order of 60% at post-mortem, a figure considerably less than that which seems to be necessary before behavioural deficits are observed in monkeys8°. These data form the basis of the 'frontal caudate loop' theory. Can dopamine depletion, either in the caudate or the prefrontal cortex itself or both, serve as an adequate explanation for the 'frontal' deficits described earlier? Evidence from positron emission tomography (PET) suggests that in vivo dopamine levels in caudate may be considerably higher than those revealed by post-mortem studies. Nahmias et al. 81 found normal presynaptic levels of 6-[18F]fluoroL°dopa (6-FD), an analogue of levodopa, in patients with unilateral motor symptoms. This is thought to suggest normal accumulation of the fluorodopamine within the terminals of nigrostriatal neurones. Martin et al. 82 assessed patients in a more advanced stage of the disease, and found that in approximately 50% of patients, the 6-FD level was within the normal range. The functional significance of the depletion in the remaining 50% was not assessed. It is likely, from these data, that caudate dopamine depletion sufficient to cause cognitive impairment will be found in only a proportion of patients, at least in the early stages of the disease. This, in fact, fits the observed pattern of results in group studies, where most patients often produce scores on tests sensitive to frontal lobe dysfunction that fall within the normal range. The level of dopamine depletion necessary to cause cognitive impairment is open for speculation. From the evidence of the motor symptoms of PD, it is clear that the striatum is capable of a large degree of compensation for dopamine depletion, at least for the putamen. It must be assumed that the same holds true for the caudate. One test of the dopamine model is to assess the patients on and off levodopa medication. Of the handful of studies in the literature, only one focused on tests thought to be sensitive to the functional integrity of the prefrontal cortex. Gotham et al. 25 assessed performance on the WCST47, on a test of visual conditional associative learning 37, a test of subject-ordered pointing based on one described by Petrides and Milner 24, and a test of verbal fluency that involved generating words from one semantic category, or alternating between two different categories. No significant difference was found between the mean performances on and off medication, for any of the measures taken. While there was a tendency for patients to be more impaired on verbal fluency when offmedication, they tended to be more impaired on the conditional learning task and subject-ordered pointing when on medication. This pointed to a possible adverse effect of levodopa in these patients on some aspects of cognition. This suggestion was TINS, VoL 13, No. 1, 1990

strengthened by the finding that, when on medication, the dose of levodopa was positively associated with errors on the conditional learning task. This adverse effect could be seen as the effect of 'overstimulation' of the caudate or prefrontal cortex by levodopa, the dose of which had been fitrated against the motor symptoms due to the more severe putamen dopamine depletion. From the PET data, a group of patients beyond the early stages of the illness will contain some individuals with depleted caudate (and probably prefrontal) dopamine, and some with normal levels. All may have similar, severe dopamine depletion in the putamen. The effects of levodopa stimulation, therefore, may be to enhance cognitive function in some patients and to impair it in others. The net effect, on the group as a whole, may be no change between the medicated and unmedicated states. This suggests that unselected group studies may be an inappropriate way to assess the significance of striatal or prefrontal dopamine levels on cognitive function. Information from a variety of sources in neuroscience may help to explain the substrate of at least some of the cognitive deficits found in PD, but we do not yet understand enough to present a coherent theory. To develop further understanding, a combination of behavioural investigation and in vivo measurement of brain neurotransmitter levels is required. In the meantime, the dopamine hypothesis remains at least a plausible reason for the 'frontaltype' impairment in PD. However, it may be that there are many 'routes' to the disruption of the 'complex' loops. Marked dopamine depletion in either the caudate or prefrontal cortex may be sufficient to cause impairment. In other patients, 'subthreshold' depletions in both regions may have an additive effect. In other patients, the functional integrity of the frontal cortex may be compromised by reduced cholinergic or noradrenergic activity, which again may have an additive effect with dysfunctions in other neuronal systems. It is likely that animal studies will be necessary to show the behavioural consequences of such combined neuronal disruptions.

Concluding remarks Research into the nature and cause of cognitive dysfunction in PD has been undergoing a process of evolution in recent years. From a rich base of empirical investigations, there have emerged a variety of descriptions of the cognitive deficits and the conditions under which they are observed. We are now moving from description to theory. Two tentative approaches have been described, one attempting to provide a theoretical framework for the deficits in terms of psychological processes, and the other attempting to integrate the neuropsychological data with our knowledge of the neurobiology of PD and the normal brain. Neither is being presented as a definitive theory. Rather, we intended to illustrate two approaches providing ways forward. Ultimately, of course, it is to be hoped the theories that they generate, or that replace them, will converge. As an illustration, Bloxham et al. 83 proposed that some deficits in attention and reaction time in PD might be explained by an increase in 'neuronal noise', secondary to striatal dopamine deficiency. Such a theory might have implications for processing resources not necessarily in terms of their absolute level, but in the 27

level of resources that might have to be allocated to achieve a given signal strength over background neuronal noise. Finally, it must be said that PD is a complex multisystem disease with a great deal of variability both between individual patients and within individuals through the course of the illness. It is likely that no single cognitive psychological or neurobiological theory will be sufficient to explain all of the evidence on cognitive dysfunction in PD. The same is probably true for other neurodegenerative diseases such as Alzheimer's and Huntington's diseases. Comparative neuropsychology provides a means of assessing the relative importance of different neuronal systems in producing different patterns of impairment 7. In the end we will probably need a 'family' of theories. This does not make PD an unsuitable subject for study. The brain is a complex entity which works through the interactive effect of an array of different systems. If we are to understand how this is achieved then we cannot avoid studying instances where these interactions go wrong. Provided we remind ourselves of the complexity, PD provides us with a valuable testbed to explore these processes.

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Moleculargeneticstudiesof manic-depressionand schizophrenia M i c h a e l J. O w e n

a n d M i c h a e l J. M u l l a n

The application of molecular genetics to the study of mental disorders has begun in earnest. Most of the initial interest has focused on the functional psychoses as these common and debilitating disorders have long been known to have a significant genetic component. A number of groups have now reported data from RFLP linkage studies of both schizophrenia and bipolar affective disorder (manic-depression). Unfortunately the results are already conflicting with early findings of linkage unconfirmed by subsequent studies. For manic-depression, the first claim of linkage to DNA markers came in 1987 when Egeland and colleagues reported that two markers on chromosome 11, the insulin gene (INS) and the cellular oncogene cHarvey-ras-1 (HRAS1), were linked to the occurrence of illness in a large Amish kindred group 1. Relatives without bipolar disorder were scored as affected if they had suffered from schizoaffective disorder, atypical psychosis or major depression, since there is evidence that all these conditions can be genetically related to bipolar illness. Almost immediately, however, two further studies ruled out linkage to the same markers in Icelandic 2 and North American pedigrees 3. Indeed, to this date there have been no published replications of the chromosome 11 linkage in spite of a number of attempts 4-6. This discrepancy, together with previous studies showing linkage between bipolar disorder and the traditional (nonDNA), X-linked markers G6PD 7 and colour blindness 8, has generally been interpreted as evidence for non-allelic genetic heterogeneity. Further support for the notion of heterogeneity has come from more recent studies that confirm linkage between manic-depression and markers on the X chromosome in several Israeli and Belgian families 9' lo, as well as the observation that X-linkage was excluded in the American and Icelandic pedigrees by the presence of father-to-son transmission 2'3. The finding of genetic linkage in schizophrenia followed the report of a family in which a schizophrenic illness was segregating with an unbalanced translocation of chromosome 5, so that a portion of this chromosome was trisomic in the affected TINS, Vol. 13, No. 1, 1990

individuals 11. Sherrington and colleagues 12 subsequently reported linkage of the disease to two markers from the same region of chromosome 5 in seven kindred groups multiply affected by schizophrenia - five from Iceland and two from the UK. Famflies containing cases of bipolar affective disorder were excluded from analysis on the grounds that these might contain a second disease gene. Weak evidence for linkage was found when analysis was restricted to cases with schizophrenia. However, the degree of cosegregation increased when cases of schizophreniaspectrum personality disorder were included in the schizophrenia phenotype. This is perhaps not unexpected, since these disorders are known to be genetically related to schizophrenia la. More surprising was the observation that the evidence for linkage increased further when family members were included who had received other psychiatric diagnoses such as major and minor affective disorder, alcoholism and phobic disorder, which are not generally believed to be genetically related to schizophrenia (so-called 'fringe' cases). The authors point out that only five of the 'fringe' cases were informative for linkage analysis and so this result may have occurred by chance. They conclude that their findings indicate the existence of a dominantly inherited genetic defect in this region of chromosome 5 conferring susceptibility to schizophrenia. Furthermore, this defect seems to predispose to schizophrenia-spectrum disorders and possibly a variety of other psychiatric conditions. At the same time, Kennedy and colleagues 14 reported that they had failed to find linkage between schizophrenia and DNA polymorphisms in a large, geographically isolated, Swedish family. The immediate conclusion was that this discrepancy reflects heterogeneity in the genetic aetiology of schizophrenia with a mutation in a different gene being responsible for illness in the Swedish family t4' is. It is important to note that the results of Sherrington et al. t2 rest predominantly upon data from three of their seven families, since the polymorphisms studied were not fully informative. Moreover, although these authors did not find statistical evidence for non-allelic heterogeneity, strong evidence that all the families

© 1990.ElsevierSciencePublishersLtd,(UK) 0166- 2236/90/I02.00

MichaelJ. Owenand MichaelJ. Mullanare at the Departmentof Biochemistryand Ivlo/ecularGenetics, 5tMary'sHospital MedicalSchool, London W21P6, UK.

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