Juan Fernandez-Ruiz a,∗,1, Luis Velasquez-Perez b,1, Rosalinda Dıaz a, Rene Drucker-Colın c,Ruth Perez-Gonzalez b, Nalia Canales b, Gilberto Sanchez-Cruz b, Edilberto Martınez-Gongora b,
Yaquelın Medrano b, Luis Almaguer-Mederos b, Carola Seifried d, Georg Auburger d
a Laboratorio de Neuropsicologıa, Departamento de Fisiologıa, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Mexicob Clınica para la Investigacion y Rehabilitacion de las Ataxias Hereditarias, Holguın, Cuba
c Departamento de Neurociencias, Instituto de Fisiologıa Celular, Universidad Nacional Autonoma de Mexico, Mexicod Department of Neurology, University Hospital, Frankfurt am Main, Germany
Received 31 October 2006; received in revised form 26 March 2007; accepted 4 April 2007Available online 10 April 2007
bstract
Patients with spinocerebellar ataxia type 2 (SCA2), develop severe pontine nuclei, inferior olives, and Purkinje cell degeneration. This form ofutosomal dominant cerebellar ataxia is accompanied by progressive ataxia and dysarthria. Although the motor dysfunction is well characterizedn these patients, nothing is known about their motor learning capabilities. Here we tested 43 SCA2 patients and their matched controls in prismdaptation, a kind of visuomotor learning task. Our results show that their pattern of brain damage does not entirely disrupt motor learning. Rather,
atients had impaired adaptation decrement, but surprisingly a normal aftereffect. Moreover, the mutation degree could discriminate the degreef adaptation. This pattern could reflect the net contribution of two adaptive mechanisms: strategic control and spatial realignment. Accordingly,CA2 patients show an impaired strategic control that affects the adaptation rate, but a normal spatial realignment measured through the aftereffect.ur results suggest that the neural areas subserving spatial realignment are spared in this form of spinocerebellar ataxia.2007 Elsevier Ltd. All rights reserved.
Spinocerebellar ataxia type 2 (SCA2) is a genetic-based dis-rder of muscle coordination (ataxia) commonly found in Cuba,ith primary symptoms of progressively diminished velocity
accades, poor coordination of speech musculature (dysarthria),nd absence of neurological reflexes such as the knee jerk reac-ion (areflexia) (Durr et al., 1995; Orozco et al., 1989; Pangt al., 2002). SCA2 is a polyglutamine (PolyQ) disorder thatrises from the repeated genetic codon (CAG) that codes for glu-amine, which produces severe degeneration of pontine nuclei,
nferior olives, and Purkinje cells in the cerebellum (Geschwind,erlman, Figueroa, Treiman, & Pulst, 1997). It could be said that
his degeneration triad, without any other severe nuclei degen-
∗ Corresponding author at: Laboratorio de Neuropsicologia, Departamento deisiologıa, Facultad de Medicina, U.N.A.M., A.P. 70-250, C.P. 04510, Mexico,.F., Mexico. Tel.: +52 55 56232123; fax: +52 55 56232395.
ration distinguish SCA2 from the rest of the ataxias (Schols,auer, Schmidt, Schulte, & Riess, 2004). This degeneration isccompanied by olfactory dysfunction (Fernandez-Ruiz et al.,003; Velazquez-Perez et al., 2006), and slower saccades thatorrelate highly with the number of CAG trinucleotide repeti-ions (Velazquez-Perez et al., 2004). Although much of their
otor impairment has been characterized, nothing is knownbout their capacity to learn visuomotor tasks. Here we testedheir capability to adapt to lateral displacing prisms. Prism adap-ation is a phenomenon in which the visual and motor systemsre gradually brought into correspondence in response to a visualhift introduced by the prisms (Redding & Wallace, 2006). Stud-es addressing the involvement of brain regions in this task haveocused on the possible role played by the basal ganglia, the neo-ortex and the cerebellum. Several studies have demonstratedhat patients with basal ganglia disorders have intact prism
daptation (Stern, Mayeux, Hermann, & Rosen, 1988; Weiner,allett, & Funkenstein, 1983). In contrast, studies about theeocortical role on prism adaptation, suggest a role for the ven-ral premotor cortex (Kurata & Hoshi, 1999). Also, the posterior
aritetal cortex (PPC) has been shown to be active during a prismdaptation task using functional imaging (Clower et al., 1996).owever, its contribution to the process is still unclear since two
ecent studies testing bilateral optic ataxia patients showed con-icting results regarding the deficits of these patients in prismdaptation (Newport & Jackson, 2006; Pisella et al., 2004).
The cerebellum has been shown to be important for prismdaptation in both animal (Baizer & Glickstein, 1974; Baizer,ralj-Hans, & Glickstein, 1999) and patient studies (Martin,eating, Goodkin, Bastian, & Thach, 1996; Morton & Bastian,004; Pisella et al., 2005; Weiner et al., 1983), though it did nothow learning related activity in the prism adaptation functionalmaging study (Clower et al., 1996). Although these studieshowed great variability in the population tested, they suggesthat there are certain areas within the cerebellum that are moreritical than others for prism adaptation. In fact it has been shownhat during episodic ataxia it is possible to observe normal prismdaptation (Miall & Silburn, 1997).
The aim of the present study was to test prism adaptationnd its aftereffect in a large homogeneous population of SCA2atients. The correlations of these measurements with the mani-estations typical of this disease were also obtained. Our resultsuggest that SCA2 produces a significant deficit in the adaptationate, and the final magnitude that depends on the CAG mutationength. However, the neuronal degeneration in these patientseems to spare the mechanisms pertaining to aftereffects.
. Methods
.1. Subjects
Forty-three patients (21 male and 22 female patients) with ages rangingrom 26 to 70 years (mean, 41.6; standard deviation [S.D.], 11.6), age at onsetrom 14 to 53 years (mean, 29.56; S.D., 10.23), disease duration from 4 to0 years (mean, 12.54; S.D., 6.06), and polyglutamine repeat sizes from 34 to3 repetitions (mean, 40.54; S.D., 3.56) were admitted to the Centre for theesearch and of Hereditary Ataxias in Holguın for this study. The diagnosis ofCA2 was based on genealogical descent from the founder population, on theisease manifestation with cerebellar ataxia and dysarthria and on molecularenetic determination of the repeat expansions described elsewhere (Auburgert al., 1990). The clinical assessment was conducted using the Internationalooperative Ataxia Rating Scale (ICARS) (Trouillas et al., 1997) that evalu-tes the core clinical symptoms in cerebellar diseases: postural and gait ataxia,imb ataxia, speech disorders and oculomotor disorders (Storey, Tuck, Hester,ughes, & Churchyard, 2004). The Mini-Mental State Examination (MMSE)as also applied (Folstein, Folstein, & McHugh, 1975). A group of 43 age andender-matched unpaid healthy adult volunteers with no history of neurologi-al injury or psychiatry disease from Holguın province (21 male and 22 femaleubjects) with ages ranging from 25 to 72 years (means, 41.8; S.D., 11.9) serveds controls. Subjects with previous history of any other major disorder thatould affect visuomotor performance were not entered into the study. All SCA2atients and controls were right handed. The procedures followed were in accor-ance with the ethical standards of the committees on human experimentationf both the Centre for the Research and of Hereditary Ataxias in Holguın andhe Universidad Nacional Autonoma de Mexico. In addition, all subjects gaveheir informed consent prior to the experiments in accordance with the Helsinkieclaration (Council for International Organizations of Medical Sciences andorld Health Organization, 2002).
.2. Prism adaptation procedure
A detailed description of the procedure and our modifications, can be foundlsewhere (Martin et al., 1996); (Fernandez-Ruiz & Diaz, 1999). The sub-
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ects threw clay balls (weight: 10 g) at a 12-cm × 12-cm cross drawn on aarge sheet of parcel paper centred at shoulder level and placed 2 m away. Theubjects were instructed to make each toss overhand during the whole experi-ent, to use the right hand, and to throw the balls to the location where they
aw the target. The subjects had an unobstructed view of the target during thentire session. The head was unrestrained, and no directions were given aboutrunk, shoulder or head/neck posture. However, they were not allowed to lookown at their hand as they collected the next ball from a tray located next tohem.
The experiment had three conditions. Under each condition the subjectshrew 26 balls. During the baseline condition the subjects did not wear prisms.n the prism condition subjects wore 30 diopter Fresnel 3M Press-on plasticenses (3M Health Care, Specialties Division, St. Paul, MN, USA) that pro-uce a deviation of light to the right. During condition POST the subjectsad the prisms removed before continuing to throw balls. The location of thempacts was plotted sequentially by trial number (abscissa) versus horizontalisplacement (in centimetres) from a vertical line passing through the targetentre (ordinate). Impacts to the left of the target were plotted as negative val-es and impacts to the right were plotted as positive values. Four additionaleasures were calculated from the collected data of both experiments. First,
ariable errors were calculated for each subject by obtaining the standard devi-tion of the horizontal distance made during the baseline throws. Second, andaptation magnitude was obtained by subtracting the horizontal distance to thearget on the final throw from that on the initial throw while wearing the prismsPRISM condition). Third, adaptation and de-adaptation rates were obtained bynalysing the rate of change of the throws distance to the target in each trialuring PRISM and POST conditions respectively. Fourth, an aftereffect mea-ure was defined as the ball’s impact horizontal distance to the target on therst throw after removing the prisms. It is important to note that the first throw
n the POST condition is a real measurement of aftereffect not contaminatedy any kind of expectation or feedback, including possible corollary dischargenformation.
.3. Electronystagmographic recordings
These recordings followed the same method as derived elsewhereVelazquez-Perez et al., 2004). Horizontal and vertical eye movements wereecorded binocularly with silver–silver chloride electrodes over the right andeft outer canti and a two-channel Otoscreen AC electronystagmograph (Jaeger-oennies, Hochberg, Germany) with a band pass filter of 0.02–70 Hz, aensitivity of 200 V/division, a time base of 1000 ms/division, a time constant ofs, and a sampling rate of 200 Hz. Eye movements were elicited with a circularhite target subtending an angle of 0.7◦ on a black background. The distanceetween the patient and monitor as well as head position were controlled byhin/head supports. At least 10 horizontal centrifugal saccades in either direc-ion were recorded for 10◦ predictable amplitudes. Comparison of independentalibrations at a 30◦ angle before and after all recordings were used to controlgainst artifacts.
.4. Saccade analysis
The traces in ASCII format were imported into MATLAB software (version.1; Natick, MA). A program written in-house was used for manual identificationf saccade onset and offset (Velazquez-Perez et al., 2004). Maximal saccadeelocity (MSV in ◦/s) was obtained through third-order polynomial fits of theaw signal. Conditional MSV averages were calculated for saccade directionleft/right) using Microsoft Excel.
. Results
.1. Motor and mental performance
.1.1. Ataxia scoreThe SCA2 patient’s ataxia score using ICARS was
2694 J. Fernandez-Ruiz et al. / Neuropsychologia 45 (2007) 2692–2698
Fig. 1. Mean saccade velocity (MSV) (A) and motor performance results (B)in controls (black bars) and SCA2 (gray bars). Variable errors (B) are the base-line throws standard deviation of the mean obtained for each subject and thenaveraged across subjects. SCA2 patients show slower saccade velocities andla
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Fig. 2. Visuomotor learning results using the prism adaptation task in controls(black bars) and SCA2 (gray bars). The total adaptation magnitude (left) wasi(B
de
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a&(fect correlation was found for the normal subjects (Pearson’scorrelation coefficient, r2 = −0.38, p < 0.01), but not for theSCA2 subjects (r2 = −0.12, p = 0.17) (Fig. 4).
arger variable errors than control subjects. Asterisk (*) denotes p < 0.01. Barsre S.E.M.
.1.2. Saccade velocitySCA2 patients showed a characteristic reduction in saccade
elocity that has been previously reported. Since the Levene’sest for Equality of Variances was not significant, a t-test forquality of means with equal variances not assumed was per-ormed. The results showed significant differences between theontrol group and the SCA2 patient group (t = 11.9, d.f. = 28,< 0.01) (Fig. 1A).
.1.3. Variable errorsDuring the baseline condition, subjects threw balls at the tar-
et without visual perturbation, so it was possible to evaluateheir motor performance in the task. Since the Levene’s Test forquality of Variances was not significant, a t-test for equality ofeans with equal variances not assumed was performed showingsignificant difference between controls and patients (t = −10.6,.f. = 63.4, p < 0.001). The variable errors scores were as follows:ON = 4.58, SCA2 = 12.08 (Fig. 1B).
.1.4. MMSEThe MMSE score for the controls was 28.8 ± 1.3 SDM and
or the SCA2 patients was 27 ± 2.6 SDM.
.2. Prism adaptation
.2.1. Adaptation magnitudeAfter finishing the baseline phase, subjects donned prisms
nd made another 26 throws. Adaptation magnitude was calcu-ated by subtracting the distance to the target of the 26th PRISMhrow from the first PRISM throw. Fig. 2 shows the adaptation
agnitude for both groups. A Student’s t-test analysis for inde-endent samples not assuming equal variances shows that thereere adaptation magnitude differences between the two groups
t = 2.6, d.f. = 70.8, p < 0.05).
.2.2. Adaptation rate
A General Linear Model (GLM) multivariate analysis
howed significant differences between both groups (F = 25.9,.f. = 1, 84, p < 0.01). A GLM pairwise comparison with Bon-erroni adjustment for multiple comparisons showed significant
Fgt(t
mpaired in SCA2 subjects compared to the control group, while the aftereffectright) had the same magnitude in both groups. Asterisk (*) denotes p < 0.05.ars are S.E.M.
ifferences (p < 0.01) between controls and SCA2 for all throwsxcept for throws 1, 3 and 21 (Fig. 3 PRISM phase).
.2.3. AftereffectThe Student’s t-test analysis showed that aftereffects mag-
itudes were similar for both groups as can be seen in Fig. 2t = 2.74, d.f. = 77.32, p = 0.78). A GLM pairwise compari-on with Bonferroni adjustment for multiple comparisons didot show significant differences between controls and SCA2atients either during the de-adaptation rate (after the prisms areemoved and the throws distances go back to the centre withach throw) (Fig. 3, POST phase).
.3. Correlations
.3.1. Adaptation and aftereffectNormally there is a correlation between adaptation and
ftereffect magnitudes at the individual level (Fernandez-RuizDiaz, 1999), that is absent in basal ganglia disorders
Fernandez-Ruiz et al., 2003). Here a normal adaptation afteref-
ig. 3. Raw data per trial in the three prism adaptation conditions. The SCA2roup shows a slower adaptation rate in the prism condition (middle). Duringhis condition there were significant differences (p < 0.01) between the controlblack circles) and SCA2 (gray circles) group for all trials except for prismhrows 1, 3 and 21.
J. Fernandez-Ruiz et al. / Neuropsychologia 45 (2007) 2692–2698 2695
F A2 (g
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aeaeaftereffect were similar in magnitude, while the group with thelow mutation had a typical smaller aftereffect compared withthe adaptation (p < 0.01) (Fig. 6B).
ig. 4. Correlations between adaptation and aftereffect for control (left) and SCroup did not show a significant correlation between adaptation and aftereffect.
.3.2. Disease-related variablesAmong all the variables disease-related, three were signifi-
antly correlated with the adaptation magnitude. First, there wasnegative correlation between adaptation magnitude and the
umber of CAG repetitions in the mutated allele (r2 = −0.41,< 0.01) (Fig. 5). Second, there was a positive correlationetween adaptation magnitude and saccade velocity (r2 = 0.41,< 0.01). Third, there was a significant negative correlationetween adaptation and the variable error (r2 = −0.33, p < 0.03).he magnitude of the aftereffect did not show any significantorrelation with the number of CAG repetitions, the saccadeelocity, nor with the variable error.
.4. Subdivision of the SCA2 population
The pattern of results obtained suggests that the patient popu-ation could be split into groups based on the mutation magnitudes measured with the number of CAG repeats. The comparisonetween the subgroup with the low mutation (37.9 ± 0.4 S.E.M.)ersus the group with the high mutation (43.2 ± 0.69 S.E.M.)howed that the later group had significant impairments in
he rate of adaptation (F = 3.18, d.f. = 26, p < 0.01), and totaldaptation magnitude (t = 3.5, d.f. = 38, p < 0.01) but not in theftereffect measure (Fig. 6A and B). In fact, the group with theow mutation was not different from their matched controls in
ig. 5. Correlation between adaptation and the CAG repetitions length (negativeorrelation, p < 0.01).
FlccdtahiA
right) groups. The control group had a significant correlation, while the SCA2
ny prism adaptation measure. The large mutation group, how-ver, was different from its control group in both adaptation rate,nd magnitude (t = 4.4, d.f. = 37.7, p < 0.01), but not in the after-ffect. Finally, in the large mutation group the adaptation and
ig. 6. Subdivision of SCA2 patients in two groups using the CAG repetitionength as the discriminating parameter. (A) The low mutation group (dark cir-les) showed a normal adaptation rate while the high mutation group (lightircles) showed an impaired adaptation rate (p < 0.01). Note that there were noifferences in the aftereffect de-adaptation rate. Lines are log trend lines; for sta-istical analysis see text. (B) The low mutation group (dark bars) show a largerdaptation magnitude than the high mutation group (light bars). The aftereffect,owever, was similar in both subgroups. Adaptation and aftereffect were signif-cantly different for the low mutation group, but not for the high mutation group.sterisk (*) denotes p < 0.01. n.s., non-significant. Bars are S.E.M.
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696 J. Fernandez-Ruiz et al. / Neur
. Discussion
There are two major findings in the present study. First, SCA2atients showed an impaired visuomotor performance during thedaptation phase of the task that depends on the CAG mutationegree. Second, they did not show an aftereffect impairment,or a correlation between adaptation and aftereffect magnitudesFernandez-Ruiz & Diaz, 1999). The present results also showedhat the deterioration in the adaptation correlated with the motorerformance and saccade velocity, suggesting that structures thategenerate in this disease may contribute to both adaptation andotor performance.
.1. Adaptation
The present results are the first demonstration of a visuo-otor adaptation deficit in SCA2 patients. The patients showsignificant adaptation impairment that correlated with theirotor performance measured through the variable errors and
accadic velocity. This result contrasts with those found in basalanglia patients that despite having different degrees of motormpairments did show normal adaptation (Fernandez-Ruiz et al.,003a). The adaptation impairment shown by SCA2 patientsas also dependent on the CAG mutation degree. This adapta-
ion deficit supports the notion that the cerebellum is importantor prism adaptation, a hypothesis initially advanced in primatesBaizer & Glickstein, 1974; Baizer et al., 1999), and later con-rmed in humans (Weiner et al., 1983). However, not all theerebellum seems to be important for the adaptation processince it has been shown that different areas of regional cerebellaramage could lead to different patterns of impairment (Martint al., 1996). Only lesions including the climbing fibres fromhe contralateral inferior olive, mossy fibres (in the contralat-ral pontocerebellar nuclei) and the posterior inferior cerebellarrtery territory cortex were critical for prism adaptation. In theresent study we tested spinocerebellar ataxia type 2 patientshat, as a population, are characterized by a consistent pattern ofignificant degeneration of the Purkinje cells, the pontine nucleind the inferior olive, which would be critical for prism adap-ation (Durr et al., 1995; Orozco et al., 1989; Pang et al., 2002;chols et al., 2004). In light of the neurological deterioration pro-le of these patients, it seems surprising that they show somerism adaptation. It should be highlighted, however, that there iscorrelation between the severity of the mutation and the impair-ent of adaptation, where the high mutation subgroup showedlarger impairment. This is important since it has been reported
hat larger number of CAG repetitions lead to more aggressiveeurological deteriorations (Giunti et al., 1998) and in this case,arger adaptation deficits.
.2. Aftereffects
Recent theoretical advances suggest that adaptation and after-
ffect could be partly the result of independent processes.ftereffects seem to be related to a process that has been called
patial realignment of reference frames, in contrast to strategicalibration that seems to be related to the strategic control of
dftb
hologia 45 (2007) 2692–2698
he task-work space (Clower & Boussaoud, 2000; Fernandez-uiz, Diaz, Moreno-Briseno, Campos-Romo, & Ojeda, 2006;edding & Wallace, 2002; Redding & Wallace, 2006). The
patial realignment is a slow developing process that bringsnto align the several unique sensorimotor coordinate systemsspatial maps), and does not seem to depend on cognitive pro-esses like attention. In contrast, the strategic calibration is anttentional-dependent, fast developing process that identifies theresent condition of the changing task-work space (Redding &allace, 2002),This theoretical framework suggests that it could be pos-
ible to obtain normal adaptation followed by no aftereffects,nd vice versa (Redding, Rossetti, & Wallace, 2005). In fact, alose analysis of the study by Martin et al. (1996) reveals thatubjects showing apparent good adaptation (a much larger “Dur-ng” than “Adapted” measure) showed no significant aftereffecti.e. patients JR, JM, RL1 and LF2 left arm); and subjects withegligent adaptation showed normal aftereffects (i.e. patientsE both arms, MM right arm, and DW left arm). However, the
mall number of cases per condition precludes a possible gen-ralization. The present results obtained with 43 SCA2 patientseem to fit the pattern of an impaired adaptation with normalftereffects even after a CAG sub grouping. In fact, the afteref-ect measure did not correlate with any other measure that webtained, including MMSE, education, age, or years after theeginning of the first symptoms.
.3. Strategic calibration and spatial realignment
The results suggest that the pattern of neurological degen-ration in SCA2 patients affect the strategic calibration andherefore the prism adaptation rate, but not the aftereffect that
ainly depends on spatial realignment. Evidence for theseypotheses comes first from the fact that SCA2 patients showeficits in executive functions (Burk et al., 2003) and thatmpairments of executive functions during aging seems to affectrism adaptation rate, but not diminish the aftereffect magni-ude (Fernandez-Ruiz, Hall, Vergara, & Diaz, 2000). Followinghis rationale, it can be argued that if the strategic calibrationere the only process affected in the SCA2 patients, then the
daptation magnitude that normally is the result of both strate-ic calibration and spatial realignment would be similar to theftereffect magnitude. In fact our results showed that the SCA2ubgroup with the normal adaptation show the typical largerdaptation/smaller aftereffect pattern, however, the subgroupith an impaired adaptation shows similar adaptation and after-
ffect magnitudes (Fernandez-Ruiz & Diaz, 1999). It shouldlso be noted that not only the aftereffect magnitude is notmpaired, but the normalization rate during the POST testing (de-daptation) is similar between controls and patients, suggestinghat the adaptation deficit is not merely a difference in the wayatients and controls use the feedback from the previous trial toorrect their response for the next trial, but there is a genuine
eficit in the strategic calibration used when the patients per-orm while wearing the prisms. It has previously been suggestedhat the strategic calibration depended on the PPC integrityecause a patient with bilateral optic ataxia showed prism adap-
ation (Pisella et al., 2004). However a recent report in anotherilateral optic ataxia patient showed a different behaviouralattern that precludes any clear conclusion on the possibleole of the PPC on prism adaptation (Newport & Jackson,006).
Our data does not exclude the possibility that other cerebellaregions spared in SCA2, like deep cerebellar nuclei (Raymond,isberger, & Mauk, 1996) contribute to the aftereffect, espe-ially since it has been demonstrated that some cerebellaratients are impaired in this measure (Morton & Bastian, 2004;isella et al., 2005; Weiner et al., 1983). If that is the case,
t would be important to dissect the specific contribution ofach cerebellar area for the different processes involved in prismdaptation (Baizer et al., 1999; Pisella et al., 2005).
In sum, we propose that the pattern of olivopontocerebel-ar degeneration affecting SCA2 patients partly disrupts thedaptation rate of prism adaptation by affecting the strategicalibration process, however, the SCA2 degeneration patternoes not affect the spatial realignment, and in consequence theatients still show some adaptation and its associated afteref-ect. Other cerebellar areas spared in SCA2 may contribute tohe spatial realignment.
.4. Conclusions
Here we report that SCA2 patients show a significant visuo-otor deficit. The degree of this deficit is directly related to
he number of CAG repetitions in the mutation, so it is possi-le to cluster SCA2 patients depending on the mutation extent.uch grouping helped to classify SCA2 patients into two groups:daptation normal versus adaptation impaired. Regardless of therouping, SCA2 patients are not impaired in the prism aftereffectuggesting that the neural areas subserving the spatial alignmentrocess are spared in this disease.
cknowledgements
Authors are indebted to patients, control individuals, ando the Cuban Ministry of Health for the cooperation given.he research was supported in part by a UNAM grant PAPIIT
N213802. We are grateful to Aarlenne Khan and Isaac Kurtzeror their useful comments and language related editing.
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