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Published Online: 29 April 2015

The Impact of Emotional Distress on Motor Blocks and Festination in Parkinson’s Disease

Publication: The Journal of Neuropsychiatry and Clinical Neurosciences

Abstract

Recent studies suggest that depression and anxiety in patients with Parkinson’s disease may predispose them to freezing. Although festination is also frequent, the association with emotional disorders has not been examined. The aim of the authors was to clarify the association between freezing and festination with anxiety, depressive disorders, and emotional distress. The authors examined a consecutive series of 95 patients with Parkinson’s disease using comprehensive psychiatric assessments and a new instrument specifically designed to assess the severity of freezing, festination, and emotional distress (Motor Blocks and Festination Scale). All patients were assessed with the Motor Blocks and Festination Scale, the Mini International Neuropsychiatric Interview, and scales to measure the severity of mood and anxiety disorders. A linear regression analysis showed that both motor blocks and festination were significantly associated with emotional distress and deficits on activities of daily living. Conversely, there was no significant association between motor blocks or festination and generalized anxiety disorder, panic disorder, agoraphobia, social phobia, or depression. Motor blocks and festination are significantly associated with emotional distress, but no significant associations were found with anxiety or affective disorders.
About one half of patients with Parkinson’s disease (PD) have sudden and transient motor blocks (MBs) during walking, speaking, or writing.15 MBs are among the most distressing symptoms in PD,6 but the mechanism remains poorly known.7 PD brings with it a range of stresses and challenges with which a patient must cope. MBs are more frequent and severe when patients with PD are exposed to situations producing emotional distress, such as walking in crowded places, speaking to audiences, or signing documents while being watched.8 Lieberman found that anxiety and panic attacks, but not depression, were more common among patients with freezing of gait (FoG) compared with patients with PD without this condition.9 Depression was also found to be associated with FoG,10 and Giladi and Hausdorff11 speculated that depression and anxiety may decrease the threshold for FoG. Nevertheless, the association between anxiety, depression, and MBs has been rarely examined, and the few pioneering studies assessed depression and anxiety with severity rating scales only.9,10
Festination is the tendency to speed up and lose normal amplitude during quick, repetitive movements that may involve gait, speech, and writing.12,13 There are few studies on the clinical correlates of festination in PD. Giladi and coworkers13 used the Festination of Gait Questionnaire to assess 81 patients with PD and found festination in 32% of the sample. Patients with festination had a significantly younger age at symptom onset, longer duration of PD, more severe freezing, and were on a higher mean daily levodopa dose compared with patients without festination. Moreau and coworkers14 found oral festination to be as frequent as gait festination and freezing.
Another important clinical aspect never formally examined is the presence and severity of emotional distress concomitant to MBs and festination. Thus, whether patients with MBs or festination and emotional distress have an underlying anxiety of affective disorder remains unknown. To assess MBs, festination, and emotional distress in a structured and objective way, we designed and validated a specific scale to assess the severity and correlates of MBs, festination, and emotional distress in PD [the Motor Blocks and Festination Scale (MBFS)]. The MBFS allows determination of the presence and severity of MBs and festination, as well as the presence of emotional distress. This instrument was specifically designed to allow measures of emotional distress for each specific type of MB and festination (see Appendix).
The main aim for the present study was to examine the impact of concomitant stress, generalized anxiety disorder, panic disorder, agoraphobia, social phobia, and depression on MBs and festination in PD. On the basis of previous findings,9 we hypothesized that concomitant emotional distress and anxiety disorders, but not major depression, would show a significant association with MBs and festination.

Patients and Methods

Patients

A consecutive series of 104 patients with idiopathic PD who attended the PD Community Clinic at Fremantle Hospital (Australia) at regular follow-up visits were invited to participate in a cross-sectional study on the clinical correlates of MBs and festination in PD. Nine patients refused participation, leaving a total sample of 95 patients assessed. All patients met the United Kingdom PD Society Brain-Bank clinical criteria for idiopathic PD.15 Patients with a history of brain lesions, neuroleptic medication use, lack of response to antiparkinsonian drugs, or a diagnosis of dementia based on DSM-IV criteria were excluded from the study. The study was approved by the Human Research Ethics Committee at Fremantle Hospital and by the Ethics Committee at the Raul Carrea Institute of Neurological Research-Fleni.

Neurological Examination

After the methodology of the study had been fully explained, informed written consent was obtained from all the participants. Patients were assessed by a neurologist with the Unified Parkinson’s Disease Rating Scale (UPDRS).16 All patients were examined during the maximal benefit of the medication. A neurologist also assessed a subsample of 24 patients with the FoG Questionnaire (FoG-Q),1 a six-item instrument that measures the presence and severity of FoG. Motor blocks and festination were explicitly demonstrated to all patients by a neurologist.

Psychiatric Examination

A clinical psychologist or research nurse blind to neurological findings assessed all patients with the Mini International Neuropsychiatric Interview.17 Based on the Mini International Neuropsychiatric Interview responses, DSM-IV axis I diagnoses of minor and major depression, generalized anxiety disorder, panic disorder, social phobia, and agoraphobia were made using the inclusive approach.18 All patients were also assessed with the following instruments: the Mini-Mental State Examination (MMSE),19 the Hamilton Depression Rating Scale (HAM-D),20 and the Hamilton Anxiety Rating Scale (HAM-A)21 (the HAM-A was scored on the last 62 patients assessed due to late inclusion of this scale). Daily doses of different classes of antidepressants were rated with the Unipolar Composite Antidepressant Rating,22 and levodopa dose equivalents were calculated based on the scheme of Tomlinson and coworkers.23

Statistical Analysis

Statistical analyses for continuous variables were carried out using means and standard deviations and unpaired t tests. Correlation coefficients were calculated with Pearson’s r. Frequency distributions were calculated using chi-square and Fisher’s exact tests. All p values are two tailed. Test–retest and interrater reliability was calculated with intraclass correlations (ICCs) based on two-way random effects models and averaged measures. Cronbach’s alpha was used to assess internal validity, and nonparametric correlations were used to calculate convergent and divergent validity. The overall chi-square tests from a full model multivariate linear regression were used to test the clinical predictors of MBs and festination. Criteria for inclusion of variables were based on exploratory univariate analyses (Tables 2 and 3) and on ad hoc selection of variables relevant for the analysis. If the overall test was significant, we followed up with individual tests.24

Results

Demographic and Clinical Characteristics

Our sample consisted of 63 men and 32 women, with a mean age (± standard deviation) of 67±8.7 years, mean education of 13.6±2.7 years, and a mean duration of illness of 8.7±4.6 years. Mean MMSE score was 26.8±3.6 points, and mean UPDRS motor score was 34.3±13.0 points. Nine patients (10%) were at Hoehn-Yahr stage I, 29 patients (31%) were at stage II, 45 patients (47%) were at stage III, and 12 patients (12%) were at stage IV. Based on the Mini International Neuropsychiatric Interview assessment, 13 patients (14%) met DSM-IV criteria for minor depression, 15 patients (16%) had major depression, 11 patients (12%) had generalized anxiety disorder, 13 patients (14%) had agoraphobia, 2 patients (2%) had social phobia, and no patient had a panic disorder without agoraphobia.

MBFS (Appendix)

We designed the MBFS with the following aims: 1) to assess the presence and severity of different modalities of MBs (either in gait, speech, or writing) in PD3; 2) to assess the presence and severity of festination; and 3) to assess the presence and severity of emotional distress during MBs and festination. To obtain adequate face validity for the instrument, a pilot scale was constructed based on existing clinical information and instruments rating FoG and festination.1,14,2528 Additional items were added to the scale to assess MBs and festination on speech and writing. A pilot version of the MBFS was assessed on a group of 20 patients with PD and was modified to include specific questions about the presence and severity of emotional distress during MBs and festination. The final version of the MBFS is a rater-assessed instrument that includes both quantitative and qualitative items to rate and describe MBs and festination in PD. Briefly, quantitative items (1a, 2a, 3a, 8a, 9a, 10a, 11a, and 12a) rate the severity of MBs and festination on walking, speaking, and writing, and each item is followed by a specific question about the presence and severity of concomitant emotional distress. MBs were considered present whenever patients scored 1 or more on at least one item, and a total MB motor score was calculate by adding all the quantitative items. To determine the impact of emotional distress, an MB stress score was calculated as the sum of scores of the specific question for concomitant emotional distress (included in items 1b, 2b, 3b, 8b, 9b, 10b, 11b, and 12b) divided by the total number of motor items answered positive. The same strategy was used to calculate the festination motor score and the festination stress score. Qualitative items (4, 5, 6, and 7) were also assessed but were not considered for diagnostic or scoring purposes.
The MBFS showed a high internal consistency (Cronbach’s alpha for the MBFS MB section=0.86; festination section=0.92). Test–retest reliability was examined in a consecutive series of 10 patients who were assessed twice (median interval: 21 days) and was very strong [intraclass correlation coefficient (ICC)=0.91; 95% confidence interval (CI)=0.65–0.98]. Interrater reliability was assessed twice in 18 patients (median interval=17 days) by two independent raters blind to each other’s ratings and was very strong (ICC=0.88; 95% CI=0.68–0.95). Test–retest reliability for the MBFS stress section was strong (ICC=0.70; 95% CI=0.18–0.92), and the interrater reliability was very strong (ICC=0.91; 95% CI=0.76–0.96). Convergent and divergent validity was calculated as per the study of Giladi et al.1 Findings were remarkably similar, suggesting strong convergent and divergent validity (Table 1). We further assessed convergent validity in a subsample of 24 patients who were assessed with the MBFS (FoG section) and the FOG-Q by two independent raters blind to each other scores, and the correlation was significant (Pearson’s r=0.56, p<0.005). The MBFS was assessed by an examiner after the patient was assessed by the neurologist with the UPDRS, when examples of MB and festination were provided.
TABLE 1. Convergent and Divergent Validity for the Motor Blocks and Festination Scale-Gait (MBFS-Gait) and for the Freezing of Gait-Questionnaire (FoG-Q)1
 MBFS-gaitFoG-Q
UPDRS-ADLs0.400.34
UPDRS-motor0.280.31
UPDRS-mentation0.200.20
UPDRS-freezing0.430.65
UPDRS-walking0.230.37
UPDRS-tremor0.070.05
UPDRS-depression0.160.15
UPDRS-cognition0.110.12
Numbers correspond to r values. UPDRS: Unified Parkinson’s Disease Rating Scale.

MB and Festination Findings

Seventy-eight patients (82%) of the 95 patients had MBs (one patient had to be excluded due to missing values on the MBFS). Forty-one patients (43%) had FoG, 64 patients (68%) had MBs with speech, and 55 patients (59%) had MBs with writing. Fifty-two patients (55%) had festination. Twenty-nine patients (31%) had festination on walking, 40 patients (42%) had festination on speech, and 40 patients (42%) had festination on writing. Both MB and festination were present in 52 patients (55%), and FoG and festination on walking were present in 29 patients (31%). There were strong correlations between MB motor and festination motor scores (r=0.70, df=94, p<0.0001), MB gait and MB speech (r=0.39, p<0.0001), MB gait and festination gait (r=0.53, df=94, p<0.0001), festination gait and festination speech (r=0.52, df=94, p<0.0001), and MB speech and festination speech (r=0.85, df=94, p<0.0001).

Association Between MB and Festination and Psychiatric Disorders

Seventy-eight patients (82%) scored positive for one or more types of MBs. There were no significant differences between patients with or without MB on the frequency of minor depression (10% versus 29%, respectively), major depression (18% versus 6%, respectively), agoraphobia (12% versus 24%, respectively), social phobia (3% versus 0%, respectively), or generalized anxiety disorder (13% versus 6%, respectively). Similarly, there were no significant differences between patients with (N=52) or without festination (N=43) on any of the psychiatric diagnoses (minor depression: 11% versus 17%, respectively; major depression: 22% versus 7%; agoraphobia: 19% versus 7%; social phobia: 2% versus 2%; generalized anxiety disorder: 15% versus 7%).
Patients with MBs and emotional distress had more severe MBs and festination, more frequent falls due to freezing, more severe deficits on activities of daily living (UPDRS section), and higher UPDRS motor scores than patients with MBs without emotional distress (Table 2). Conversely, there were no significant differences between patients with MBs with or without emotional distress on any of the psychiatric variables (Table 2). Patients with festination and emotional distress (N=28) had significantly higher festination and MB motor scores, more frequent falls due to festination, and more severe deficits on activities of daily living (UPDRS section) than patients with festination without emotional distress (Table 3). Finally, we compared patients with FoG and emotional distress (N=18) with patients with FoG and no emotional distress (N=23). Patients with emotional distress were more prone to falls due to freezing than patients with FoG and no emotional distress (mean±SD=0.56±0.51 versus 0.10±0.30, respectively, t=3.48, df=39, p<0.0001). Patients with FoG and emotional distress also had more severe MBs (9.67±5.09 versus 5.39±3.59, t=3.15, df=39, p=0.003) and more severe festination (6.28±5.15 versus 2.35±3.58, t=2.87, df=39, p<0.01) than patients with FoG and no emotional distress.
TABLE 2. Demographic and Clinical Differences Between Patients With PD With MB and Concomitant Stress (N=35) and Patients With PD With MB and No Stress (N=43)
 MB without stress [mean (standard deviation)]MB with stress [mean (standard deviation)]t test/χ2p
Age (years)67.6 (9.0)69.0 (8.4)0.710.47
Education (years)13.0 (2.6)13.3 (2.8)0.720.56
Mean levodopa dose707 (315)652 (416)0.640.51
MBFS MB motor score4.34 (3.7)7.77 (5.1)3.270.001
MBFS falls due to freezing0.06 (0.2)0.42 (0.50)2.870.002
MBFS festination motor score2.23 (3.5)5.35 (5.4)2.910.003
Mini Mental State Examination27.2 (3.2)26.4 (3.9)0.780.43
UPDRS-ADLs14.7 (6.1)18.4 (6.7)2.520.01
UPDRS-motor30.4 (12.4)38.6 (12.8)2.830.006
Hamilton Depression Scale8.5 (4.9)10.2 (5.3)1.500.13
Hamilton Anxiety Scale (N=27, N=35)10.7 (7.6)11.4 (8.0)0.320.74
GAD (N=4, N=6)11%14%1.280.25
Agoraphobia (N=3, N=6)9%14%2.470.11
Social phobia (N=0, N=2)0%5%0.030.84
Minor depressiona (N=3, N=5)9%12%4.140.12
Major depressiona (N=5, N=9)14%21%4.140.12
UCAR0.51 (1.0)0.74 (1.0)0.990.32
GAD: generalized anxiety disorder; MB: motor block; MBFS: Motor Blocks and Festination Scale; PD: Parkinson’s disease; UCAR: Unipolar Composite Antidepressant Rating.
a
df=2.
TABLE 3. Demographic and Clinical Differences Between Patients With PD With Festination and Concomitant Stress (N=28) and Patients With PD With Festination and No Stress (N=24)
 Festination-no stress [mean (standard deviation)]Festination with stress [mean (standard deviation)]t testp
Age (years)67.4 (7.3)68.5 (8.5)0.490.62
Education (years)13.2 (2.3)13.0 (2.7)0.300.76
Mean levodopa dose660 (323)623 (378)0.370.71
MBFS festination score3.75 (3.6)7.86 (5.1)3.270.001
MBFS falls due to festination0.67 (0.65)0.22 (0.44)2.870.002
MBFS MB motor score6.50 (4.31)8.43 (6.2)2.910.003
Mini Mental State Examination26.7 (4.0)26.5 (3.6)0.270.78
UPDRS-ADLs16.9 (6.6)18.5 (6.2)2.520.01
UPDRS-motor34.8 (11.9)39.4 (13.4)1.290.20
Hamilton Depression Scale9.3 (4.9)10.8 (5.8)0.560.33
Hamilton Anxiety Scale (N=19, N=21)11.2 (8.8)10.8 (7.8)0.170.86
GAD (N=4, N=4)17%11%1.280.25
Agoraphobia (N=5, N=5)21%18%2.470.11
Social phobia (N=0, N=1)0%4%0.030.84
Minor depressiona (N=0, N=5)0%21%4.140.12
Major depressiona (N=4, N=8)14%33%4.140.12
UCAR0.58 (1.01)1.07 (1.24)1.530.13
a
df=2.
A multiple linear regression analysis was calculated for patients with MBs, with MB motor scores as the dependent variable, and UPDRS-ADL scores, MB stress scores, duration of illness, MMSE scores, and LED scores as independent variables. The model was statistically significant (R2=0.46; F(6,77)=10.10, p<0.0001). The variables that accounted for a significant part of the variance were the MB stress score (beta=0. 36; p<0.0001) and UPDRS-ADL scores (beta=0.46; p<0.0001). A similar analysis was calculated for the festination motor scores as the dependent variable. The model was statistically significant (R2=0.68; F(6,51)=6.77, p<0.0001). The variables that accounted for a significant part of the variance were the MB stress score (beta=0. 33; p<0.01) and UPDRS-ADL scores (beta=0.58; p<0.0001).

Discussion

We examined the association between MBs and festination and common psychiatric disorders in PD such as anxiety and depression. We also examined the presence and severity of emotional distress concomitant with MBs and festination using a newly designed instrument that was specifically designed for this study, and there were several important findings. First, there was a significant association between the severity of both MBs and festination and emotional distress. Conversely, there was no significant association between MBs or festination and anxiety disorders (generalized anxiety disorder, agoraphobia, social phobia, and panic disorder) or minor or major depression. Second, patients with MBs and emotional distress had more severe MBs and festination, more frequent falls due to freezing, more severe deficits on ADLs, and higher UPDRS motor scores than patients with MBs and no emotional distress. Third, MBs and festination were significantly associated, and this association was true for both gait and speech manifestations.
Recent studies examined clinical correlates and putative mechanisms of MBs in PD. Lieberman9 reported higher anxiety and more frequent panic attacks among patients with MBs compared with patients without MBs, but no association was found between MBs and depression. Conversely, FoG has been related to the presence of depression in the context of two large drug trials.10,29 The LARGO study10 used the FoG-Q and found a significant association between more severe freezing and higher depression scores, but patients with major depression were excluded from the study. One important limitation common to all these studies is that anxiety and depression were assessed with severity rating scales and not with more appropriate structured psychiatric interviews and standardized diagnostic criteria.
Our study used a specific instrument to measure emotional distress during MBs and festination, and we diagnosed anxiety disorders and major depression using the Mini International Neuropsychiatric Interview and DSM-IV criteria for anxiety and affective disorders. We were unable to find significant associations between MBs or festination and specific anxiety disorders such as generalized anxiety disorders, panic disorder, agoraphobia, social phobia, or depression. Conversely, we found a significant association between MBs and emotional distress, supporting the suggestion of Giladi and Hausdorff11 that patients with PD are predisposed to MBs by the stress induced when confronting time-critical motor challenges.
To our knowledge, this is the first study to examine the association between festination and anxiety disorders. Although we found a significant association between festination and emotional distress, there was no significant association between festination and any anxiety disorder or depression. The strong association between MBs and festination suggests that both disorders may share a common mechanism and are both related to emotional distress.
The question now arises as to whether emotional distress is a cause or a consequence of MBs or festination. Our finding that about 50% of patients with MBs/festination had no emotional distress suggests this factor is neither necessary nor sufficient to produce MBs or festination. It is possible that, in predisposed individuals, emotional distress may greatly increase the severity of MBs/festination. Nevertheless, this is a cross-sectional study, and the direction of causality cannot be established. When we compared patients with MBs with or without emotional distress, we found that patients with emotional distress had more severe MBs, festination, falls due to freezing, more severe deficits in ADLs, and higher UPDRS motor scores than patients with PD with MBs but without emotional distress. These findings suggest that patients with MBs and emotional distress have more advanced illness and that distress may amplify the expression of MBs. Conversely, a linear regression showed that neither duration of illness nor UPDRS motor scores are significantly related to MBs or festination, suggesting that severity of illness may not account for emotional distress. Maidan and coworkers30 measured heart rate in 10 patients with PD with FoG to examine the impact of stress in the mechanism of FoG. They found a significant increase in heart rate just before freezing, which persisted and increased during the FoG period. This finding suggests that emotional arousal is not a mere consequence of FoG, but it is not a clear causative factor either. Our findings may be construed as suggesting that emotional distress is an intrinsic nonmotor manifestation of MBs and festination. Although MBs and festination are associated with moving in the context of time-critical motor challenges,11 emotional distress may result from moving in emotionally arousing contexts (e.g., those increasing the chance of patients becoming self-conscious of potential motor failure). Both the motor and emotional expression of MBs may result from dysfunction of brain areas that integrate motion and emotion.31 In support, Snijders and coworkers32 recently demonstrated a significant association between FoG and structural and functional alterations in the mesencephalic locomotor region, an important motor output of the emotional motor system.31
Finally our finding of a significant association between MBs/festination and emotional distress may have important clinical implications. Patients with PD may benefit from learning behavioral techniques to dampen the severity of stress, as well as from small doses of anxiolytic agents to be used in circumstances with a high chance of triggering severe MBs/festination. The efficacy of these therapeutic options should be the focus of future studies.
Several limitations of our study should be pointed out. First, our sample was relatively small, and results should be replicated in larger samples. Conversely, our study is the first to assess the association between MBs/festination and anxiety and affective disorders using a structured psychiatric interview and a specific instrument to measure MB, festination, and emotional distress. Second, the MBFS assessed emotional distress concomitant with MBs and festination, and the chronology between the emotional and motor events should be studied in more detail. Duration of MBs and festination is an important variable to assess severity and should be included in future revisions of the MBFS. Third, the reliability and validity of the MBFS should be explored further. We were unable to assess the validity of the MBFS sections for speech and writing MBs and festination, as there are no gold standard instruments to assess these conditions. Fourth, although we subsumed both self-awareness and anxiety under emotional distress during MBs and freezing, these psychological constructs are not identical. Finally, future studies should examine the relevance of fear of falls and relevant personality traits such as catastrophizing and rumination in the production of emotional distress associated with MBs and festination.

References

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Information & Authors

Information

Published In

Go to The Journal of Neuropsychiatry and Clinical Neurosciences
Go to The Journal of Neuropsychiatry and Clinical Neurosciences
The Journal of Neuropsychiatry and Clinical Neurosciences
Pages: 121 - 126
PubMed: 25923851

History

Received: 11 March 2013
Accepted: 5 February 2014
Published in print: Spring 2015
Published online: 29 April 2015

Authors

Details

Sergio Starkstein, M.D., Ph.D.
From the School of Psychiatry and Clinical Neurosciences (SS, MD, SB) and Schools of Medicine and Pharmacology (MW), University of Western Australia and Fremantle Hospital, Western Australia, Australia; Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Western Australia, Australia (VB); and Raul Carrea Institute of Neurological Research, FLENI, Buenos Aires, Argentina (VB, MM)
Milan Dragovic, Ph.D.
From the School of Psychiatry and Clinical Neurosciences (SS, MD, SB) and Schools of Medicine and Pharmacology (MW), University of Western Australia and Fremantle Hospital, Western Australia, Australia; Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Western Australia, Australia (VB); and Raul Carrea Institute of Neurological Research, FLENI, Buenos Aires, Argentina (VB, MM)
Simone Brockman, M.Sc.
From the School of Psychiatry and Clinical Neurosciences (SS, MD, SB) and Schools of Medicine and Pharmacology (MW), University of Western Australia and Fremantle Hospital, Western Australia, Australia; Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Western Australia, Australia (VB); and Raul Carrea Institute of Neurological Research, FLENI, Buenos Aires, Argentina (VB, MM)
Mark Wilson, M.B.B.S.
From the School of Psychiatry and Clinical Neurosciences (SS, MD, SB) and Schools of Medicine and Pharmacology (MW), University of Western Australia and Fremantle Hospital, Western Australia, Australia; Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Western Australia, Australia (VB); and Raul Carrea Institute of Neurological Research, FLENI, Buenos Aires, Argentina (VB, MM)
Veronica Bruno, M.D.
From the School of Psychiatry and Clinical Neurosciences (SS, MD, SB) and Schools of Medicine and Pharmacology (MW), University of Western Australia and Fremantle Hospital, Western Australia, Australia; Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Western Australia, Australia (VB); and Raul Carrea Institute of Neurological Research, FLENI, Buenos Aires, Argentina (VB, MM)
Marcelo Merello, M.D.
From the School of Psychiatry and Clinical Neurosciences (SS, MD, SB) and Schools of Medicine and Pharmacology (MW), University of Western Australia and Fremantle Hospital, Western Australia, Australia; Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Western Australia, Australia (VB); and Raul Carrea Institute of Neurological Research, FLENI, Buenos Aires, Argentina (VB, MM)

Notes

Send correspondence to Sergio E. Starkstein, M.D., Ph.D.; e-mail: [email protected]

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