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.

Programming parameters of subthalamic deep brain stimulators in Parkinson's disease from a controlled trial.

BACKGROUND: Programming algorithms have never been tested for outcome. The EARLYSTIM study showed superior outcomes of deep brain stimulation of the subthalamic nucleus (STN-DBS) over best medical treatment in early Parkinson's disease (PD). Patients were programmed according to common guidelines but customized for each patient. METHODS: Stimulation parameters were systematically documented at 1, 5, 12, and 24 month in the cohort of 114 patients who had bilateral STN-DBS at 24 month. We investigated the influence of atypical programming, changes of stimulated electrode contacts and stimulation energy delivered. Outcomes were the Unified Parkinson's Disease Rating Scale (UPDRS) motor and ADL-subscores, health-related quality of life (PDQ-39) summary index and mobility- and ADL-subscores. RESULTS: At 1/5/12/24 months follow up, mean amplitude (1.8/2.5/2.6/2.8 V), impedance (1107/1286/1229/1189 Ω) and TEED (33.7/69.0/84.4/93.0 V2*µs*Hz/Ω) mainly increased in the first 5 months, while mean pulse width (60.0/62.5/65.1/65.8 µs), frequency (130/137.7/139.1/142.7 Hz) remained relatively stable. Typical programming (single monopolar electrode contact) was used in 80.7% of electrodes. Double monopolar (11/114) and bipolar (2/114) stimulation was only rarely required. There was no significant difference in clinical outcomes between the patient groups requiring contact changes (n = 32/28.1%) nor between typical (n = 83/72.8%) versus non-typical programming. Energy used for STN-DBS was higher for the dominant side of PD. CONCLUSION: In the first 5 months an increase in amplitude is required to compensate for various factors. Monopolar stimulation is sufficient in 80% of patients at 24 months. Homogeneous stimulation strategies can account for the favorable outcomes reported in the Earlystim study.

Quality of life predicts outcome of deep brain stimulation in early Parkinson disease.

OBJECTIVE: To investigate predictors for improvement of disease-specific quality of life (QOL) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications. METHODS: We performed a secondary analysis of data from the previously published EARLYSTIM study, a prospective randomized trial comparing STN-DBS (n = 124) to best medical treatment (n = 127) after 2 years follow-up with disease-specific QOL (39-item Parkinson's Disease Questionnaire summary index [PDQ-39-SI]) as the primary endpoint. Linear regression analyses of the baseline characteristics age, disease duration, duration of motor complications, and disease severity measured at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) (UPDRS-III "off" and "on" medications, UPDRS-IV) were conducted to determine predictors of change in PDQ-39-SI. RESULTS: PDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups (p < 0.05). The higher the baseline score (worse QOL) the larger the improvement in QOL after 24 months. No correlation was found for any of the other baseline characteristics analyzed in either treatment group. CONCLUSION: Impaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in patients with PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS. CLINICALTRIALSGOV IDENTIFIER: NCT00354133.

Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial.

BACKGROUND: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. METHODS: We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. FINDINGS: Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0·65 points [SE 0·15]) and did not change with medical therapy alone (-0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. INTERPRETATION: In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. FUNDING: German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.

Reversal learning reveals cognitive deficits and altered prediction error encoding in the ventral striatum in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative condition characterized by a triad of movement disorder, neuropsychiatric symptoms and cognitive deficits. The striatum is particularly vulnerable to the effects of mutant huntingtin, and cell loss can already be found in presymptomatic stages. Since the striatum is well known for its role in reinforcement learning, we hypothesized to find altered behavioral and neural responses in HD patients in a probabilistic reinforcement learning task performed during functional magnetic resonance imaging. We studied 24 HD patients without central nervous system (CNS)-active medication and 25 healthy controls. Twenty HD patients and 24 healthy controls were able to complete the task. Computational modeling was used to calculate prediction error values and estimate individual parameters. We observed that gray matter density and prediction error signals during the learning task were related to disease stage. HD patients in advanced disease stages appear to use a less complex strategy in the reversal learning task. In contrast, HD patients in early disease stages show intact encoding of learning signals in the degenerating left ventral striatum. This effect appears to be lost with disease progression.

Levodopa inhibits habit-learning in Parkinson's disease.

Mixed dopaminergic medication, comprising dopamine agonists and levodopa, may affect habit-learning in patients with Parkinson's disease (PD). However, the specific impact of levodopa on this effect is unknown. We assessed habit-learning in 20 non-demented PD-patients both with and without levodopa. We observed intact habit-learning in PD-patients OFF-medication. In contrast, the administration of 200 mg of levodopa impaired habit-learning. We conclude that potential deficits in habit-learning in PD may be attributed to the intake of levodopa.

Effects of dopaminergic and subthalamic stimulation on musical performance.

Although subthalamic-deep brain stimulation (STN-DBS) is an efficient treatment for Parkinson's disease (PD), its effects on fine motor functions are not clear. We present the case of a professional violinist with PD treated with STN-DBS. DBS improved musical articulation, intonation and emotional expression and worsened timing relative to a timekeeper (metronome). The same effects were found for dopaminergic treatment. These results suggest that STN-DBS, mimicking the effects of dopaminergic stimulation, improves fine-tuned motor behaviour whilst impairing timing precision.

Differential role of dopamine in emotional attention and memory: evidence from Parkinson's disease.

Consistent with the hypothesis that dopamine is implicated in the processing of salient stimuli relevant to the modification of various behavioral responses, Parkinson's disease is associated with emotional blunting. To address the hypothesis that emotional attention and memory are modulated by dopaminergic neurotransmission in Parkinson's disease, we assessed 15 nondemented patients with Parkinson's disease while on and off dopaminergic medication and 15 age-matched healthy controls. Visual stimuli were presented, and recognition was used to assess emotional memory. Response latency was used as a measure of emotional attention modulation. Stimuli were varied based on valence (pleasant, neutral, and unpleasant) and arousal (high and low) dimensions. Controls had significantly better memory for positive than negative stimuli, whereas patients with Parkinson's disease tested off medication had significantly better memory for negative than positive items. This negativity bias was lost when they were tested while on dopaminergic medication. Reaction times in patients with Parkinson's disease off medication were longer than in healthy controls and, paradoxically, were even longer when on medication. Further, although both healthy controls and patients with Parkinson's disease in the "off" state had arousal-induced prolongation of reaction time, this effect was not seen in patients with Parkinson's disease on medication. These data indicate that dopaminergic neurotransmission is implicated in emotional memory and attention and suggest that dopamine mediates emotional memory via the valence dimension and emotional attention via arousal. Furthermore, our findings suggest that emotional changes in Parkinson's disease result from the effects of both the disease process and dopaminergic treatment.

Preserved emotional modulation of motor response time despite psychomotor slowing in young-old adults.

Whereas aging affects cognitive and psychomotor processes negatively, the impact of aging on emotional processing is less clear. Using an "old-new" binary decision task, we ascertained the modulation of response latencies after presentation of neutral and emotional pictures in "young" (M = 27.1 years) and "young-old" adults with a mean age below 60 (M = 57.7 years). Stimuli varied on valence (pleasant, neutral, and unpleasant) and arousal (high and low) dimensions. Young-old adults had significantly longer reaction times. However, young and young-old adults showed the exact same pattern of response time modulation by emotional stimuli: Response latencies were longer for high-arousal than for low-arousal pictures and longer for negative than for positive or neutral stimuli. This result suggests that the specific effects of implicitly processed emotional valence and arousal information on behavioral response time are preserved in young-old adults despite significant age-related psychomotor decline.

Emotional processing affects movement speed.

Emotions can affect various aspects of human behavior. The impact of emotions on behavior is traditionally thought to occur at central, cognitive and motor preparation stages. Using EMG to measure the effects of emotion on movement, we found that emotional stimuli differing in valence and arousal elicited highly specific effects on peripheral movement time. This result has conceptual implications for the emotion-motion link and potentially practical implications for neurorehabilitation and professional environments where fast motor reactions are critical.

The pattern of cognitive-functional decline in elderly essential tremor patients: an exploratory-comparative study with Parkinson's and Alzheimer's disease patients.

OBJECTIVE: Essential tremor (ET) is a neurological disorder that produces motor, cognitive, and functional disability. However, there has been no investigation linking cognitive impairment with functional disability in ET. Therefore, we examine the similarities and differences between ET, Alzheimer's disease (AD), and Parkinson's disease (PD) in terms of the linkage between cognitive and functional impairment. DESIGN: Thirty-four ET, 26 PD, and 31 AD subjects were tested for cognition (Mini-Mental State Examination [MMSE]), motor disability (United Parkinson's Disease Rating Scale part III [UPDRS-III]), and functional disability (Minimum Data Set-Activities of Daily Living Section [MDS-ADL]). RESULTS: As expected, in PD and AD subjects, MDS-ADL scores significantly correlated with UPDRS-III and MMSE scores. The ET subjects showed a different pattern of functional disability with MDS-ADL scores significantly correlating only with MMSE scores, and with the orientation MMSE modalities. CONCLUSIONS: Our findings highlight the need to be more cognizant of the nonmotor aspects of ET, which in some patients may be more functionally disabling than the motor features themselves.

The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism.

OBJECTIVE: To determine the effects of dopaminergic medication withdrawal in an elderly, demented and minimally ambulatory nursing home population with parkinsonism in New York City. METHODS: In our double-blind, randomized study, 11 patients (7 males, 4 females) were randomized into 2 groups: one group underwent levodopa medication withdrawal (experimental group) and the other group continued on their levodopa (control group). Patients were evaluated weekly over the course of a month with a neurologic examination and a series of assessment tools, including the motor UPDRS (Unified Parkinson's disease rating scale), Hoehn and Yahr staging scale, the Mini-Mental State Examination (MMSE) and the Nursing Assistant Behavioral Detection Form. SETTING: An academic nursing home in New York City. RESULTS: The patients had a mean age of 82.00 +/- 10.14 years, with a mean MMSE score of 9.50 +/- 6.60 out of 30.00 maximum. The control and experimental groups did not differ significantly with respect to age (P = .52), dementia severity (P = .35), nor severity of PD symptoms as measured by the UPDRS (P = .22) and Hoehn and Yahr staging (P = .65). Overall, no significant changes were observed between the control and experimental groups in cognitive, behavioral, and motor function across each time period. Of interest, 2 of the drug withdrawal patients showed modest improvements in cognitive function as measured by the MMSE. CONCLUSION: Our findings suggest that in patients with advanced parkinsonism and dementia, dopaminergic medication withdrawal may be a feasible way to reduce polypharmacy and potential medication-related side effects, with a minimal risk of worsening motor deterioration. Therefore, our findings may have potential implications for a medication intervention that could prevent potential deleterious side effects and improve health-related quality of life in this frail population.

Dopaminergic modulation of emotional memory in Parkinson's disease.

The aim of this study was to assess the effect of dopaminergic treatment on emotional memory in patients with Parkinson's disease (PD). We tested memory for emotional and neutral visual stimuli in ten non-demented PD patients on and off dopaminergic medication. Patients recalled significantly more emotional items during the off- than on-medication testing session. In contrast, treatment condition did not affect memory for neutral items. These findings demonstrate that emotional memory deficits observed in PD may result from dopaminergic treatment and suggest an involvement of dopaminergic neurotransmission in emotional processing.

Prevalence of movement disorders in an elderly nursing home population.

We studied the prevalence of movement disorders in a large nursing home population (397 patients, mean age 86 years) in New York City. Patients were first evaluated by specially trained research coordinators and final clinical diagnoses were confirmed by a movement disorder specialist. A movement disorder was identified in 21% of patients (83/397). The most frequent movement disorders were essential tremor (ET) (8.8%) and parkinsonism (7.1%). Only half of those admitted with a diagnosis of parkinsonism were confirmed in their diagnosis by the movement disorder specialists. Three percent of patients exhibited drug-induced tremor, 1.3% had dystonia, 0.5% had myoclonus and 0.3% had generalized dyskinesias. Overall, our findings underline the high frequency of movement disorders in a nursing home population. The discrepancy between our findings and the prevalence rates for parkinsonism reported on the initial transfer diagnosis emphasizes the difficulty of accurate diagnosis of movement disorders and in particular parkinsonism.

Clinical usefulness of the Parkinson's disease sleep scale.

OBJECTIVE: To test the usefulness of the Parkinson's disease sleep scale (PDSS) in identifying sleep disorders in the clinical practice setting. METHODS: Sixty-two PD patients were evaluated with the PDSS and the Epworth sleepiness scale (ESS). A cut-off of less than five for each PDSS item as an indicator of substantial sleep disturbance was chosen. If the ESS was equal to or greater than eight, patients were referred to a sleep disorder specialist and possible polysomnography. RESULTS: The mean total PDSS score was 104.7+/-21.5,which correlated with the mean Hoehn and Yahr score (1.9+/-0.9) as well as the mean ESS score (9.7+/-4.7). A significant correlation was also found between the ESS score and several items of the PDSS. CONCLUSIONS: The PDSS was useful in identifying sleep disturbances which were not previously diagnosed, such as sleep maintenance insomnia and excessive daytime sleepiness. Problems with the PDSS include ambiguities of some questions, lack of quantification and an inability to identify specific sleep disturbances such as sleep apnea.

Subthalamic stimulation differentially modulates declarative and nondeclarative memory.

Declarative memory has been reported to rely on the medial temporal lobe system, whereas non-declarative memory depends on basal ganglia structures. We investigated the functional role of the subthalamic nucleus (STN), a structure closely connected with the basal ganglia for both types of memory. Via deep brain high frequency stimulation (DBS) we manipulated neural activity of the STN in humans. We found that DBS-STN differentially modulated memory performance: declarative memory was impaired, whereas non-declarative memory was improved in the presence of STN-DBS indicating a specific role of the STN in the activation of memory systems.

Processing of temporal duration information in working memory after frontodorsal tumour excisions.

This study aimed to test the hypothesis that impairments of temporal duration processing after frontal lobe lesions reflect deficits in executive monitoring functions rather than a domain-specific deficit in the maintenance of duration information in working memory. Patients with frontodorsal lesions, clinical controls with post-central lesions, and healthy controls performed recognition and classification tasks, which should allow for testing maintenance and monitoring functions, respectively. Results showed mild non-selective impairments of the frontal patients on both temporal and spatial recognition tasks, but a marked selective degradation on temporal classification while performance on spatial classification was unimpaired. This suggests that maintenance of duration information in working memory after frontal lesions is basically preserved but that, depending on executive task characteristics, there is a specific deficit in the strategic organization of this type of information.