Reinforcement-based processes actively regulate motor exploration along redundant solution manifolds.

From a baby's babbling to a songbird practising a new tune, exploration is critical to motor learning. A hallmark of exploration is the emergence of random walk behaviour along solution manifolds, where successive motor actions are not independent but rather become serially dependent. Such exploratory random walk behaviour is ubiquitous across species' neural firing, gait patterns and reaching behaviour. The past work has suggested that exploratory random walk behaviour arises from an accumulation of movement variability and a lack of error-based corrections. Here, we test a fundamentally different idea-that reinforcement-based processes regulate random walk behaviour to promote continual motor exploration to maximize success. Across three human reaching experiments, we manipulated the size of both the visually displayed target and an unseen reward zone, as well as the probability of reinforcement feedback. Our empirical and modelling results parsimoniously support the notion that exploratory random walk behaviour emerges by utilizing knowledge of movement variability to update intended reach aim towards recently reinforced motor actions. This mechanism leads to active and continuous exploration of the solution manifold, currently thought by prominent theories to arise passively. The ability to continually explore muscle, joint and task redundant solution manifolds is beneficial while acting in uncertain environments, during motor development or when recovering from a neurological disorder to discover and learn new motor actions.

Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial.

BACKGROUND: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING: Outpatient. PATIENTS: 150 patients with PD and constipation. INTERVENTION: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION: Longer treatment periods need to be investigated in future studies. CONCLUSION: ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE: Enterin, Inc.

'Anxious fluctuators' a subgroup of Parkinson's disease with high anxiety and problematic on-off fluctuations.

Anxiety that occurs in association with on-off dopamine medication fluctuations is a major cause of distress, dysfunction, and lower quality of life in people with Parkinson's disease (PD). However, the association between anxiety and on-off fluctuations is poorly understood and it is difficult to predict which patients will suffer from this atypical form of anxiety. To understand whether fluctuating anxiety in PD exists as part of an endophenotype that is associated with other signs or symptoms, we prospectively assessed the change in anxiety and a battery of clinical variables when transitioning from the off-dopamine medication state to the on state in 200 people with PD. We performed latent profile analysis with observed variables as latent profile indicators measuring the on-off-state difference in anxiety, depression, motor function, daily functioning, and the wearing off questionnaire 19 item scale (WOQ-19) in order to model unobserved (i.e., latent) profiles. A two-class model produced the best fit. The majority of participants, 69%, were categorized as having a 'typical on-off response' compared to a second profile constituting 31% of the sample who experienced a worsening in anxiety in the off state that was three times that of other participants. This profile referred to as "anxious fluctuators" had a Hamilton Anxiety Rating Scale change between the off and on medication state of 10.22(32.85) compared to 3.27 (7.62), higher depression scores, greater disability and was less likely to improve on select WOQ-19 items when in the on-state. Anxious fluctuators were more likely to be male and have a family history of anxiety disorder. Given the adverse impact of this profile we believe it may be important to distinguish patients with a typical on-off response from those with this more problematic course of fluctuations.

A central processing sensory deficit with Parkinson's disease.

Parkinson's disease (PD) is a progressive degenerative disease manifested by tremor, rigidity, bradykinesia, and postural instability. Deficits in proprioceptive integration are prevalent in individuals with PD, even at early stages of the disease. These deficits have been demonstrated primarily during investigations of reaching. Here, we investigated how PD affects sensory fusion of multiple modalities during upright standing. We simultaneously perturbed upright stance with visual, vestibular, and proprioceptive stimulation, to understand how these modalities are reweighted so that overall feedback remains suited to stabilizing upright stance in individuals with PD. Eight individuals with PD stood in a visual cave with a moving visual scene at 0.2 Hz while an 80-Hz vibratory stimulus was applied bilaterally to their Achilles tendons (stimulus turns on-off at 0.28 Hz) and a ±1 mA bilateral monopolar galvanic stimulus was applied at 0.36 Hz. The visual stimulus was presented at different amplitudes (0.2°, 0.8° rotation about ankle axis) to measure: the change in gain (weighting) to vision, an intramodal effect; and a simultaneous change in gain to vibration and galvanic stimulation, both intermodal effects. Trunk/leg gain relative to vision decreased when visual amplitude was increased, reflecting an intramodal visual effect. In contrast, when vibration was turned on/off, leg gain relative to vision was equivalent in individuals with PD, indicating no reweighting of visual information when proprioception was disrupted through vibration (i.e., no intermodal effect). Trunk and leg angle gain relative to GVS also showed no reweighting in individuals with PD. These results are in contrast to previous results with healthy adults, who showed clear intermodal effects in the same paradigm, suggesting that individuals with PD not only have a proprioceptive deficit during standing, but also have a cross-modal sensory fusion deficit that is crucial for upright stance control.

Postoperative symptoms of psychosis after deep brain stimulation in patients with Parkinson's disease.

OBJECT: Cases of postoperative psychosis in Parkinson's disease patients receiving deep brain stimulation (DBS) treatment have previously been published. However, the magnitude of symptom incidence and the clinical risk factors are currently unknown. This retrospective study sheds light on these issues by investigating psychosis in a group of 128 Parkinson's disease patients who received DBS implants. METHODS: A retrospective chart review was performed to obtain surgery dates, follow-up clinic visit dates, and associated stimulation parameter settings (contacts in use and the polarity of each along with stimulation voltage, frequency, and pulse width) for each patient. Unified Parkinson's Disease Rating Scale II Thought Disorder scores, used as a clinical assessment tool to evaluate the presence of psychosis at each visit, were also collected. The data were compiled into a database and analyzed. RESULTS: The lifetime incidence of psychosis in this cohort of patients was 28.1%. The data suggest that risk of psychosis remains fairly constant throughout the first 5 years after implantation of a DBS system and that patients older at the time of receiving the first DBS implant are not only more likely to develop psychosis, but also to develop symptoms sooner than their younger counterparts. Further analysis provides evidence that psychosis is largely independent of the clinically used electrode contact and of stimulation parameters prior to psychosis onset. CONCLUSIONS: Although symptoms of psychosis are widely seen in patients with Parkinson's disease in the years following stimulator placement, results of the present suggest that most psychoses occurring postoperatively are likely independent of implantation and stimulation settings.

Application of depression rating scales in patients with Parkinson's disease with and without co-Occurring anxiety.

BACKGROUND: In patients with Parkinson's disease (PD), depressive symptom rating scales facilitate identification of depressive disorders, which are common and disabling. Anxiety disturbances in PD, which lack valid assessment scales, frequently co-occur with PD-depression, are under-recognized, and require different interventions than depressive disorders. Whether high anxiety rates in PD confound depression scale performance or if any depression scales also predict anxiety disturbances is not known. OBJECTIVE: To test the impact of co-occurring anxiety disorders on psychometric properties of depression rating scales in depressed PD patients and compare disability between PD patients with anxiety, depression, and comorbid anxiety and depressive disorders. METHODS: PD subjects (n = 229) completed self-report and clinician-administered depression scales. Receiver operating characteristic curves were developed to estimate psychometric properties of each scale in those with depression alone, anxiety alone, and comorbid depression and anxiety. Between-group differences on all measures were examined. RESULTS: Comorbid anxiety did not affect the psychometric properties of any scale when identifying depressive disorders, but is associated with greater symptom severity and disability. Depression-scale scores were not significantly different between subjects with anxiety disorders only and those without depressive or anxiety diagnoses. CONCLUSIONS: Co-occurring anxiety disorders do not impact performance of depression rating scales in depressed PD patients. However, depression rating scales do not adequately identify anxiety disturbances alone or in patients with depression.

Pharmacologic treatment of anxiety disorders in Parkinson disease.

OBJECTIVE: Neither best practices nor an evidence base for the pharmacologic treatment of anxiety in Parkinson disease (PD) has been established. This study investigated pharmacologic treatment of anxiety disorders in idiopathic PD and the associated clinical features. DESIGN: Cross-sectional. SETTING: Three community-based movement disorder neurology practices. PARTICIPANTS: 250 subjects with PD. MEASUREMENTS: Anxiety disorder diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Current medications were provided by the treating neurologists at the time of interview. RESULTS: Among subjects with anxiety disorders only, 53% were untreated with medications. When anxious subjects with comorbid depressive disorders were included, 70.8% were on medications effective for treatment of anxiety. Subjects with anxiety and comorbid depressive disorders were more likely to be treated for their psychiatric disturbances than subjects with anxiety disorders alone (odds ratio: 8.33), as were subjects with comorbid motor fluctuations (odds ratio: 3.65). There were no differences in the types of anti-anxiety medications used in regard to the presence of depression or motor fluctuations. CONCLUSIONS: These findings suggest that over half of nondepressed PD patients with clinically significant anxiety are untreated with medication. A better understanding of the role of clinical features associated with anxiety in PD, such as depression and motor fluctuations, may improve the recognition and treatment of anxiety disorders in this population.

Prevalence of psychotic symptoms in a community-based Parkinson disease sample.

OBJECTIVES: : To determine the prevalence of psychotic phenomena, including minor symptoms, in a Parkinson disease (PD) sample and compare the clinical correlates associated with the various psychotic phenomena. To evaluate the extent to which cases met National Institute of Neurological Diseases and Stroke (NINDS)/National Institute of Mental Health (NIMH)-proposed criteria for PD-associated psychosis. METHODS: : A total of 250 patients with idiopathic PD and Mini Mental State Exam scores greater than 23 from three community-based movement disorder clinics underwent comprehensive research diagnostic evaluations by a geriatric psychiatrist as part of a study on mood disorders in PD. Psychotic symptoms were categorized using a checklist, which included a breakdown of hallucinations, delusions, and minor symptoms. Clinical characteristics of groups with minor and other psychotic symptoms were compared. The NINDS/NIMH criteria for PD-psychosis were retrospectively applied. RESULTS: : Of the total sample, 26% of patients were found to have any current psychotic symptoms, with 47.7% of those having isolated minor symptoms, and 52.3% having hallucinations and/or delusions. Compared to those with no current psychiatric symptoms, minor symptoms were associated with more depressive symptoms and worse quality of life, and 90.8% of those with psychotic symptoms fulfilled the NINDS/NIMH proposed criteria. CONCLUSIONS: : Psychotic symptoms are common in PD patients, with minor psychotic phenomena present in nearly half of affected patients in a community-based sample. Psychotic symptoms, including minor phenomena, were clinically significant. The NINDS/NIMH PD-psychosis criteria captured the clinical characteristics of psychosis as it relates to PD. Longitudinal studies are needed to determine whether minor psychotic symptoms represent a precursor to hallucinations and delusions, and to further validate diagnostic criteria.

Anxiety and self-perceived health status in Parkinson's disease.

Both anxiety and depression are associated with lower self-perceived health status (HS) in persons with Parkinson's disease (PD). Given the high co-morbidity with depression and other non-motor symptoms, it is unclear whether anxiety disorders, in general, versus specific anxiety subtypes have an independent effect on HS in PD. To examine this question, comprehensive assessments of motor and non-motor symptoms from 249 subjects with idiopathic PD followed in three community-based movement disorders neurology practices were analyzed. HS was measured using the 8-item PD Questionnaire (PDQ-8). Psychiatric diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Stepwise multiple regression analyses were used, with the PDQ-8 score as the dependent variable, to identify independent predictors of HS among motor, psychiatric, and other non-motor variables. Among the anxiety disorders, only anxiety associated with motor fluctuations was an independent predictor of HS after accounting for co-morbid depression and other clinical features. In addition, depressive disorders were also an independent predictor of lower HS. Prevention or treatment of state-dependent anxiety may improve HS in persons with PD.

'Staircase' square-wave jerks in early Parkinson's disease.

BACKGROUND/AIMS: Visually guided saccades and gaze-fixation ability were recorded in patients with early Parkinson's disease (PD). METHODS: Magnetic search coil system was used to measure horizontal and vertical eye positions. RESULTS: 'Staircase' visually guided saccades (multiple hypometric saccades separated by an intersaccadic interval) and 'staircase' square-wave jerks (SWJ) were present in all patients. The SWJ amplitude (total amplitude of the series of hypometric saccades comprising the SWJ) was abnormally large (mean 2°). SWJ frequency was also abnormally high (50-70 intrusions/min). CONCLUSION: Loss of dopaminergic neurons in the substantia nigra pars compacta leading to phasic excitation of the substantia nigra pars reticulata and, in turn, phasic inhibition of the superior colliculus (SC), may account for 'staircase' visually guided saccades in these patients. This mechanism, however, does not explain abnormally large SWJ, which in the traditional view results from decreased inhibition upon SC. The abnormally large SWJ could be due to a compensatory increase in frontal eye field activity secondary to the increased inhibition upon the SC. Abnormally large and frequent SWJ are often used clinically to distinguish multi-system atrophy from idiopathic PD. Our study, however, suggests that idiopathic PD cannot be excluded if the patient has large-amplitude SWJ.

Predicting outcomes in Parkinson's disease: comparison of simple motor performance measures and The Unified Parkinson's Disease Rating Scale-III.

The Unified Parkinson's Disease Rating Scale (UPDRS) part III is the principal motor assessment method for Parkinson's disease (PD), but has recognized limitations including subjectivity and insensitivity. Easy to administer, objective, quantitative tests that are good indicators of PD progression could offer advantages in both clinical and research settings. We administered four simple, motor performance measures--functional reach, timed hall walk, a timed block sort task, and timed dotting--as well as the UPDRS to 609 PD patients of a single neurologist. The unadjusted Spearman correlations of these performance measures with the UPDRS motor score (UPDRS III) ranged from 0.29 to 0.49. Moreover, these measures generally had high reliability on repeated testing. We defined specific outcomes in PD--overall disability, gait instability and falls, as well as non-motor outcomes of depression, dementia, and psychosis, and assessed the ability of the measures to predict these outcomes over the entire follow-up of the cohort (average: 2.4 years) and over the first year of follow-up. The associations between the measures and the outcomes were generally stronger and more precise for the performance measures than for the UPDRS III. A summary score of the performance measures was a particularly good predictor of the outcomes. These motor performance measures could provide a rapid, simple means of assessing PD progression that could benefit both clinical and research endeavors.

Prevalence of anxiety disorders and anxiety subtypes in patients with Parkinson's disease.

Anxiety disorders are common in Parkinson's disease (PD), but are not well characterized. This study determined the prevalence and clinical correlates of all DSM-IV-TR anxiety disorder diagnoses in a sample of 127 subjects with idiopathic PD who underwent comprehensive assessments administered by a psychiatrist and neurologist. A panel of six psychiatrists with expertise in geriatric psychiatry and/or movement disorders established by consensus all psychiatric diagnoses. Current and lifetime prevalence of at least one anxiety disorder diagnosis was 43% (n = 55) and 49% (n = 63), respectively. Anxiety disorder not otherwise specified, a DSM diagnosis used for anxiety disturbances not meeting criteria for defined subtypes, was the most common diagnosis (30% lifetime prevalence, n = 38). Compared with nonanxious subjects, panic disorder (n = 13) was associated with earlier age of PD onset [50.3 (12.2) vs. 61.0 (13.7) years, P < 0.01], higher rates of motor fluctuations [77% (10/13) vs. 39% (25/64), P = 0.01] and morning dystonia [38% (5/13) vs. 13% (8/62), P < 0.03]. This high prevalence of anxiety disorders, including disturbances often not meeting conventional diagnostic criteria, suggests that anxiety in PD is likely underdiagnosed and undertreated and refined characterization of anxiety disorders in PD is needed. In addition, certain anxiety subtypes may be clinically useful markers associated with disease impact in PD.

Corticobasal degeneration.

Corticobasal degeneration (CBD) is a neurodegenerative disorder characterized clinically by a combination of cortical and basal ganglia signs. Pathologically, it is classified as a tauopathy. The most distinctive clinical feature is its unilateral or markedly asymmetric presentation; among parkinsonian syndromes, with rare exceptions, only Parkinson's disease presents with such asymmetry. The most common presenting cortical features include apraxia (patients often complain of a "useless" limb), aphasia (usually nonfluent), parietal lobe sensory signs (agraphesthesia, extinction, astereognosis), frontal dementia, or myoclonus. Basal ganglia signs include rigidity, akinesia, limb dystonia, and postural instability. The diagnosis is often challenging for three reasons: 1) The full complement of findings are rarely seen at presentation; 2) If CBD is not suspected, subtle but relevant findings (eg, extinction, language impairment, myoclonus, or apraxia) may not be searched for or appreciated; 3) The clinical picture of CBD has substantial overlap with a variety of other parkinsonian and dementing illnesses. The differential diagnosis includes Parkinson's disease, progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, and Alzheimer's disease. The clinical diagnosis is not confirmed pathologically in up to half of cases, so the term corticobasal syndrome is often preferred during life, reserving the term corticobasal degeneration for pathologically verified cases. Treatment of CBD is primarily supportive, and most patients die within 10 years of onset. Parkinsonian signs may improve to a modest degree with levodopa, clonazepam can suppress myoclonus, and botulinum toxin can relieve dystonia. Early speech therapy, physical therapy, and occupational therapy, as well as assist devices such as a rolling walker may improve functioning and reduce complications such as aspiration pneumonia and falls. With time, however, most patients lose their independence and mobility. Throughout the course of the illness (particularly when it is advanced), caring for the caregiver is as important as caring for the patient.

Adult-onset primary lower limb dystonia.

The lower extremity is affected infrequently in adult-onset primary dystonia in contrast to childhood-onset dystonia, which typically begins in the foot. When dystonia affects the foot in an adult, it is usually on a secondary basis. We present findings on 17 patients (11 women, 6 men; average age of onset 48.4 years; average time to diagnosis 2.7 years) with adult-onset primary foot dystonia. Prior to diagnosis, most patients underwent extensive testing and treatment, including unnecessary surgeries. Only the left lower extremity was involved in 8 patients, only the right in 7, and both in 2. The most common patterns were plantar flexion of all toes and inversion of the foot, typically activated with standing or walking. Only 2 patients had dystonia elsewhere. There was a family history of possible dystonia in 2 patients. One of five tested for DYT1 was positive, in the absence of a family history. One of eight patients treated with levodopa experienced mild improvement. Six of eight treated with botulinum toxin improved. No patient has been observed to have a secondary cause of dystonia. The prognosis, with regard to progression or spread to other body parts, has been favorable. Although uncommon, foot dystonia on a primary basis, not due to DYT1, can begin in adulthood. In this series of patients, the diagnosis was often not recognized, leading to extensive and unnecessary testing and treatment and emphasizing the need for wider recognition.

Smothering dystonia in a patient with oromandibular dystonia.

A case report is presented of a patient with pathologically confirmed striatonigral degeneration who experienced episodic syncope as a result of oromandibular dystonia obstructing inhalation through her mouth and nose.

Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson's disease.

OBJECTIVE: To evaluate the efficacy and safety of donepezil, an acetylcholinesterase inhibitor, as a treatment for cognitive impairment and dementia in patients with Parkinson' s disease (PD). METHODS: Using a randomized, double-blind, placebo-controlled design, nine patients received placebo and seven patients received donepezil (2.5-10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary efficacy outcomes were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. Secondary efficacy outcomes were psychiatric symptom and activities of daily living ratings. Primary safety measures were motor signs and assessments of adverse effects. RESULTS: Patients on donepezil showed selective and significant (p<0.05) improvement on the memory subscale of the Dementia Rating Scale. There was also a trend toward improvement on a measure of psychomotor speed and attention. There were no group differences in psychiatric status, motor function, or activities of daily living as measured at baseline or end-point. Adverse effects resulted in premature withdrawal of four patients on donepezil, two for peripheral cholinergic effects and one for increased parkinsonism. Side effects were associated with dosage increases. CONCLUSION: Donepezil has a beneficial effect on memory and may improve other cognitive deficits in patients with PD and cognitive impairment. However, variable tolerability in our sample underscores the need for careful monitoring when prescribing donepezil to patients with PD, especially with dosage increases.