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1.  Aspiration and swallowing in Parkinson disease and rehabilitation with EMST 
Neurology  2010;75(21):1912-1919.
Dysphagia is the main cause of aspiration pneumonia and death in Parkinson disease (PD) with no established restorative behavioral treatment to date. Reduced swallow safety may be related to decreased elevation and excursion of the hyolaryngeal complex. Increased submental muscle force generation has been associated with expiratory muscle strength training (EMST) and subsequent increases in hyolaryngeal complex movement provide a strong rationale for its use as a dysphagia treatment. The current study's objective was to test the treatment outcome of a 4-week device-driven EMST program on swallow safety and define the physiologic mechanisms through measures of swallow timing and hyoid displacement.
This was a randomized, blinded, sham-controlled EMST trial performed at an academic center. Sixty participants with PD completed EMST, 4 weeks, 5 days per week, for 20 minutes per day, using a calibrated or sham, handheld device. Measures of swallow function including judgments of swallow safety (penetration–aspiration [PA] scale scores), swallow timing, and hyoid movement were made from videofluoroscopic images.
No pretreatment group differences existed. The active treatment (EMST) group demonstrated improved swallow safety compared to the sham group as evidenced by improved PA scores. The EMST group demonstrated improvement of hyolaryngeal function during swallowing, findings not evident for the sham group.
EMST may be a restorative treatment for dysphagia in those with PD. The mechanism may be explained by improved hyolaryngeal complex movement.
Classification of evidence:
This intervention study provides Class I evidence that swallow safety as defined by PA score improved post EMST.
= confidence interval;
= expiratory muscle strength training;
= maximum expiratory pressure;
= penetration–aspiration;
= Parkinson disease;
= Swallowing Quality of Life Questionnaire;
= upper esophageal sphincter;
= University of Florida Movement Disorders Center;
= Veterans Affairs.
PMCID: PMC2995389  PMID: 21098406
2.  Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites 
Neurology  2012;78(9):649-657.
To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research.
Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations.
Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies.
Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.
PMCID: PMC3286230  PMID: 22345219
3.  Evidence-based guideline update: Treatment of essential tremor 
Neurology  2011;77(19):1752-1755.
This evidence-based guideline is an update of the 2005 American Academy of Neurology practice parameter on the treatment of essential tremor (ET).
A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 2004 and April 2010.
Results and Recommendations:
Conclusions and recommendations for the use of propranolol, primidone (Level A, established as effective); alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate (Level B, probably effective); nadolol, nimodipine, clonazepam, botulinum toxin A, deep brain stimulation, thalamotomy (Level C, possibly effective); and gamma knife thalamotomy (Level U, insufficient evidence) are unchanged from the previous guideline. Changes to conclusions and recommendations from the previous guideline include the following: 1) levetiracetam and 3,4-diaminopyridine probably do not reduce limb tremor in ET and should not be considered (Level B); 2) flunarizine possibly has no effect in treating limb tremor in ET and may not be considered (Level C); and 3) there is insufficient evidence to support or refute the use of pregabalin, zonisamide, or clozapine as treatment for ET (Level U).
PMCID: PMC3208950  PMID: 22013182
4.  Dissociating apathy and depression in Parkinson disease 
Neurology  2006;67(1):33-38.
To examine the hypothesis that apathy is a core feature of Parkinson disease (PD) and that apathy can be dissociated from depression.
Eighty patients with PD and 20 patients with dystonia completed depression and apathy measures including the Marin Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), and Centers for Epidemiologic Studies–Depression Scale (CES-D).
There was a significantly higher severity and frequency of apathy in PD (frequency = 51%, 41/80) than in dystonia (frequency = 20%, 4/20). Apathy in the absence of depression was frequent in PD and did not occur in dystonia (PD = 28.8%, dystonia = 0%).
Patients with Parkinson disease (PD) experienced significantly higher frequency and severity of apathy when compared with patients with dystonia. Apathy may be a “core” feature of PD and occurs in the absence of depression.
PMCID: PMC2911155  PMID: 16832074
5.  Emotion and ocular responses in Parkinson’s Disease 
Neuropsychologia  2011;49(12):3247-3253.
Parkinson’s disease (PD) is a neurodegenerative disease that affects motor, cognitive, and emotional functioning. Previous studies reported reduced skin conductance responses in PD patients, compared to healthy older adults when viewing emotionally arousing pictures. Attenuated skin conductance changes in PD may reflect peripheral autonomic dysfunction (e.g., reduced nerve endings at the sweat gland) or, alternatively, a more central emotional deficit. The aim of the current study was to investigate a second measure of sympathetic arousal—change in pupil dilation. Eye movements, a motor-based correlate of emotional processing, were also assessed. Results indicated that pupil dilation was significantly greater when viewing emotional, compared to neutral pictures for both PD patients and controls. On the other hand, PD patients made fewer fixations with shorter scan paths, particularly when viewing pleasant pictures. These results suggest that PD patients show normal sympathetic arousal to affective stimuli (indexed by pupil diameter), but differences in motor correlates of emotion (eye movements.)
PMCID: PMC3384545  PMID: 21839756
emotion; arousal; Parkinson’s disease; pupil; eye movement
6.  Patient-Specific Analysis of the Relationship Between the Volume of Tissue Activated During DBS and Verbal Fluency 
NeuroImage  2010;54S1:S238-S246.
Deep brain stimulation (DBS) for the treatment of advanced Parkinson’s disease involves implantation of a lead with four small contacts usually within the subthalamic nucleus (STN) or globus pallidus internus (GPi). While generally safe from a cognitive standpoint, STN DBS has been commonly associated with a decrease in the speeded production of words, a skill referred to as verbal fluency. Virtually all studies comparing pre-surgical to post-surgical verbal fluency performance have detected a decrease with DBS. The decline may be attributable in part to the surgical procedures, yet the relative contributions of stimulation effects are not known. In the present study, we used patient-specific DBS computer models to investigate the effects of stimulation on verbal fluency performance. Specifically, we investigated relationships of the volume and locus of activated STN tissue to verbal fluency outcome. Stimulation of different electrode contacts within the STN did not affect total verbal fluency scores. However, models of activation revealed subtle relationships between the locus and volume of activated tissue and verbal fluency performance. At ventral contacts, more tissue activation inside the STN was associated with decreased letter fluency performance. At optimal contacts, more tissue activation within the STN was associated with improved letter fluency performance. These findings suggest subtle effects of stimulation on verbal fluency performance, consistent with the functional non-motor subregions/somatopy of the STN.
PMCID: PMC2908727  PMID: 20362061
verbal fluency; DBS; cognition; mood; microlesion
7.  The trajectory of apathy after deep brain stimulation: From pre-surgery to 6 months post-surgery in Parkinson’s disease☆ 
Parkinsonism & related disorders  2011;17(3):182-188.
Deep brain stimulation (DBS) has been associated with increased apathy in patients with PD, yet studies lack longitudinal data and have not assessed differences between sites of implantation (i.e. STN versus GPi). We assessed apathy prior to surgery and 6 months post-surgery using a longitudinal designe–latent growth curve modeling. We hypothesized that apathy would increase post-surgery, and be related to subthalamic nucleus (versus globus pallidus interna) implantation. Forty-eight PD patients underwent unilateral surgery to either GPi or STN and completed the Apathy Scale prior to surgery and 2, 4, and 6 months post-surgery. Forty-eight matched PD controls completed the Apathy Scale at a 6-month interval. Results indicated apathy increased linearly from pre- to 6-months post-DBS by .66 points bi-monthly, while apathy in the control group did not change. There was no relationship between apathy and DBS site. Higher baseline depression was associated with higher baseline apathy, but not with change in apathy. Middle-aged adults (<65) had a steeper trajectory of apathy than older adults (≥65). Apathy trajectory was not related to motor severity, laterality of DBS, levodopa medication reduction, or motor changes after surgery.
PMCID: PMC3045850  PMID: 21256069
Parkinson’s disease; Apathy; Deep brain stimulation; Latent growth curve modeling
8.  Is the N-Back Task a Valid Neuropsychological Measure for Assessing Working Memory? 
The n-back is a putative working memory task frequently used in neuroimaging research; however, literature addressing n-back use in clinical neuropsychological evaluation is sparse. We examined convergent validity of the n-back with an established measure of working memory, digit span backward. The relationship between n-back performance and scores on measures of processing speed was also examined, as was the ability of the n-back to detect potential between-groups differences in control and Parkinson's disease (PD) groups. Results revealed no correlation between n-back performance and digit span backward. N-back accuracy significantly correlated with a measure of processing speed (Trail Making Test Part A) at the 2-back load. Relative to controls, PD patients performed less accurately on the n-back and showed a trend toward slower reaction times, but did not differ on any of the neuropsychological measures. Results suggest the n-back is not a pure measure of working memory, but may be able to detect subtle differences in cognitive functioning between PD patients and controls.
PMCID: PMC2770861  PMID: 19767297
Working memory; Executive function; Information processing speed; Parkinson's disease; Neuropsychology
9.  Startle reflex hyporeactivity in Parkinson's disease: an emotion-specific or arousal-modulated deficit? 
Neuropsychologia  2009;47(8-9):1917-1927.
We previously reported that patients with Parkinson's disease (PD) demonstrate reduced psychophysiologic reactivity to unpleasant pictures as indexed by diminished startle eyeblink magnitude (Bowers et al., 2006). In the present study, we tested the hypothesis that this hyporeactivity was primarily driven by diminished reactivity to fear-eliciting stimuli as opposed to other types of aversive pictures. This hypothesis was based on previous evidence suggesting amygdalar abnormalities in PD patients coupled with the known role of the amygdala in fear processing. To test this hypothesis, 24 patients with Parkinson's disease and 24 controls viewed standardized sets of emotional pictures that depicted fear, disgust (mutilations, contaminations), pleasant, and neutral contents. Startle eyeblinks were elicited while subjects viewed these emotional pictures. Results did not support the hypothesis of a specific deficit to fear pictures. Instead, the PD patients had reduced reactivity to mutilation pictures relative to other types of negative pictures in the context of normal subjective ratings. Further analyses revealed that controls displayed a pattern of increased startle eyeblink magnitude for “high arousal” versus “low arousal” negative pictures, regardless of picture category, whereas startle eyeblink magnitude in the PD group did not vary by arousal level. These results suggest that previous findings of decreased aversion-modulated startle is driven by reduced reactivity to highly arousing negative stimuli rather than to a specific category (i.e., fear or disgust) of emotion stimuli.
PMCID: PMC2709833  PMID: 19428424
basal ganglia; emotion; neurophysiology; neurological disorders; neurodegenerative disorders
10.  Are Two Leads Always Better Than One: An Emerging Case for Unilateral Subthalamic Deep Brain Stimulation in Parkinson’s disease 
Experimental neurology  2008;214(1):1-5.
Bilateral subthalamic (STN) deep brain stimulation (DBS) provides significant symptom relief for the majority of well-screened patients suffering with Parkinson’s disease (PD). Implantation of stimulating electrodes bilaterally in a single session has become standard in most operating theaters worldwide. There is, however, limited evidence-based support for this approach. Although bilateral surgical procedures have been shown, using standardized clinical ratings, to provide greater motor benefits compared to unilateral procedures, bilateral procedures are more likely to be associated with increased acute and long- term complications including post-operative confusion, speech difficulties and cognitive dysfunction. Unilateral stimulation has been shown to provide significant benefits for appendicular and axial symptoms. The relative benefit of implanting one versus two sides and whether the degree of benefit associated with the second side is worth the potential risk of doing so have not been examined systematically. The relative magnitude of benefit associated with unilateral versus bilateral procedures is likely to vary from patient to patient, particularly in those patients with asymmetric symptomatology. As such, there are likely subsets of patients who do not require and therefore should not be exposed to the potential complications associated with bilateral simultaneous implantation. This review and commentary will outline our current understanding of the benefits associated with unilateral and bilateral STN DBS and discuss the role of unilateral or staged unilateral procedures as an alternative surgical approach for patients with advanced PD.
PMCID: PMC2888769  PMID: 18718469
11.  Parkinson's disease in women: A call for improved clinical studies and for comparative effectiveness research 
Maturitas  2010;65(4):352-358.
The incidence and prevalence of Parkinson's disease (PD) is expected to rise precipitously over the next several decades, as will the associated healthcare related costs. The epidemiology and disease manifestations of PD may differ when comparing women to men. Women are for example less likely to acquire PD, and in several studies have demonstrated a delayed onset of motor symptoms. Women, however, are more likely to experience PD-related complications that may lead to disability (e.g. depression and medication-associated dyskinesia). Further, there are purported differences in the treatment and treatment outcomes in PD men compared to women. Whether estrogen, other hormonal activity, or whether multiple factors underpin these findings remains unknown. Also unknown is whether estrogen itself may represent a therapeutic option for symptomatic PD treatment. This review summarizes what is known about gender differences in epidemiology, clinical features, treatment outcomes (medical and surgical/deep brain stimulation), and social impact among all available PD studies. We offer expert opinion regarding the shortcomings of the current evidence, and we propose a detailed list of studies that will help to clarify important gender related PD questions. Our hope is that this review will spark comparative effectiveness research into improving care and outcomes in women with PD.
PMCID: PMC2875870  PMID: 20117891
Parkinson's Disease; Women; Gender differences; Estrogen; Epidemiology; Disease characteristics; Treatment; Social impact
12.  The Persistent Effects of Unilateral Pallidal and Subthalamic Deep Brain Stimulation on Force Control in advanced Parkinson’s patients 
Parkinsonism & related disorders  2008;14(6):481-488.
The persistent effects of unilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi) or subthalamic nucleus (STN) on specific movement parameters produced by Parkinson’s disease (PD) patient’s are poorly understood. The aim of this study was to determine the effects of unilateral GPi and STN DBS on the force producing capabilities of PD patients during maximal efforts and functional bimanual dexterity. Clinical and biomechanical data were collected from 14 unilaterally implanted patients (GPi=7; STN=7), at least 13 months post-DBS surgery, while On and Off stimulation in the absence of medication. Unilateral DBS of either location produced a 33% improvement in UPDRS Motor Scores. Significant gains in maximum force production were present in both limbs during unimanual efforts. The greatest increase in maximum force, for both limbs, was under bimanual conditions. Force in the contralateral limb increased more than 30% during bimanual efforts while ipsilateral force increased by 25%. Unilateral DBS improved grasping force control and consistency of digit placement during the performance of a bimanual dexterity task. The clinical and biomechanical data indicate that unilateral DBS of GPi or STN results in persistent improvements in the control and coordination of grasping forces during maximal efforts and functional dexterous actions. Unilateral DBS implantation of either site should be considered an option for those patients in which bilateral procedures are contraindicated.
PMCID: PMC2605295  PMID: 18342565
deep brain stimulation; globus pallidus pars interna; force control; Parkinson’s disease; subthalamic nucleus; bilateral deficit; hand function
13.  Brain penetration effects of microelectrodes and DBS leads in STN or GPi 
To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)).
Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant “collision/implantation” or “microlesion” effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified.
47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery—off medications, on DBS (12 h medication washout), (5) 6 months postoperatively—off medication and off DBS (12 h washout) and (6) 6 months—on medication and off DBS (12 h washout).
Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar.
This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.
PMCID: PMC3791596  PMID: 19237386
14.  The late positive potential, emotion and apathy in Parkinson’s disease 
Neuropsychologia  2013;51(5):960-966.
Parkinson’s disease is associated with emotional changes including depression, apathy, and anxiety. The current study investigated emotional processing in non-demented individuals with Parkinson disease (PD) using an electrophysiological measure, the centro-parietal late positive potential (LPP). Non-demented patients with Parkinson’s disease (n=17) and healthy control participants (n=16) viewed pleasant, neutral, and unpleasant pictures while EEG was recorded from a 64-channel geodesic net. The Parkinson patients did not differ from controls in terms of early electrophysiological components that index perceptual processing (occipital P100, N150, P250). Parkinson patients, however, showed reduced LPP amplitude specifically when viewing unpleasant, compared to pleasant, pictures as well as when compared to controls, consistent with previous studies suggesting a specific difference in aversive processing between PD patients and healthy controls. Importantly, LPP amplitude during unpleasant picture viewing was most attenuated for patients reporting high apathy. The data suggest that apathy in PD may be related to a deficit in defensive activation, and may be indexed cortically using event-related potentials.
PMCID: PMC3681426  PMID: 23320979
Parkinson’s disease; ERP; Late positive potential; Apathy; Emotion
15.  The Interplay of Concurrent Positive and Negative Interpersonal Events in the Prediction of Daily Negative Affect and Fatigue for Rheumatoid Arthritis Patients 
The purpose of the present study was to examine the interaction of daily concurrent positive interpersonal events (PIE) and negative interpersonal events (NIE) on the daily experience of negative affect and fatigue in a sample of men and women with rheumatoid arthritis (RA). The blunting hypothesis posits that NIE nullify the beneficial influence of PIE whereas the buffering hypothesis posits that PIE offset the adverse influence of NIE. Participants completed up to 30 consecutive daily diaries in which they reported ratings for fatigue and negative affect, along with the occurrence of PIE and NIE throughout the day. Multilevel modeling was used to examine the interaction of daily PIE and NIE on daily negative affect and fatigue. In support of the blunting hypothesis, on days when NIE were diminished, PIE were associated with a greater reduction in fatigue. In contrast, consistent with the buffering hypothesis, on days when PIE were elevated, NIE were associated with a lesser increase in negative affect. Whereas the main effects of PIE and NIE carried over to the next day, the joint effects of PIE and NIE did not. The clinical utility of assessing the impact of co-occurring PIE and NIE is discussed.
PMCID: PMC3212834  PMID: 20658831
fatigue; negative affect; rheumatoid arthritis; interpersonal events; stress
16.  Panic and fear induced by deep brain stimulation 
Mood, cognitive, and behavioural changes have been reported with deep brain stimulation (DBS) in the thalamus, globus pallidus interna, and anterior limb of the internal capsule/nucleus accumbens region.
To investigate panic and fear resulting from DBS.
Intraoperative DBS in the region of the right and then left anterior limb of the internal capsule and nucleus accumbens region was undertaken to treat a 52 year old man with treatment refractory obsessive‐compulsive disorder (OCD). Mood, anxiety, OCD, alertness, heart rate, and subjective feelings were recorded during intraoperative test stimulation and at follow up programming sessions.
DBS at the distal (0) contact (cathode 0−, anode 2+, pulse width 210 ms, rate 135 Hz, at 6 volts) elicited a panic attack (only seen at the (0) contact). The patient felt flushed, hot, fearful, and described himself as having a “panic attack.” His heart rate increased from 53 to 111. The effect (present with either device) was witnessed immediately after turning the device on, and abruptly ceased in the off condition
DBS of the anterior limb of the internal capsule and nucleus accumbens region caused severe “panic.” This response may result from activation of limbic and autonomic networks.
PMCID: PMC2077710  PMID: 16484657
deep brain stimulation; fear; panic

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