cognitive components of reaction time parkinson's...

6Journal of Neurology, Neurosurgery, and Psychiatry 1992;55:658-664

Cognitive components of reaction time inParkinson's disease

Nigel Jordan, Harvey J Sagar, James A Cooper

AbstractStudies of reaction time in Parkinson'sdisease (PD) have suggested a selectivedeficit in simple reaction time (SRT),compared with choice reaction time(CRT). This finding has been interpretedas a deficit in motor preprogramming butcould involve other factors, such as atten-tional focussing and stimulus predictabili-ty. Moreover, not all studies show thesame selective deficit, possibly because ofdifferences in patient selection and treat-ment effects. The neurochemical basis ofRT deficits in PD remains unclear.Accordingly, the contribution of cognitivefactors to impaired RT was assessed in alarge group of PD patients, includingearly untreated cases, and performancewas examined in relation to clinical vari-ables and the effect of treatment in longi-tudinal study. Motor output was constantin both SRT and CRT tasks. In the SRTtask, all stimuli required a response; inthe CRT task, subjects were required torespond to only one of the two possiblestimuli. Attentional focussing on SRT wasexamined by variation of the intervalbetween cue and stimulus; effects of stim-ulus uncertainty were evaluated from acomparison of SRT and CRT; temporalpredictability of the stimulus was exam-ined from a comparison of conditions inwhich the interval between warning signalard imperative stimulus was constant orvariable. The PD patients showed similardeficits in SRT and CRT, but normaleffects of cue-stimulus interval and tem-poral predictability. Reaction time corre-lated with measures of global cognitivecapacity and frontal-lobe function, as wellas motor disability. Treatment had noeffect on SRT or CRT, despite clinicalbenefit. These findings indicate that RTdeficits in PD are not due to impairedattentional focussing or stimulus predict-ability but are compatible with a deficit inhigher-order processes concerned withthe orientation of both cognitive andmotor responses to a stimulus. Theseprocesses are not substantially dopamine-dependent but may be served by non-dopaminergic neurotransmission.

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Motor deficits, notably akinesia, are universalclinical features of Parkinson's disease. Howev-

er, a number of cognitive deficits have alsobeen recognised involving attention, memory,frontal lobe function, conceptual ability andvisuospatial function.' 2 The relationshipbetween the cognitive and motor disturbancesis unclear, but deficits in "higher order" motorcontrol, such as motor sequencing,34 doublesimultaneous movements5 and the learning ofnew motor skills6 have been recognised in PDand may be based more on cognitive dysfunc-tion than pure motor impairment.Formal explorations of the role of cognitive

factors in the initiation of movement arescanty. Results of experiments on motor reac-tion time, however, have been used to supportthe concept of a deficit in the "preprogram-ming" of movement in PD. Specifically, PDpatients have been claimed to show prolonga-tion of simple reaction time (SRT), in whichsubjects respond in the same way to all stimuliregardless of nature, but not choice reactiontime (CRT) where a different response isrequired depending on the stimulus. Thus, forexample, a difference between SRT and CRTof approximately 100 to 200 ms in normalelderly subjects7 contrasts with a difference ofonly 50 ms in patients with PD.89 The advan-tage gained by normal subjects in SRT com-pared with CRT has been attributed to theability to make advanced preparation of themovement in SRT but not CRT; thus theinability of PD patients to benefit in SRTcompared to CRT has been ascribed to adeficit in this motor preprogramming. Otherfactors, however, could explain the pattern ofresults on SRT and CRT in PD. In particular,attentional factors would be expected to be lessimportant in CRT, where no advance prepara-tion is possible, than in SRT where the samepreparation is required for all responses. Forexample, the response required from an awai-ted stimulus is uncertain in CRT but not inSRT so that attentional focussing may contrib-ute less to efficient performance in CRTcompared to SRT. In normal subjects, RT isdependent on the interval between a warningsignal and the imperative stimulus that tells thesubject to move; with increasing warningintervals, RT becomes faster. These observa-tions indicate that response preparation isinvolved in the movement tapped by thereaction time tasks. In PD, some studies haveshown that reaction time does not decreasewith increasing warning intervals in the waythat it does in normal subjects and otherstudies have demonstrated an effect of atten-tional manipulation on the SRT deficits ofPD.'° These observations suggest that part of

Department ofNeurology andUniversityDepartment ofMedicine, RoyalHallamshire Hospital,Sheffield, UKN JordanH J SagarJ A CooperCorrespondence to:Dr SagarReceived 19 March 1991and in revised form24 September 1991.Accepted 4 November 1991

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Cognitive components of reaction time in Parkinson's disease

Table 1 Characteristics of subject groups. Figures given as means and, in brackets,standard error of the mean

DiseaseDuration Education NART KCRS

Group M:F Age (years) (years) JQ score

Healthy Control 13:11 58-6 (4-2) - 10-3 (0-7) 108 (67) -Parkinson Untreated 18:14 57-7 (3 6) 1-6 (0-2) 9-4 (05) 102 (6-0) 15-0 (1-3)ParkinsonTreated 20:14 59 9 (3-1) 4-1 (2 3) 9-9 (0 6) 110 (6 6) 19 0 (2 0)

the deficit in SRT in PD may arise fromcognitive factors involved in attentional focus-sing, stimulus prediction or response selec-tion.

In addition to these difficulties of inter-pretation, the pattern of results is not con-sistent across studies as some authors havefound equal prolongation of SRT and CRT inPD." The reasons for these discrepancies areunclear but may be related to other clinicalvariables that influence reaction time butwhich have not been accounted for in theexperimental design and which differ betweenstudies. Thus, for example, cognitive impair-ment may influence reaction time independ-ently ofmotor control; depression may prolongreaction time through its effect of producingpsychomotor retardation; disease chronicityand the nature and duration of treatment mayinfluence SRT and CRT differentially. 2 More-over, the varied nature of the tasks employed inprevious reports may account for some of thedifferences described.This study examined SRT in PD; CRT was

also examined using a go/no-go paradigm inwhich motor response was constant; responsewas manipulated only by altering the instruc-tions to the subject. Thus because motorpreprogramming is possible for all responses,we did not address the question of the extent towhich PD patients select and execute a motorprogramme (Marsden 1982). This study isparticularly concerned with the role of cogni-tive factors in the origin of impaired SRT inPD and considers the following questions:(1) Is slowed response execution of PDpatients in an externally cued SRT task affec-ted by nonspecific response preparation (atten-tional focussing)?This was addressed from twocomponents of the design: First, by manipula-tion of the interval between warning signal andimperative stimulus; and, second, from theeffects of stimulus uncertainty as shown by acomparison of conditions in which all stimulirequire a response (SRT) and those in whichonly some stimuli require a response (CRT).(2) Is slowed response execution of PDpatients in an externally cued SRT task affec-ted by poor temporal predictability of thestimulus? Temporal predictability is addressedby comparing the effects of SRT conditionswith a fixed interval between warning signaland imperative stimulus, which the subjectscan learn to predict, and those in which theinterval was randomly varied.(3) Is slowed response execution of PDpatients in an externally cued SRT task corre-lated with cognitive deficits and depression?(4) Are any of these factors improved by drugtreatment? This question is addressed by com-paring patients on and off medication and by

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longitudinal study of patients before and aftertreatment.

MethodsSubjectsThe subject groups comprised 32 patients withnewly-diagnosed, untreated PD, 34 patientswith PD currently being treated and 24 healthycontrol subjects (HCS) (table 1). Newly-diagnosed PD patients were drawn from con-secutive referrals to the Department ofNeurology. The diagnosis was based on thepresence of akinesia plus rigidity, rest tremoror postural instability and absence of clinicalsigns of other causes of Parkinsonism. TreatedPD patients were willing participants drawnfrom the outpatient clinics of the NeurologyDepartment. The subject groups did not differsignificantly in age, sex or IQ. The untreatedand treated PD subgroups differed signifi-cantly in disease duration but not in clinicalmotor disability. Thus more advanced diseasein the treated PD group was masked bytreatment so that, for the purposes of thisexperiment, the groups were matched in clin-ical motor disability. Medication in the treatedgroup comprised a single drug in 31 patients: alevodopa preparation (14 patients, mean dose200 mg/day, range 100 to 500 mg/day), bro-mocriptine (11 patients, mean dose 15 mg/day,range 4 to 35 mg/day), or benzhexol (6patients, mean dose 8 mg/day, range 2 to30 mg/day). Three patients were receivingpolypharmacy, usually a levodopa preparationplus an anticholinergic drug.Twenty one of the untreated patients were

reassessed after randomisation to monotherapyof levodopa, bromocriptine or benzhexol.Although some individual patients in the benz-hexol or bromocriptine-treated groups showeda weak clinical response, treatment produced asignificant improvement in clinical motor disa-bility in the total group, as measured by scoreon the King's College Rating Scale (KCRS)(p < -0 1). Fourteen of the control subjectswere reassessed at a similar interval.None of the subjects had a past history of

head injury, alcohol abuse or other neuro-logical or general medical condition that mightproduce motor or cognitive impairment. Nosubject was receiving psychoactive medication.None of the untreated patients had receivedlevodopa or bromocriptine at any time beforethe study.

ProcedureThe memory and orientation section of theBlessed Dementia Scale (BDS)'3 was used toquantify the degree of overall cognitive impair-ment. Intelligence quotient (IQ) was estimatedusing the National Adult Reading Test. 14Memory was assessed using the WechslerMemory Scale"5 which provides a memoryquotient (MQ) parallel to IQ in intelligence.Frontal lobe function was assessed from thenumber of categories, number of perseverativeresponses and number of cards to first categoryon the Wisconsin Card Sorting Test(WCST).'6 Affective disturbance was quanti-


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fied by the Beck Depression Inventory(BDI)."7 Overall motor disability was assessedusing the Kings College Rating Scale (KCRS),a detailed quantitative measure of clinicalsymptoms and signs.'8 Finger dexterity (FineFinger Movements; FFM) was evaluated fromthe ability of subjects to rotate a spindlebetween the thumb and forefinger of eachhand; results were expressed as the number ofrevolutions achieved in thirty seconds, aver-aged across the two hands.

Simple reaction time (SRT)(1) Standard cue-stimulus interval During theexperiment, the subject sat facing a VDUmonitor, positioned at eye level. The hand tobe tested was supported by an arm rest fixed tothe chair so that the index finger could becomfortably placed on the response button.SRT was assessed using a BBC Master Seriesmicrocomputer and high resolution VDUmonitor. Subjects received an auditory warn-ing signal of 250 ms duration, one secondbefore the imperative stimulus, a yellow col-oured square of 25 cm2 area, which appearedcentrally on the screen. Subjects were requiredto respond to the appearance of the stimulus asrapidly as possible with a single press of thespace carriage bar of the computer keyboard.The subjects were given standardised instruc-tions and allowed a practice trial of tenresponses to achieve asymptotic improvementin performance. Trials proper required twentyresponses from each hand. Both hands weretested, separately and in random order. Thecomputer measured responses within an accu-racy of ten ms. Results are expressed as themean of the responses from the two hands.

(2) Variable cue-stimulus interval In a secondexperimental condition, the interval betweenwarning signal and imperative stimulus wasvaried. As in the first condition, an auditorytone of 250 ms duration was presented beforethe appearance of the stimulus, a 25 cm2yellow square, on the VDU screen. In thissecond condition, however, the intervalbetween the warning signal and the appearanceof the stimulus was varied in 100 ms stepsbetween 100 and 1500 ms, presented in ran-dom order. Five responses were required ateach of the fifteen intervals to give a total ofseventy-five responses for each hand. Patientswere given standardised instructions andallowed ten practice responses. Results areexpressed as the mean SRT for each of the 15cue-stimulus intervals averaged across bothhands.

Choice reaction time (CRT) As in the standardSRT condition, subjects received an auditorywarning signal of 250 ms duration, one secondbefore the presentation of the stimulus. ForCRT, however, the stimuli were of two differ-ent types, yellow and purple squares each of25 cm2. Stimuli were presented in randomorder. Subjects were required to respond to theyellow square throughout to minimise thememory demands of the task. Forty responses(twenty correct responses) were carried out for

each hand, and results were calculated as themean of all correct responses.

Statistical analysis Differences between datasets were evaluated by repeated measuresanalysis of variance (ANOVA). Paired compar-isons were made using unpaired or pairedStudent's t test (two-tailed, except whereindicated otherwise). Correlations betweenvariables were assessed using Pearson's corre-lation coefficient.

ResultsEffects of temporal predictabilityEffects oftemporal predictability were assessedfrom a comparison of the SRT condition inwhich the interval between the warning signaland the imperative stimulus was constant andthat in which it varied randomly. A repeatedmeasures ANOVA of Group (treated PD,untreated PD, HCS) by Condition (fixedinterval, variable interval) revealed maineffects of Group (p < 0-001) and Condition(p = 0-005) but no interaction (p = 0 75).Planned paired comparisons showed that thetwo PD groups were impaired on both tasks,relative to healthy control subjects (p < 0-001)but did not differ from each other. The maineffect of Condition was accounted for by animprovement in RT when the stimulus becamepredictable (fixed interval condition).Treatment had no effect on temporal pre-

dictability as shown by a repeated measuresANOVA of Group by Condition for the twoPD subgroups only. The main effect of Condi-tion was again significant (p < 0-01) but theeffect of Group and the Group by Conditioninteraction were not significant.

Subsequent analyses assessed the effect ofstimulus uncertainty and attentional focussingon RT.

Fixed cue-stimulus interval (fig 1)Effect of stimulus uncertainty was assessed bya repeated measures ANOVA of Group (trea-ted PD, untreated PD, HCS) by Condition(SRT, CRT). The analysis showed main effectsof Group (p = 0-001) and Condition

500 SRT

El CRT0E

.2 200

100

uHCS PD De Novo PD treated

Figure 1 Simple and choice reaction time in fixedcue-stimulus condition (mean and SEM). De novo andtreated PD patients showed prolonged simple and choicereaction time but the groups did not differfrom each other.

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Figure 2 Simple reaction

time in variablecue-stimulus condition(mean and SEM). Denovo and treated PDpatients showed prolongedSRT at all intervals butdid not differfrom normalsubjects in the effect ofinterval on SRT

500 r-

0

40

E l

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200 I I I 1 III0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Interval (csec)

(p < 0-00001) but no interaction (p = 0-85).Planned paired comparisons showed that boththe newly diagnosed, untreated patients andthose already taking medication were slowerthan the normal control subjects (p < 0'01)but the two PD subgroups did not differsignificantly from each other. Similar analyseswere carried out for SRT and CRT separately.Results showed that untreated patients wereslower than the controls in both SRT(p < 0'0005) and CRT (p < 0 002), as were

the treated patients (p = 0001, p < 0O005respectively); the two PD subgroups did notdiffer from each other in either condition(p = 0-9, p = 0 7).

Variable cue stimulus interval (fig 2)Attentional focussing was assessed by a repeat-ed measures ANOVA of Group by Condition(cue-stimulus interval). The analysis showedmain effects of Group (p < 0O001) and Condi-

Figure 3 SRT and CRT(mean and SEM) before(1) and after (2)treatment in de novo PDcompared with normalsubjects assessed on twooccasions, separated by asimilar intervaL Treatmenthad no effect on response.

4001

0

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._

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E

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1| SRT

300 _

200 _

100 _

0'

600 [

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non (p < 0-0001) but no Group by Conditioninteraction. Thus although slower overall, bothPD subgroups benefitted normally from theadvance information provided by the cue.Planned paired comparisons showed that bothPD subgroups, untreated and treated, differedfrom the control group (p < 0-01) but the twoPD subgroups did not differ significantly fromeach other.

Effect of treatment in longitudinal study (fig 3)For patients tested before and after treatment,repeated measures ANOVA of Group by Con-dition (SRT, CRT) by Assessment (first andsecond assessments for control group; beforeand after treatment for PD group) showedmain effects of Group (p < 0 002) and Condi-tion (p < 0-0001) but no interactions of Con-dition by Assessment (p = 0 32), Group byCondition (p = 0 55) or Group by Assessment(p = 0-56). The lack of significant interactionsindicates that treatment did not improve sim-ple or choice reaction time of the PD patientsdespite significant improvement in clinicalmotor disability. Moreover, the nature of thedrug treatment did not affect performance inthe PD group. Thus reaction time appears tobe largely independent of treatment in PD.

Correlations of reaction-time with cognitive,affective and clinical motor disability (table 2)These correlations were performed on the totalPD group because no significant differenceswere found between the two PD subgroups.Significant correlations were found betweenboth simple and choice reaction time andclinical motor score as measured by the KCRS(r = 050, p = 0-0001 and r = 054, p < 0-0001respectively) and FFM (r = 0-61, p < 0-0001and r = 0 55, p < 00001 respectively). Cogni-tive capacity as measured by the BDS correlat-ed with both SRT and CRT (r = 0.35,p < 0.01 and r = 0 30, p < 0-05 respectively).In addition, number of perseverative responsescorrelated significantly with SRT (r = 0 37;p < 0-01) although not with CRT (r = 0 04;p = 0-8 1); no significant correlation was foundbetween RT and the other cognitive measures(table 2). No correlations were found betweeneither simple or choice reaction times anddepression, as measured by the BDI (r = 0-25,p = 0-27 and r = 0-12, p = 060 respectively).Furthermore, comparison between those PDpatients deemed depressed and those deemednon-depressed according to score on the BDIshowed no significant differences for SRT(p = 0 35) or CRT (p = 0 44).

Table 2 Correlation coefficients (r) between reaction time(SRT, CRT) and measures of cognitive, affective andclinical motor disability

SRT CRT

BDS 0-35 0 30BDI 0-25 0-12MQ - 0-23 -0-12WCST

categories - 0-27 0-18perseverative responses 0-37 0 04cards to 1st category - 0 09 - 0 11

Fine finger movements 0 61 0-55KCRS score 0-50 0-54

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DiscussionThis study examined the effects of attentionalfocussing, temporal predictability and stimulusuncertainty on SRT and go/no-go CRT in PDand related performance to other cognitive andaffective measures and the effects of treatment.The results indicate that:(1) The prolonged SRT in PD was not causedby lack of temporal predictability, stimulusuncertainty or poor attentional focussing.(2) None of the factors examined in this RTstudy was affected by therapy sufficient toproduce improvement in clinical motor disa-bility.(3) RT in PD was correlated with cognitiveimpairment.

SRT-CRT differences in PDResults of studies of SRT and CRT in PD arecontroversial; some studies have shown aselective abnormality of SRT89' whereasothers have shown deficits in both SRT andCRT.'220 Reasons for these discrepancies arenot clear but may relate to patient selection aswell as experimental design.

"Choice" in a CRT experiment may bechoice of movement or choice of correctstimulus. Most studies have used choice ofmovement as the response variable, includingright or left index finger,9 direction of move-ment in response to the appearance of acursor,19 right or left movement,12 and right orleft arm, direction and extent of movement.20In our experiment, however, "choice" was oneof correct stimulus, the motor response beingconstant. The critical difference between thisand previous studies is that in our CRTexperiment not all the stimuli required amovement whereas, in other studies, eachstimulus required a movement, albeit of adifferent nature. Our CRT paradigm used aconstant motor output; subjects were simplyrequired to decide whether or not to respond.We cannot therefore address directly the issueof motor preprogramming deficits in PD.However, the finding of equivalently impairedperformance on the SRT and CRT taskssuggests that the PD patients are not specifi-cally affected by uncertainty as to whether ornot the stimulus will appear; that is, slownessof response in PD is unlikely to be due toabnormal response criteria. In so far as these"confidence ratings" are a reflection of atten-tional control and executive processes, such asprediction, the results suggest that deficits inthese domains are not influential at this simplelevel of response.

Effects of attentional focussingWe predicted that a deficit in attentionalfocussing in PD would lead to greater slowingof SRT at shorter cue-stimulus intervals butthis result was not obtained. Indeed, thepattern of response across cue-stimulus inter-vals was qualitatively normal after the first100 ms. Normal effects of variable cue-stim-ulus interval have also been shown by Rafal etal.2" Thus the results of the variable cue-stimulus condition suggest that abnormal SRTin PD is either the simple result- of motor

slowing, is due to poor attentional focussingwithin the first 100 ms or is due to higher ordercognitive deficits. The correlations betweenSRT, CRT and global cognitive capacity asassessed by the Blessed Dementia Scale, andbetween SRT and perseverative responses onthe Wisconsin Card-Sorting Test, support arole of cognitive deficits in the origin ofabnormal reaction time in PD. Surprisingly,depression was found to have no influence onreaction time in this experiment. Other obser-vations from our laboratory, however, do sup-port an effect of depression upon reaction timewhen assessed in an uncued paradigm.22 Ingeneral, the results suggest a substantial effectof cognitive factors in reaction time in PD butdo not support specific deficits in attentionalfocussing, or stimulus prediction. AlthoughBloxham et al23 showed differences in the effectof cue-stimulus interval on SRT of PD andcontrol subjects, the major difference was atthe longest interval (3200 ms) and the authorsconcluded that PD patients function in SRT asif performing a secondary task but allocateattentional resources normally. Our results arecompatible with this interpretation. Of partic-ular interest in our study is the finding of asignificant correlation between SRT and num-ber ofperseverative responses on theWisconsinCard-Sorting Test, a traditional measure offrontal-lobe function. Although no correlationwas found with CRT, and interpretation mustbe tentative at this stage, this result doessuggest that frontal-lobe function may be acritical influence on reaction time in PD and,by implication, in the genesis of normalmovement.

Brain-behaviour relationships in reaction timetasksThe basal ganglia have been considered impor-tant in the preparation, selection and executionof learned motor programmes.24 In SRT, allstimuli require a response so that the move-ment can be prepared in advance of thestimulus; in CRT, by contrast, the requiredmovement depends upon the nature of thestimulus, so that the movement cannot beprepared in advance. The finding in somestudies of a selective deficit in SRT relative toCRT in PD has led to the suggestion thatpatients with PD are impaired in motor pre-programming, that is, the ability to self-directthe preparation and selection of motor pro-grammes in advance of an external stimulus torespond.8 9 19SRT and CRT have been considered to

depend upon separate routes for action. A"fast" route for SRT is dependent on atten-tional focussing; a direct route for CRT isslower and attentional focussing is notrequired.25 The fast route is largely controlledby internal control of attention whereas thedirect route is largely automatic and controlledby external stimuli. The Bereitschaftspotentialor "readiness" potential is detectable as amidline cortical potential immediately preced-ing voluntary movement and may arise fromactivation of the loop between the supplemen-tary motor area (SMA), the basal ganglia and



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the ventrolateral thalamus; the SMA is con-sidered to be involved in "motor readiness."26In PD, some studies indicate diminution in theamplitude of this potential27 implying disrup-tion of links with the supplementary motorarea as critical to the origin of disorderedvoluntary movement in PD. More recentlypositron emission tomography has demon-strated activation of the SMA when normalsubjects carry out motor tasks dependent oninternal cues (where movement preparation ispossible in advance) and especially on tasks inwhich they generate a random selectionbetween different movements.28 Preliminaryobservations in PD suggest impaired activationof the SMA during attempts to conduct thesetasks (Passingham, personal communication).Together, these observations suggest that afundamental deficit in disordered voluntarymovement in PD arises from disruption of thebasal ganglia-SMA connections which leads toa deficit in the execution of motor outputthrough internal cues. With externally-cuedmovement, input from the sensory cortex feedsdirectly into premotor cortex, bypassing theSMA, so that PD patients perform thesemovements much better.29.How can these conclusions be related to the

results of our study? Factors that influencedmotor readiness might be expected to havedisproportionate effects in PD if they operatedthrough the SMA but this prediction was notfulfilled and other explanations must be con-sidered. First, the finding that RT in PD is notdifferentially influenced by attentional focus-sing, temporal predictability or stimulus uncer-tainty suggests that these attentional factorsmay be acting independently of the SMA andare acting through a direct route to thepremotor cortex. Second, the lack of effectmay be related to the experimental design. Thewarning signal acts as an external cue so thatthe effects of interval in this design mayoperate preferentially on the premotor cortex.Further studies should examine the effects ofinterstimulus interval in a continuous, uncuedreaction time paradigm. Third, the PD patientsmay achieve normal effects of attentionalmanipulation in RT tasks by attentional over-compensation. PET studies, for example, haveshown that cortical activation is inversely relat-ed to cognitive performance in a verbal fluencytask, implying that poor performers show lessefficient cortical metabolism.30This hypothesispredicts that the attentional manipulationsincorporated in the experiment reported herewould be accompanied by supernormal activityin frontostriatal pathways in PD.

Effects of treatmentSeveral studies have considered the relation-ship between reaction time and activity indopaminergic pathways, by observing theeffect of medication or the changes during on-off swings. Rafal et al2' studied ten patients,four before and after treatment with levodopaand six during marked on-off swings. Analysesof reaction times were performed in terms ofunremediated, that is, before treatment or"off' and remediated, that is, after treatment

or "on". The unremediated patients had slowerreaction times than the remediated patients.All cases, however, had advanced disease, thedisease duration ranging from six to twentyyears; the cognitive and affective state of thepatients is unclear; the changes in clinicalmotor disability were marked; the results werederived from a mixed group of patients,including some with age of onset as young as27 years and one who had undergone athalamotomy; and treatment was variableamong subjects. Similar problems hamperinterpretation of other studies. Pullman et al'2examined five patients aged 29-61 years withHoen and Yahr disability ratings of II to IV,who were not clinically depressed, before andafter intravenous infusions of levodopa. Thetreatment switched the patients from an "off'to an "on" state. This change was associatedwith improvement in choice but not simplereaction time. This result suggests that simplereaction time is not exclusively dopaminedependent. Starkstein et alP studied sixpatients with a mean illness duration of 11 6years who showed marked motor fluctuations,including dyskinesia. SRT did not change fromthe "off' to the "on" state although movementtime improved significantly. This study pro-vides further evidence of a dissociationbetween SRT and clinical motor disability asmeasured by movement time and suggests thatsimple reaction time is not mediated throughdopamine.The studies to date have not compared

reaction time in untreated and treated groupsand have not directly addressed the effect ofinitiation of treatment in early, untreated PD.A recent study, however, has shown involve-ment of dopamine in motor readiness in ratswith unilateral dopamine depletion induced byhydroxydopamine injections into the stria-tum.32 Unlike the patients of our study, theseanimals showed a failure to improve SRTperformance as a function of interval betweenwarning signal and imperative stimulus. How-ever, 6-hydroxydopamine produces profounddopamine depletion within the striatum; ourpatients, as a group, had a short diseaseduration and relatively mild disease (table 1).Thus the discrepancy between our study andthat of Brown and Robbins may be due todifferences in the extent ofdopamine depletionwithin the striatum. Our results do not excludean effect of dopamine on reaction time in moresevere PD; nevertheless, the observation thatdopamine depletion sufficient to cause clinicalsigns of PD is not necessarily accompanied bydeficits in motor readiness suggests that motorreadiness is dependent on very low levels ofdopaminergic neurotransmission or, perhapsmore likely, involves non-dopaminergic as wellas dopaminergic systems. On-off swings areassociated with change in affect-arousal33which may be dependent on noradrenergicactivity.34 Reaction time and vigilance arerelated to CSF levels of the noradrenalinemetabolite 3 methoxy-4-hydroxyphenylethy-lene glycol (MHPG).35 Thus reaction timemay be partially dependent on the integrity ofnoradrenergic pathways whereas movement



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time is related principally to dopaminergicactivity.

In conclusion our study showed that earlyuntreated patients with PD show prolongationof SRT which is not due to deficits inattentional focussing, stimulus anticipation or

temporal predictability. The deficits correlatewith cognitive and motor measures but do notimprove on treatment, despite clinical benefit.The results suggest that PD patients showslowing in processes concerned with orienta-tion ofboth cognitive and motor responses to a

stimulus. The deficits are not exclusively relat-ed to nigrostriatal dopamine deficiency.

This research was supported by grants from Roche Products,UK and the Parkinson's Disease Society, UK. We thank DrsGAB Davies-Jones, J Gumpert and G Venables for referringpatients for study, Dr N Harvey for provision of some of theBeck scores on the PD group and Dr E Sullivan for usefuldiscussion.

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