Disentangling Bradykinesia and Rigidity in Parkinson Disease: Evidence from Short- and Long-Term Subthalamic Nucleus Deep Brain Stimulation.

OBJECTIVE: Bradykinesia and rigidity are considered closely related motor signs in Parkinson disease (PD), but recent neurophysiological findings suggest distinct pathophysiological mechanisms. This study aims to examine and compare longitudinal changes in bradykinesia and rigidity in PD patients treated with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: In this retrospective cohort study, the clinical progression of appendicular and axial bradykinesia and rigidity was assessed up to 15 years after STN-DBS in the best treatment conditions (ON medication and ON stimulation). The severity of bradykinesia and rigidity was examined using ad hoc composite scores from specific subitems of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III). Short- and long-term predictors of bradykinesia and rigidity were analyzed through linear regression analysis, considering various preoperative demographic and clinical data, including disease duration and severity, phenotype, motor and cognitive scores (eg, frontal score), and medication. RESULTS: A total of 301 patients were examined before and 1 year after surgery. Among them, 101 and 56 individuals were also evaluated at 10-year and 15-year follow-ups, respectively. Bradykinesia significantly worsened after surgery, especially in appendicular segments (p < 0.001). Conversely, rigidity showed sustained benefit, with unchanged clinical scores compared to preoperative assessment (p > 0.05). Preoperative motor disability (eg, composite scores from the UPDRS-III) predicted short- and long-term outcomes for both bradykinesia and rigidity (p < 0.01). Executive dysfunction was specifically linked to bradykinesia but not to rigidity (p < 0.05). INTERPRETATION: Bradykinesia and rigidity show long-term divergent progression in PD following STN-DBS and are associated with independent clinical factors, supporting the hypothesis of partially distinct pathophysiology. ANN NEUROL 2024.

Caregivers' burden and deep brain stimulation for Parkinson disease: A systematic review of qualitative studies.

BACKGROUND AND PURPOSE: The impact of subthalamic nucleus deep brain stimulation (STN-DBS) on caregivers' burden is understudied. We perform a systematic review and meta-synthesis aggregating qualitative studies involving partners of people with Parkinson disease (PwP) to explore their experiences and unmet needs. METHODS: A systematic review for retrieving qualitative studies included six databases: MEDLINE, Embase, CINAHL, Cochrane, PsycInfo, and Scopus. Inclusion criteria were as follows: (i) studies on the experience of caregivers of PwP in the context of STN-DBS, (ii) English peer-reviewed articles, and (iii) qualitative or mixed methods studies reporting caregivers' quotations. After the appraisal of included studies, we performed meta-synthesis of qualitative findings. Descriptive themes and conceptual elements related to PwP partners' experiences and unmet needs were generated. RESULTS: A total of 1108 articles were screened, and nine articles were included. Three categories were identified: (i) dealing with Parkinson disease (PD) every day (the starting situation characterized by the impact of PD on ordinary life; the limitations to partners' socialization; partners' efforts in stepping aside for love and care activities), (ii) facing life changes with STN-DBS (the feeling of being unprepared for changes; the fear and concern due to loved ones' behavioral changes; struggling to find an explanation for those changes), and (iii) rebuilding the role of caregiver and partner after STN-DBS. CONCLUSIONS: This meta-synthesis elucidates concerns, challenges, and unmet needs of partners of PwP who underwent STN-DBS. It is important to provide them with information, education, and adequate support to face these challenges. Professionals need to involve partners in the care and decision process, because STN-DBS-related outcomes do not depend solely on the well-being of PwP but also on the well-being of individuals surrounding them.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interplay between speech and gait variables in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation: A long-term instrumental assessment.

OBJECTIVE: To evaluate correlations between speech and gait parameters in the long term and under different medication and subthalamic nucleus deep brain stimulation (STN-DBS) conditions in a cohort of advanced Parkinson's disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Axial symptoms were evaluated using a standardized clinical-instrumental approach. Speech and gait were assessed by perceptual and acoustic analyses and by the instrumented Timed Up and Go (iTUG) test, respectively. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. RESULTS: Twenty-five PD patients with a 5-year median follow-up after surgery (range 3-7 years) were included (18 males; disease duration at surgery: 10.44 [SD 4.62] years; age at surgery: 58.40 [SD 5.73] years). In the off-stimulation/off-medication and on-stimulation/on-medication conditions, patients who spoke louder had also the greater acceleration of the trunk during gait; whereas in the on-stimulation/on-medication condition only, patients with the poorer voice quality were also the worst to perform the sit to stand and gait phases of the iTUG. Conversely, patients with the higher speech rate performed well in the turning and walking phases of the iTUG. CONCLUSIONS: This study underlines the presence of different correlations between treatment effects of speech and gait parameters in PD patients treated with bilateral STN-DBS. This may allow us to better understand the common pathophysiological basis of these alterations and to develop a more specific and tailored rehabilitation approach for axial signs after surgery.

Predictors of Long-Term Outcome of Subthalamic Stimulation in Parkinson Disease.

OBJECTIVE: This study was undertaken to identify preoperative predictive factors of long-term motor outcome in a large cohort of consecutive Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: All consecutive PD patients who underwent bilateral STN-DBS at the Grenoble University Hospital (France) from 1993 to 2015 were evaluated before surgery, at 1 year (short-term), and in the long term after surgery. All available demographic variables, neuroimaging data, and clinical characteristics were collected. Preoperative predictors of long-term motor outcome were investigated by performing survival and univariate/multivariate Cox regression analyses. Loss of motor benefit from stimulation in the long term was defined as a reduction of less than 25% in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores compared to the baseline off-medication scores. As a secondary objective, potential predictors of short-term motor outcome after STN-DBS were assessed by performing univariate and multivariate linear regression analyses. RESULTS: In the long-term analyses (mean follow-up = 8.4 ± 6.26 years, median = 10 years, range = 1-17 years), 138 patients were included. Preoperative higher frontal score and off-medication MDS-UPDRS part III scores predicted a better long-term motor response to stimulation, whereas the presence of vascular changes on neuroimaging predicted a worse motor outcome. In 357 patients with available 1-year follow-up, preoperative levodopa response, tremor dominant phenotype, baseline frontal score, and off-medication MDS-UPDRS part III scores predicted the short-term motor outcome. INTERPRETATION: Frontal lobe dysfunction, disease severity in the off-medication condition, and the presence of vascular changes on neuroimaging represent the main preoperative clinical predictors of long-term motor STN-DBS effects. ANN NEUROL 2021;89:587-597.

The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long-term independence and quality of life after subthalamic stimulation in Parkinson disease.

BACKGROUND AND PURPOSE: Studies on long-term nonmotor outcomes of subthalamic nucleus stimulation in Parkinson disease (PD) are scarce. This study reports on very long-term non-motor and motor outcomes in one of the largest cohorts of people with advanced PD, treated for >10 years with subthalamic nucleus stimulation. The main outcome was to document the evolution of independence in activities of daily living. The secondary outcomes were to measure the change in quality of life, as well as non-motor and motor outcomes. METHODS: Patients were studied preoperatively, at 1 year, and beyond 10 years after subthalamic stimulation with an established protocol including motor, non-motor, and neuropsychological assessments. RESULTS: Eighty-five people with PD were included. Independence scores in the off-medication condition (measured with the Schwab & England Activities of Daily Living Scale) as well as quality of life (measured with the Parkinson's Disease Questionnaire [PDQ]-37) remained improved at longest follow-up compared to preoperatively (respectively, p < 0.001, p = 0.015). Cognitive scores, measured with the Mattis Dementia Rating Scale, significantly worsened compared to before and 1 year after surgery (p < 0.001), without significant change in depression, measured with the Beck Depression Inventory. Motor fluctuations, dyskinesias, and off dystonia remained improved at longest follow-up (p < 0.001), with a significant reduction in dopaminergic treatment (45%, p < 0.001). CONCLUSIONS: This study highlights the long-term improvement of subthalamic stimulation on independence and quality of life, despite the progression of disease and the occurrence of levodopa-resistant symptoms.

Do neuropsychiatric fluctuations temporally match motor fluctuations in Parkinson's disease?

INTRODUCTION: In Parkinson's disease (PD), non-motor fluctuations (NMFs), especially neuropsychiatric fluctuations, often coexist with motor fluctuations (MFs) but are often under-recognized by physicians and patients. OBJECTIVE: To investigate the relationship between MFs and neuropsychiatric fluctuations in PD. METHODS: PD patients with MFs and NMFs were enrolled. The Parkinson's Kinetigraph (PKG), a wearable device to detect MFs and dyskinesia, was used to confirm and measure MFs. The Neuropsychiatric Fluctuation Scale (NFS), a scale composed by subscores for both the ON and OFF neuropsychiatric states, was used to identify and quantify neuropsychiatric fluctuations. Patients were asked to wear the PKG for six consecutive days to identify the ON and OFF motor periods, and then to fill the NFS during the ON and OFF motor periods for three consecutive days wearing the PKG. The PKG system provided a bradykinesia score (BKS) and a dyskinesia score (DKS). Relations between BKS, DKS, and ON and OFF NFS subscores were analyzed. RESULTS: In 18 PD patients, anxiety, apathy, and depression characterized the OFF condition, whereas self-confidence, competency, and interest in doing things were typically in the ON condition. There was a positive correlation between the BKS and the OFF NFS subscores (p = 0.036, r = 0.51), whereas no correlation was found between the DKS and the ON NFS subscores (p = 0.38, r = 0.22). CONCLUSION: Neuropsychiatric fluctuations temporarily matched the OFF MFs only in the OFF condition. These findings are useful to better manage OFF NMSs and support the need to further investigate associations between non-motor and motor symptoms in PD patients.

Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease With Early Motor Complications.

BACKGROUND: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. OBJECTIVE: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). METHODS: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. RESULTS: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. CONCLUSIONS: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society.

Different effects of levodopa and subthalamic stimulation on emotional conflict in Parkinson's disease.

Parkinson's disease impairs the decoding of emotional stimuli reflecting alterations of the limbic cortico-subcortical network. The objective of this study was to assess and compare the behavioral and electrophysiological effects of both levodopa and subthalamic stimulation on emotional processing in Parkinson's disease. Operated patients (n =16) and matched healthy subjects performed an emotional Stroop task, in which the emotion expressed by a face must be recognized while ignoring an emotional distractive word and that includes a neutral control sub-task. Patients were tested in the four possible treatment conditions (off stim/off med; on stim/off med; off stim/on med; and on stim/on med). High-resolution electroencephalography was recorded while performing the task. Patients made significantly more mistakes in facial emotion recognition than healthy subjects (p < .005). Untreated patients performed worse in the emotional trials than in the control sub-task (p < .05). Fearful faces induced significantly slower reaction times than happy faces in patients (p = .0002), but not in the healthy subjects. The emotional Stroop effect with levodopa was significantly higher than with subthalamic stimulation when fearful faces were assessed (p = .0243). Conversely, treatments did not modulate the Stroop effect of the control sub-task. EEG demonstrated that, compared with the untreated state, levodopa but not subthalamic stimulation significantly increases the amplitude of the event-related potential N170 (p = .002 vs. p = .1, respectively), an electrophysiological biomarker of early aspects of facial processing. The activity of the N170 cortical sources within the right fusiform gyrus was increased by levodopa (p < .05) but not by stimulation. While levodopa normalizes the recognition of emotional facial expression and early EEG markers of emotional processing, subthalamic stimulation does not. Thus, operated patients require dopaminergic medication in addition to stimulation to treat emotional symptoms of Parkinson's disease.

Subthalamic stimulation and neuropsychiatric symptoms in Parkinson's disease: results from a long-term follow-up cohort study.

BACKGROUND: Reports on behavioural outcomes after subthalamic nucleus deep brain stimulation in Parkinson's disease are controversial and limited to short-term data. Long-term observation in a large cohort allows a better counselling and management. METHODS: To determine whether a long-term treatment with subthalamic stimulation induces or reduces impulse control behaviours, neuropsychiatric fluctuations and apathy, 69 patients treated with subthalamic stimulation are prospectively and retrospectively assessed using Ardouin Scale of Behavior in Parkinson's Disease before and after 3-10 years of stimulation. RESULTS: At a mean follow-up of 6 years, all impulse control disorders and dopaminergic addiction were significantly decreased, apart from eating behaviour and hypersexuality. Neuropsychiatric fluctuations also significantly improved (ON euphoria: 38% of the patients before surgery and 1% after surgery, P<0.01; OFF dysphoria: 39% of the patients before surgery and 10% after surgery, P<0.01). However, apathy increased (25% of the patients after surgery and 3% before, P<0.01). With the retrospective analysis, several transient episodes of depression, apathy, anxiety and impulse control disorders occurred. CONCLUSIONS: Bilateral subthalamic nucleus stimulation was overall very effective in improving impulse control disorders and neuropsychiatric fluctuations in parkinsonian patients in the long term despite a counteracting frequent apathy. Transient episodes of impulse control disorders still occurred within the follow-up. These findings recommend a close follow-up in parkinsonian patients presenting with neuropsychiatric symptoms before deep brain stimulation surgery. CLINICAL TRIAL REGISTRATION: NCT01705418;Post-results.

Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: A clinical review.

Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society.

Pallidal deep brain stimulation for dystonia: a long term study.

BACKGROUND: Pallidal deep brain stimulation (globus pallidus internus (GPi) DBS) is the best therapeutic option for disabling isolated idiopathic (IID) and inherited (INH) dystonia. Acquired dystonia (AD) may also benefit from GPi DBS. Efficacy and safety in the long-term remained to be established. OBJECTIVE: To retrospectively assess long-term clinical outcomes and safety in dystonic patients who underwent GPi DBS. METHODS: Patients were videotaped and assessed preoperatively and postoperatively (1-year and at last available follow-up) using the Burke-Fahn-Marsden Dystonia Rating Scale (motor score (BFMDRS-M); disability score (BFMDRS-D)). RESULTS: Sixty-one patients were included (follow-up 7.9±5.9 years; range 1-20.7). In IID and INH (n=37), the BFMDRS-M improved at first (20.4±24.5; p<0.00001) and last (22.2±18.2; p<0.001) follow-ups compared with preoperatively (50.5±28.0). In AD (n=19), the BFMDRS-M ameliorated at 1-year (40.8±26.5; p<0.02) and late follow-ups (44.3±24.3; p<0.04) compared with preoperatively (52.8±24.2). In INH dystonia with other neurological features (n=4) there was no motor benefit. In IID and INH, the BFMDRS-D improved at 1-year (9.5±7.5; p<0.0002) and late follow-ups (10.4±7.8; p<0.016) compared with preoperatively (13.3±6.9). In AD, the BFMDRS-D reduced at 1-year (12.0±8.1; p<0.01) and late follow-ups (12.7 ±6.1; p=0.2) compared with preoperatively (14.35±5.7). Most adverse events were hardware related. CONCLUSIONS: GPi DBS is an effective and safe treatment in most patients with dystonia.

Psychostimulant effect of dopaminergic treatment and addictions in Parkinson's disease.

BACKGROUND: Dopamine replacement therapy in PD has been associated with both behavioral addictions and dopamine addiction. OBJECTIVES: To investigate potential association between l-dopa induced neuropsychiatric fluctuations and addictions in PD. METHODS: A cohort of 102 patients with PD suffering from motor complications of l-dopa treatment was prospectively analyzed. We evaluated dopamine addiction, behavioral addictions, and neuropsychiatric fluctuations using the Ardouin scale of behavior in PD. RESULTS: Patients with (n = 51) or without (n = 51) neuropsychiatric fluctuations did not differ in age, disease duration, medication, or UPDRS III motor score during on and off drug condition. Patients with neuropsychiatric fluctuations had a higher H & Y stage in off-drug condition. A multivariate model showed that dopamine addiction (odds ratio: 8.9; P = 0.02) and behavioral addictions (odds ratio: 3.76; P = 0.033) were more frequent in the presence of neuropsychiatric fluctuations. Behavioral addictions and dopamine addiction were more frequent in the presence than in the absence of on-drug euphoria (46% vs. 13.9%; P < 0.001 and 27% vs 6.2 %; P = 0.003), while conversely, no association emerged between dopamine or behavioral addictions and presence of off-drug dysphoria. Patients with neuropsychiatric fluctuations had a poorer quality of life and a more frequent history of anxiety disorder. CONCLUSIONS: The psychostimulant effects of dopamine treatment during on-drug euphoria, rather than avoidance of off-drug dysphoria, appear to drive both behavioral addictions and abuse of medication. © 2017 International Parkinson and Movement Disorder Society.

Personality, dopamine, and Parkinson's disease: Insights from subthalamic stimulation.

BACKGROUND: Subthalamic stimulation improves the motor and neuropsychiatric symptoms of Parkinson's disease. However, the impact of this treatment on impulse control and personality is the subject of heavy debate. The objective of this study was to investigate personality changes after subthalamic stimulation. METHODS: Using Cloninger's biosocial model, we assessed personality in 73 Parkinson's disease patients before and 12 months after subthalamic stimulation accompanied by a drastic reduction in dopaminergic medication. Changes in psychobehavioral symptoms were measured using a battery of validated clinical scales (apathy, depression, anxiety, hyperemotionality, mania, psychosis, punding, and impulse control behaviors). RESULTS: One year after surgery, the harm avoidance personality domain total score increased compared with the baseline (+2.8; 34 patients; P < 0.001), as did 3 of its 4 subdomains: anticipatory worry (+0.7; 10 patients; P = 0.005), shyness (+0.6; 7 patients; P = 0.03), and fatigability (+1.1; 10 patients; P = 0.0014). Evolution of the shyness personality trait correlated with the decrease in dopaminergic medication. Total scores in the other personality domains remained unchanged, except for extravagance, a subdomain of novelty seeking, and persistence, a subdomain of reward dependence, which both decreased following surgery (-0.3; 7 patients; and -0.6; 9 patients; P = 0.03 and P = 0.0019, respectively). Although apathy increased, other psychobehavioral symptoms, including impulse control behaviors and neuropsychiatric nonmotor fluctuations, improved. Depression and anhedonia remained stable. Scores in hypodopaminergia and neuropsychiatric nonmotor OFF correlated with harm avoidance. Scores in hyperdopaminergia and neuropsychiatric nonmotor ON correlated with novelty seeking. CONCLUSIONS: When subthalamic stimulation is applied in Parkinson's disease, significant changes in personality traits are observed, which may be related to postoperative tapering of dopaminergic treatment. © 2017 International Parkinson and Movement Disorder Society.

The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson's disease.

SEE SCHRAG AND POLITIS DOI101093/AWW190 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinson's disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinson's disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores ≥ -21) and 15 non-apathetic (-36 ≤ Lille Apathy Rating Scale scores ≤ -22) drug-naïve de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [(11)C-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] (n = 29) and serotonergic [(11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] (n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression (P = 0.0004) and anxiety (P = 0.004) scores - as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively - compared to the non-apathetic ones - who were not different from the age-matched healthy subjects (n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation (n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation (n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic (n = 15) and serotonergic (n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra-ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Altogether, these findings highlight a prominent role of the serotonergic degeneration in the expression of the neuropsychiatric symptoms occurring at the onset of Parkinson's disease.

Postoperative apathy can neutralise benefits in quality of life after subthalamic stimulation for Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinson's disease, leading to improvement in health-related quality of life (HRQoL). However, an excessive decrease in dopaminergic medication can lead to a withdrawal syndrome with apathy as the predominant feature. The present study aims to assess the impact of postoperative apathy on HRQoL. METHODS: A cohort of 88 patients who underwent STN-DBS was divided into two groups, those who were apathetic at 1 year and those who were not, as measured by the Starkstein scale. HRQoL was assessed using the Parkinson's disease questionnaire 39 (PDQ-39) and was compared between the two groups. We also compared activities of daily living, motor improvement and motor complications (Unified Parkinson's Disease Rating Scale, UPDRS), depression and anxiety, as well as cognition and drug dosages. Baseline characteristics and postoperative complications were recorded. RESULTS: One year after surgery, 27.1% of patients suffered from apathy. While motor improvement was significant and equivalent in both the apathy (-40.4% of UPDRS motor score) and non-apathy groups (-48.6%), the PDQ-39 score did not improve in the apathy group (-5.5%; p=0.464), whereas it improved significantly (-36.7%; p≤0.001) in the non-apathy group. Change in apathy scores correlated significantly with change in HRQoL scores (r=0.278, p=0.009). Depression and anxiety scores remained unchanged from baseline in the apathy group (p=0.409, p=0.075), while they improved significantly in patients without apathy (p=0.006, p≤0.001). A significant correlation was found between changes in apathy and depression (r=0.594, p≤0.001). CONCLUSIONS: The development of apathy after STN-DBS can cancel out the benefits of motor improvement in terms of HRQoL. Systematic evaluation and management of apathy occurring after subthalamic stimulation appears mandatory.

Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease.

After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

Disentangling the Role of Cortico-Basal Ganglia Loops in Top-Down and Bottom-Up Visual Attention: An Investigation of Attention Deficits in Parkinson Disease.

It is solidly established that top-down (goal-driven) and bottom-up (stimulus-driven) attention mechanisms depend on distributed cortical networks, including prefrontal and frontoparietal regions. On the other hand, it is less clear whether the BG also contribute to one or the other of these mechanisms, or to both. The current study was principally undertaken to clarify this issue. Parkinson disease (PD), a neurodegenerative disorder primarily affecting the BG, has proven to be an effective model for investigating the contribution of the BG to different brain functions; therefore, we set out to investigate deficits of top-down and bottom-up attention in a selected cohort of PD patients. With this objective in mind, we compared the performance on three computerized tasks of two groups of 12 parkinsonian patients (assessed without any treatment), one otherwise pharmacologically treated and the other also surgically treated, with that of a group of controls. The main behavioral tool for our study was an attentional capture task, which enabled us to tap the competition between top-down and bottom-up mechanisms of visual attention. This task was suitably combined with a choice RT and a simple RT task to isolate any specific deficit of attention from deficits in motor response selection and initiation. In the two groups of patients, we found an equivalent increase of attentional capture but also comparable delays in target selection in the absence of any salient distractor (reflecting impaired top-down mechanisms) and movement initiation compared with controls. In contrast, motor response selection processes appeared to be prolonged only in the operated patients. Our results confirm that the BG are involved in both motor and cognitive domains. Specifically, damage to the BG, as it occurs in PD, leads to a distinct deficit of top-down control of visual attention, and this can account, albeit indirectly, for the enhancement of attentional capture, reflecting weakened ability of top-down mechanisms to antagonize bottom-up control.

Neural substrates of levodopa-responsive gait disorders and freezing in advanced Parkinson's disease: a kinesthetic imagery approach.

Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H2 (15) 0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa-responsive gait disorders and FoG, and eight age-matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor-parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor-parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper-limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa-responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery.