The Journal of Neuroscience October 1986, @IO): 3006-3009

Preserved Motor Learning in Alzheimer’s Disease: Implications for Anatomy and Behavior

Paul J. Eslinger and Antonio R. Damasio Department of Neurology, Division of Behavioral Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242

Learning and retention of 3 types of information were examined sion required in daily living at home; preserved social graces and ability in patients with Alzheimer’s disease (AD) and in normal con- to cooperateand follow instructions in structured testing sessions). None trols. While patients were unable to learn series of frequent had motor or sensory impairment, hemispatial neglect, visual agnosia, words and unfamiliar faces, they improved significantly in a visual disorientation syndrome, optic , or ocular . Dura- tion of symptomsaveraged 4 years(range 2E-9 years).The controls , showing a learning curve similar to controls. Fur- were volunteers with no history or evidence of neurologic or psychiatric thermore, no significant loss of the motor skill was evident in a disorder. The groups were similar in age (SDAT: z = 7 1.4 years, range 20 min delay trial. Such dissociation in learning has not been 58-82 years; c&t&s: 8 = 70.8 years,;ange 55-80 years;_t(l4) = 0.16, noted previously in AD, although it has been noted in D > 0.87). but educational backeround differed (SDAT: X = 10 years; caused by other disease processes. The results support the ex- controls:‘k = 16 years; t( 14) = 5.06, p < 0.01). istence of fwo, relatively independent, learning systems related There were 3 learning experiments. Each comprised 5 consecutive to “declarative” knowledge and “procedural” knowledge. Judg- learning trials and 1 delayed trial to assess retention 20 min later. In ing from the pathologic correlates of these amnesias, the dec- experiment 1, subjects held the stylus of a rotary pursuit apparatus in larative knowledge system appears to be associated with corti- their preferred hand, rested it on the small metal target, and tried to maintain contact with the target as it rotated at 30 rpm. Each of the 5 cotemporo/limbic structures, while the procedural system is leamine. trials lasted 20 set: intertrial interval was 20 sec. A stopclock likely to depend on corticocerebellar/striatal structures. The data and impulse counter measired total time on target and the number of also offer additional cognitive correlates for the selective dam- impulses (i.e., number of times the stylus lost and then regained contact age to neural systems recently identified in AD. with the target). In experiment 2, subjects listened to a lo-item grocery list and, in a A frequent early sign of Alzheimer’s disease (AD) is an unre- free- format, responded with as many items as they could, in any mitting impairment of learning and , leading to a per- order, immediately following presentation. Though no time limit for vasive global and eventually a multimodal agnosia. responding was enforced, subjects generally completed responses within While the is accompanied by other cognitive 60 sec. Instructions were repeated on each succeeding trial, urging sub- jects to recall all the items, even those already recalled on previous changes, it remains quite prominent throughout the disease. trials. Each trial was scored for number of correct items recalled. The Pervasive amnesia is also known to occur after focal damage to delayed-recall trial was followed by a recognition test comprised of the temporal lobe structures (Barbizet et al., 1978; Damasio et al., target words and distractor items. A signal detection analysis, with 1985a; Scoville and Milner, 1957), to medial diencephalic nuclei calculation of d’, was used to examine verbal recognition performance. (Butters and Cermak, 1980; Graff-Radford et al., 1985; Squire In experiment 3, subjects examined pictures of 8 unfamiliar faces for and Moore, 1979; Teuber et al., 1968), or to basal forebrain 20 sec. From a multiple-choice displa; of 20 faces, subjects then chose nuclei (Damasio et al., 1985b). Despite profound memory dis- the 8 original faces. even if thev were not certain of all choices. Though order, however, these amnesics are able to learn and retain a no time limit for reiponding was enforced, subjects generally completed variety of motor and perceptual skills (Cermak et al., 1973; responses within 60-90 sec. Performance was scored for number correct. All experimental procedures were fully completed, with the exception Cohen and Squire, 1980; Corkin, 1968; Damasio et al., 1985a; of facial learning in 1 SDAT subject whose testing was interrupted. Milner, 1966). Using standard paradigms of motor, verbal, and Analysis of facial learning, therefore, was based on the results of the 7 visual learning, we designed this study to ascertain whether a remaining pairs of subjects. For each of the learning experiments, a 2 x similar pattern of dissociation is evident in the amnesia caused 5 (Groups x Learning Trials) analysis of variance was used to examine by AD. results. Retention on the delayed trial was examined in relation to the last learning trial (trial 5) in a 2 x 2 (Groups x Trials) analysis of Materials and Methods variance. Our principal interest in the latter analysis was in determining Eight patients with the diagnosis of probable senile dementia of the if a significant interaction effect would occur. Alzheimer type (SDAT) and 8 healthv controls were studied. The SDAT subjects mei-current clinical and laboratory diagnostic criteria (Mc- Khann et al., 1984; Terry and Katzman, 1983), and were in moderate Results stages of dementia (i.e., having clearly detected major impairments of SDAT patients and controls had a similar pattern of motor anterograde and retrograde memory, temporal orientation, and other learning in experiment 1 (Fig. 1A). Analysis of time-on-target cognitive functions on neuropsychological assessment; some supervi- data revealed a significant trials effect (F(4,56) = 21.71, p < 0.001) and no interaction (p > 0.35). The SDAT group initially performed at a much lower level (55% of controls), but this Received Jan. 13, 1986; revised Apr. 14, 1986; accepted Apr. 17, 1986. difference gradually diminished to 93% (trial 4) and 87% (trial This work was supported by NINCDS Grant PO1 NS 19632-02. We thank Dr. 5) of control levels. Their improvement representeda change Arthur Benton and Dr. Daniel Tranel for their valuable criticism ofthe manuscript, of 161% over learning trials (Fig. 2), with every SDAT subject and Scott Ramsey for help with data collection. Correspondence should be addressed to Paul Eslinger, Ph.D., Department of showing improvement. Although the groups did not differ sta- Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. tistically in level of performance (F(1,14) = 2.86, p = 0.1 I), a Copyright 0 1986 Society for Neuroscience 0270-6474/86/103006-04$02,00/O trend toward a difference waspossibly evident. Given this result

3006 The Journal of Neuroscience Spared Learning in Alzheimer’s Disease 3007

A. Rotary Pursuit C. Words

6 Mean Tome Mean Number on Target of Words I Seconds) Recalled ,

H Alrheimer’a

0)’ B. Rotary Pursuit D. Faces 30

20 Meal-l Number of Impulses \ 10 ‘b 3.0

I I 0 I I I 20 r, 1 2 3 4 5 1 2 3 4 5 8 Learnmg Trlals Learnmg Trials Delay Delay Trial Trial

Figure 1. Learning and retention of a rotary pursuit motor skill, as measured by time on target (A) and number of impulses (B), recall of a lo- item grocery list (C), and recognition of 8 unfamiliar faces (0). After 5 learning trials, retention was measured after a 20 min delay. and the small sample sizes,we felt that the question of perfor- aE)oAT: 8d’ = 1.14; controls: XL? = 4.64; t(14) = 10.0, p < mance level should be subject to future study. Analysis of per- formance on the last learning trial and on the delayed trial ’ In experiment 3, the learning of unfamiliar faceswas difficult revealed no interaction (p > 0.58), group (p > 0.17) or trials for SDAT patients and controls (Figs. 1D and 2). While the (p > 0.42) effects, suggestinga comparable retention of what groups differed significantly in performance level (F( 1,12) = was learned (Fig. 3). 15.50, p < O.Ol), no trials effect Cp> 0.22) or group x trials Analysis of rotary-pursuit impulses (Fig. 1B) showed results interaction (p > 0.17) was found. Controls appearedto improve similar to time-on-target, with which it was highly correlated through the first 3 trials, but little thereafter. The SDAT group (SDAT: r = 0.79, t(6) = 3.14, p < 0.05; controls: r = 0.99, began at 85% of control levels, but by trial 3 had fallen to 66%. t(6) = 17.14, p < 0.001). A significant trials effect was found Analysis of learning and retention data revealed a significant (F(4,56) = 5.60, p < O.OOl), but no group difference (p > 0.56) interaction (F( 1,12) = 6.57,p < 0.05) as well asgroup (F( 1,12) = or interaction (p > 0.18). Analysis of performanceson the last 18.28, p < 0.01) and trials (F(1,12) = 9.81, p < 0.01) effects. learning trial and on the delayed trial revealed an interaction Retention of the SDAT group dropped to almost a chancerec- effect (F( 1,14) = 7.16, p < 0.02) with the control group showing ognition level (29% decline vs 2% for controls) (Fig. 3). more impulses and the SDAT group fewer impulses than on their last learning trial (Fig. 3). No group (p > 0.98) or trials Discussion (p > 0.23) effectswere supported. SDAT subjects showed a striking dissociation in their ability to In experiment 2, which required learning of verbal infor- learn and retain different types of information. As expected, mation, significant group (F(1,14) = 103.61, p < O.OOl), trials they were profoundly amnesic, showing poor acquisition of (F(4,56) = 4.46, p < O.Ol), and group x trials (F(4,56) = 5.92, common words and unfamiliar faces, no learning curve over p < 0.00 1) interaction effects were evident. The learning curve trials, and even poorer retention after a short delay. As with of the control group consistently improved, while that of the other amnesics,the findings suggesta lossof neural mechanisms SDAT group was flat (Figs. 1C and 2). The initial verbal per- necessaryfor learning such verbal and nonverbal information. formance level of the SDAT group was 45% of controls, but by However, the SDAT subjectslearned a motor skill in a manner trial 5 it representedonly 30% of control levels. In analysisof similar to controls, indicating preservation of the neural struc- the last learning trial and the delayed-trial data, a significant tures that integrate the visual, motor, and kinesthetic infor- interaction effect was found (F( 1,14) = 5.65, p < 0.05), as well mation usedin the task, and that permit the development and as group (F(1,14) = 161.41, p < 0.001) and trials (F(1,14) = storage of a . This dissociation has not been 27.32, p < 0.001) effects. The SDAT group fell to, almost zero observed previously in subjectswith dementia of the Alzheimer in verbal recall (73% decline vs 11% for controls) (Fig. 3). The type, although it is in keeping with a previous report that some verbal recognition task, following the delayed-recall trial, also subjectswith mild SDAT could learn a perceptual skill (Corkin, showed a performance level significantly lower than controls 1982). 3008 Eslinger and Damasio Vol. 6, No. 70, Oct. 1986

Rotary Pursuit Words Faces Rotary Pursuit Words Faces 60 200 A A rTime on IfllP”lSS f Time on Illlp”l*e.S’ Target 60 Target F (Gain) 0 Controls Improvement n Alzheimer’s (% Change) % Change 0 Controls across on Learning n Alzheimer’s Delay Trial Trials

50 - (Loss) ;; rl ll 0 m II -60 I- Figure 2. Learningof the rotary pursuitmotor skill, IO-itemgrocery Figure 3. Retentionof motor learning,verbal learningand faceleam- list, and 8 unfamiliarfaces over trials, as measuredby percentageof ing after a 20 min delay interval. In contrastto the wordsand faces, changefrom trial 1. retention of the motor skill (time on target) did not differ between controlsand patientswith Alzheimer’sdisease.

A variety of contrasting terms has been usedto conceptualize this dissociation in learning; all are aimed at characterizing the which can operate independently from the hippocampal system. fundamental distinction between the domainsof preserved and These would include components of the motor system in the disturbed memory function in the amnesias.Most notably, hu- , basalganglia, thalamus, motor and premotor cor- man cognitive research(Cohen and Squire, 1980; Moscovitch, tices, and related pathways, aswell as somatosensoryand visual 1982; Squire and Cohen, 1984) and experimental animal re- cortices. It is of interest to note, in this regard, that specific search (Mishkin and Petri, 1984; Mishkin et al., 1984) have damagein cerebellar structures has been shown to abolish con- emphasizedthat the nature of information, the characteristics ditioned motor responses(McCormick and Thompson, 1984). of the tasks, and the mode of responseare different in these It is also noteworthy that most motor system structures appear learning paradigms. The differencesare so marked that it is not resistant to the degenerative changesof Alzheimer’s disease even reasonableto compare the paradigmsin terms of difficulty; (Terry and Katzman, 1983). All of these findings support the one merely statesthat they must require different cognitive and notion that Alzheimer’s diseasecauses damage in selectedneural neural mechanisms.Cohen and Squire (1980) have applied the systems that are especially vulnerable to its pathologic mech- terms “procedural” and “declarative” knowledge to these dif- anisms. ferent types of memory. Procedural knowledgerefers to motor, It remainsto be determined whether this dissociationis char- perceptual, and even cognitive skills that are acquired incre- acteristic of all or most SDAT patients. On the basis of our mentally and principally by practicing the skill itself. Procedural current sample,we suspectthat the dissociationis likely to occur knowledgeappears to be a more comprehensive term than the in many mildly and moderately advanced cases.Furthermore, designation“habits” (Mishkin and Petri, 1984; Mishkin et al., the dissociation in learning may also be evident in other pro- 1984), which emphasizesthe strengtheningof principally stim- cedural learning paradigms. Finally, the findings may have po- ulus-responseassociations. Declarative knowledge, in contrast, tential therapeutic implications, as they suggestthat occupa- dependson the memory traces of sensoryexperiences of given tional programs focusedon motor activities might be reasonably stimuli. It rangesin complexity from the memory of a prototype successfulin these patients. By providing some rewarding re- object (e.g., a pen) to complex, autobiographic contextual mem- sponses,they might be especiallybeneficial to patients, families, ories (e.g., rememberingwhich personal pen was usedto write and caregivers engagedin the managementof this untreatable a specific report). The common words and new faces that the illness. SDAT subjectsfailed to learn in experiments 2 and 3 are ex- amples of declarative knowledge. References The marked disparity between procedural and declarative Ball, M. J. (1978) Topographicdistribution of neurofibrillarytangles learningin SDAT appearssimilar to that of the amnesiascaused and granulo-vasculardegeneration in hippocampalcortex of aging by focal lesions in and nonhuman primates, and is and dementedpatients. Acta Neuropathol.(Berlin) 74: 173-178. strong evidence that SDAT doesnot randomly or diffusely dam- Barbizet,J., P. H. Duizabo,and J. Poirier (1978) Etude anatomocli- age the anatomical substratesof learning and memory. On the niqued’un casd’encephalite amnesiante d’origine herpetique. Rev. Neurol. 134: 241-253. contrary, the cellular damageof Alzheimer’s diseasemust be Butters,N., and L. S. Cermak (1980) Alcoholic Korsakoffs Syndrome, selective and involve especially the hippocampal system (Ball, Academic,New York. 1978; Hyman et al., 1984; Kemper, 1978; McLardy, 1970; Van Cermak,L. S., R. Lewis,N. Butters,and H. Goodglass(1973) Role Hoesenet al., 1985). This systemhas been repeatedly implicated of verbal mediationin performanceof motor tasksby Korsakoff in the learning and retention of declarative knowledge, but not patients.Percept. Mot. Skills37: 259-262. in the learningof procedural knowledge(Corkin, 1968; Damasio Cohen,N. J., andL. R. Squire (1980) Preservedlearning and retention et al., 1985a; Milner, 1966). Recent reports provide new evi- of pattern-analyzingskill in amnesia:Dissociation of knowinghow dencethat Alzheimer’s diseaseinvolves highly selective cellular and knowingthat. Science210: 207-210. and laminar changein layers II and IV of entorhinal cortex and Corkin, S. (1968) Acquisition of motor skill after bilateral medial temporal-lobeexcision. Neuropsychologia 6: 255-265. in all layers of the subiculum, respectively the crucial staging Corkin, S. (1982) Somerelationships between global amnesias and areasfor hippocampal input and output from and to the cerebral the memoryimpairments in Alzheimer’sdisease. In Alzheimer’s Dis- cortex (Hyman et al., 1984; Van Hoesen et al., 1985). These ease: A Report of Progress in Research, S. Corkin, S. Davis, et al., pathologic changesare probably related to the verbal and facial eds.,pp. 149-164,Raven, New York. memory impairments in our SDAT subjects. Damasio,A. R., P. J. Eslinger,H. Damasio,G. W. Van Hoesen,and Motor learning is likely to require different neural structures, S. Cornell (1985a)Multimodal amnesiasyndrome following bilat- The Journal of Neuroscience Spared Learning in Alzheimer’s Disease 3009

era1 temporal and basal forebrain damage. Arch. Neurol. 42: 252- Mishkin, M., and H. L. Petri (1984) and habits: Some 259. implications for the analyses of learning and retention. In Neuro- Damasio, A. R., N. R. Graff-Radford, P. J. Eslinger, H. Damasio, and psychology of Memory, L. R. Squire and N. Butters, eds., pp. 287- N. Kassell (1985b) Amnesia following basal forebrain lesions. Arch. 296, Guilford, New York. Neurol. 42: 263-27 1. Mishkin, M., B. Malamut, and J. Bachevalier (1984) Memories and Graff-Radford, N. R., H. Damasio, T. Yamada, P. J. Eslinger, and A. habits: Two neural systems. In Neurobiology of Learning and Mem- R. Damasio (1985) Nonhaemorrhagic thalamic infarction. ory, G. Lynch, J. L. McGaugh, and N. M. Weinberger, eds., pp. 65- 108: 485-516. 77, Guilford, New York. Hyman, B. T., G. W. Van Hoesen, A. R. Damasio, and C. Barnes (1984) Moscovitch, M. (1982) Multiple dissociations of function in amnesia. Alzheimer’s disease: Cell-specific pathology isolates the hippocampal In Memory and Amnesia, L. S. Cermak, ed., pp. 337-370, formation. Science 225: 1 i68-1170. -- Lawrence Erlbaum, Hillsdale, NJ. Kemper, T. L. (1978) Senile dementia: A focal disease in the temporal Scoville, N. B., and B. Milner (1957) Loss of recent memory after lobe. In Senile Dementia: A Biomedical Approach, K. Nandy, ed., pp. bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 209: 105-l 13, Elsevier-North Holland, Amsterdam. 11-19. McCormick. D. A.. and R. F. Thomuson (1984) Neuronal resuonses Squire, L. R., and N. Cohen (1984) Human memory and amnesia. In of the rabbit cerebellum during acquisition and performance of a Neurobiology of Learning and Memory, G. Lynch, J. L. McGaugh, classically-conditioned nictitating-eyelid response. J. Neurosci. 4: and N. M. Weinberger, eds., pp. 3-63, Guilford, New York. 28 1 l-2822. Squire, L. R., and R. Y. Moore (1979) Dorsal thalamic lesion in a McKhann, G., D. Drachman, M. Folstein, R. Katzman, D. Price, and noted case of chronic memory dysfunction. Ann. Neurol. 6: 503-506. E. M. Stadlan (1984) Clinical diagnosis of Alzheimer’s disease: Re- Terry, R. D., and R. Katzman (1983) Senile dementia of the Alzheimer port of the NINCDS-ADRDA Work Group under the auspices of type. Ann. Neurol. 14: 497-506. Department of Health and Human Services Task Force on Alz- Teuber, H.-L., B. Milner, and H. G. Vaughan (1968) Persistent an- heimer’s Disease. Neurology 34: 939-944. teroarade amnesia after stab wound of the basal brain. Neuropsy-. . McLardy, T. (1970) Memory function in hippocampal gyri but not in chologia 6: 267-282. hippocampi. Int. J. Neurosci. 1: 113-l 18. Van Hoesen, G. W., A. R. Damasio, and B. T. Hyman (1985) Perforant Milner, B. (1966) Amnesia following operation on the temporal lobes. pathway destruction and other temporal lobe pathology in Alz- In Amnesia, C. W. M. Whitty and 0. L. Zangwill, eds., pp. 109-133, heimer’s disease. Neurology 34: 2 19. Butterworth, London.