Altered corticomotor representation in patients with Parkinson's disease.

In 6 patients with Parkinson's disease (PD) and 6 age-matched controls, transcranial magnetic stimulation was applied at 56 regions over the motor cortex and premotor cortex of each hemisphere, with the first dorsal interosseous (FDI) muscle of both hands activated at 15% maximum voluntary contraction during stimulation. For each site, motor evoked potential (MEP) landmarks were recovered, including MEP amplitude, MEP onset latency, and silent period duration. Scaled MEP amplitudes were used to construct individual cortical maps of the FDI muscles. The maps revealed an anterior displacement of the muscle representation in PD patients. This anterior shift over motor cortical areas may reflect increased contributions of corticocortical connections between motor cortex and premotor cortical areas, possibly enhanced by the visual feedback aspect of the task. These alterations may reflect adaptations to the impairments in striatocortical circuits in PD.     

Repetitive magnetic stimulation of cortical motor areas in Parkinson's disease: implications for the pathophysiology of cortical function.

We investigated the neurophysiological and clinical effects of repetitive magnetic stimulation (rTMS) delivered to the cortical motor areas in healthy subjects and patients with Parkinson's disease. rTMS was delivered with a high speed magnetic stimulator (Cadwell, Kennewick, WA) through a figure-eight coil centred on the primary motor area at a stimulus intensity of 120% motor threshold. Trains of 10 stimuli were delivered at frequencies of 5 Hz while subjects were at rest and during a voluntary contraction of the contralateral first dorsal interosseous muscle. In normal subjects at rest, the muscle evoked responses (MEPs) to each stimulus in a train of magnetic stimuli progressively increased in size during the train. rTMS left the MEPs unchanged in patients off therapy and had a small facilitatory effect in those on therapy. In normal subjects and patients, 5-Hz rTMS trains delivered during a voluntary contraction of the target muscle left the MEP unchanged in size. MEPs were followed by a silent period that increased in duration during the course of the train. The silent period duration increased to a similar extent in patients and controls. The reduced rTMS-induced facilitation of MEPs in patients with Parkinson's disease reflects a decreased facilitation of the excitatory cells in the cortical motor areas.     

Extradural motor cortex stimulation in Parkinson's disease.

Extradural motor cortex stimulation (EMCS) is a surgical procedure proposed for patients with advanced Parkinson's disease (PD) who cannot undergo deep brain stimulation (DBS). Five PD patients with motor fluctuations and dyskinesia underwent EMCS of the left hemisphere. All fulfilled CAPSIT criteria for DBS, with the exception of age > 70 years. Patients were assessed preoperatively and 6 months after surgery on and off medications, with stimulator on, and 2 weeks later with stimulator off. Outcome measures included changes in mean medication dosage (levodopa and dopamine agonists), Unified Parkinson's Disease Rating Scale (UPDRS Parts II-III and Item 39), and dyskinesias (Abnormal Involuntary Movements Scale [AIMS]). We found no significant mean changes following EMCS. However, there was a trend for a reduction of mean daily medication intake (-30%) and AIMS (-19%). There were 3 patients who reported reduced OFF time (UPDRS Item 39) and 4 of 5 who felt a subjective benefit in stability and gait. In our PD cohort, EMCS induced no objective benefit, although some subjective improvement was reported mostly on axial symptoms.     

Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease.

Electrical stimulation of deep brain structures, such as globus pallidus and subthalamic nucleus, is widely accepted as a therapeutic tool for patients with Parkinson's disease (PD). Cortical stimulation either with epidural implanted electrodes or repetitive transcranial magnetic stimulation can be associated with motor function enhancement in PD. We aimed to study the effects of another noninvasive technique of cortical brain stimulation, transcranial direct current stimulation (tDCS), on motor function and motor-evoked potential (MEP) characteristics of PD patients. We tested tDCS using different electrode montages [anodal stimulation of primary motor cortex (M1), cathodal stimulation of M1, anodal stimulation of dorsolateral prefrontal cortex (DLPFC), and sham-stimulation] and evaluated the effects on motor function--as indexed by Unified Parkinson's Disease Rating Scale (UPDRS), simple reaction time (sRT) and Purdue Pegboard test--and on corticospinal motor excitability (MEP characteristics). All experiments were performed in a double-blinded manner. Anodal stimulation of M1 was associated with a significant improvement of motor function compared to sham-stimulation in the UPDRS (P < 0.001) and sRT (P = 0.019). This effect was not observed for cathodal stimulation of M1 or anodal stimulation of DLPFC. Furthermore, whereas anodal stimulation of M1 significantly increased MEP amplitude and area, cathodal stimulation of M1 significantly decreased them. There was a trend toward a significant correlation between motor function improvement after M1 anodal-tDCS and MEP area increase. These results confirm and extend the notion that cortical brain stimulation might improve motor function in patients with PD.     

Asymmetric corticomotor excitability correlations in early Parkinson's disease.

We studied corticomotor excitability (CE) between the more and less affected sides in early Parkinson's disease (PD) patients using transcranial magnetic stimulation (TMS). Sixteen-PD patients within the first 3 years of diagnosis were studied with single-pulse TMS over each motor cortex with intensities from 40% to 100% stimulator output. Active motor evoked potentials (MEP) and cortical silent period durations (CSP) were recorded, fitted with sigmoid curves, summarized as maximal MEP/CSP, maximal MEP/CSP slope, and intensity where MEP/CSP is half-maximal (MEP/CSP-Int50), and correlated with Unified Parkinson's Disease Rating Scale scores (UPDRS). On the more affected side, higher (worse) UPDRS scores were correlated with shorter maximal CSP (r=-0.51, P=0.046). On the less affected side, higher UPDRS scores were correlated with higher MEP-Int50 (r=0.51, P=0.043) and CSP-Int50 (r=0.54, P=0.029). For the less affected side, altered CE, as indexed by higher MEP or CSP-Int50 intensities, may contribute to early clinical symptoms. On the more affected side, increases in CE, indexed by shorter CSP, may account for a greater proportion of PD symptoms. These findings are consistent with an evolution of neurophysiologic correlates in early PD patients from a less to more symptomatic state.     

Cortical thinning associated with mild cognitive impairment in Parkinson's disease

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual‐visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains. © 2014 International Parkinson and Movement Disorder Society     

Interhemispheric and ipsilateral connections in Parkinson's disease: relation to mirror movements.

Mirror movements (MM) occur in early, asymmetric Parkinson's disease (PD). To examine the pathophysiology of MM in PD, we studied 13 PD patients with MM (PD-MM), 7 PD patients without MM (PD-NM), and 14 normal subjects. Cross-correlogram did not detect common synaptic input to motoneuron pools innervating homologous hand muscles in PD-MM patients. Transcranial magnetic stimulation studies showed no significant difference in ipsilateral motor-evoked potentials between PD-MM patients and normal subjects. The MM side of PD-MM patients showed a slower increase in ipsilateral silent period area with higher level of muscle contraction than the non-MM side and normal subjects. There was less interhemispheric inhibition (IHI) at long interstimulus intervals of 20 to 50 ms in PD-MM than PD-NM. IHI reduced short interval intracortical inhibition in normal subjects and PD-NM, but not in PD-MM. IHI significantly increased intracortical facilitation in PD-MM and PD-NM patients, but not in normal subjects. Our results suggest that MM in PD is due to activation of the contralateral motor cortex. PD-MM patients had reduced transcallosal inhibitory effects on cortical output neurons and on intracortical inhibitory circuits compared to PD-NM patients and controls. These deficits in transcallosal inhibition may contribute to MM in PD patients.     

Postmortem analysis of bilateral subthalamic electrode implants in Parkinson's disease.

This is the second neuropathological report detailing bilateral electrodes targeting the subthalamic nucleus (STN) in idiopathic Parkinson's disease (PD). The patient presented with unilateral tremor-dominant parkinsonism. Bilateral STN stimulation was carried out 7 years later due to significant disease progression and severe motor fluctuations. The patient exhibited bilateral improvements in rigidity and bradykinesia both intraoperatively and postoperatively. The patient died 2 months later from aspiration pneumonia. Neuropathological examination confirmed both the diagnosis of PD and the electrode placements. The tip of the left electrode was located medially and posteriorly in the left STN and the tip of the right electrode entered the base of the thalamus/zona incerta immediately above the right STN. Tissue changes associated with the subthalamic electrode tracts included mild cell loss, astrogliosis, and some tissue vacuolation. Our postmortem analysis indicates little tissue damage associated with STN stimulation for PD.     

Long-term follow-up of globus pallidus chronic stimulation in advanced Parkinson's disease.

To assess the long-term follow-up of the globus pallidus internus (GPi) stimulation, six patients were evaluated every year by using the Unified Parkinson's Disease Rating Scale (UPDRS). Three years postoperatively, GPi stimulation led to a significant improvement of dyskinesia severity (50%, P = 0.05) and activities of daily living (subscore of quality of life scale, 9%, P = 0.05). However, the improvement induced by chronic pallidal stimulation on the mean daily duration in the off state was lost at the last assessment.     

Progression of cortical thinning in early Parkinson's disease

The aim of this study was to investigate the progression of cortical thinning and gray‐matter (GM) volume loss in early Parkinson's disease (PD). MRI and neuropsychological assessment were obtained at baseline and follow‐up (mean ± standard deviation = 35.50 ± 1.88 months) in a group of 16 early‐PD patients (H & Y stage ≤II and disease duration ≤5 years) and 15 healthy controls matched for age, gender, and years of education. FreeSurfer software was used for the analysis of cortical thickness as well as for cortical and subcortical volumetric analyses. Voxel‐based morphometry analysis was performed using SPM8. Compared to controls, PD patients showed greater regional cortical thinning in bilateral frontotemporal regions as well as greater over‐time total GM loss and amygdalar volume reduction. PD patients and controls presented similar over‐time changes in cognitive functioning. In early‐PD patients, global GM loss, amygdalar atrophy, and cortical thinning in frontotemporal regions are specifically associated with the PD‐degenerative process. © 2012 Movement Disorder Society     

OFF-off rebound dyskinesia in subthalamic nucleus deep brain stimulation of Parkinson's disease.

A 61-year-old man with Parkinson's disease (PD), motor fluctuations, and dyskinesias underwent bilateral implantation of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN). One month after surgery, DBS was optimized to bilateral monopolar settings at the most proximal electrode just superior to the STN, which improved motor fluctuations and dyskinesias. At several postoperative evaluations off medications overnight, both stimulators were turned off and within 60 seconds he developed severe dyskinesias. When the stimulators were turned back on, the dyskinesias soon resolved. This article is a first report of a unique pattern of rebound-type dyskinesia that occurred in the off medication state produced by stopping STN DBS.     

Levodopa response in long-term bilateral subthalamic stimulation for Parkinson's disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) is effective in advanced Parkinson's disease (PD), but its effects on the levodopa response are unclear. We studied the levodopa response after long-term STN-DBS, STN-DBS efficacy and predictive value of preoperative levodopa response to long-term DBS benefit in 33 PD patients with bilateral STN-DBS. Patients were assessed using the Unified Parkinson's Disease Rating Scale preoperatively (with and without medications) and postoperatively (without medications or stimulation, with only medications or stimulation, and with both medications and stimulation). Levodopa response significantly decreased postoperatively by 31.1% at 3 years and 32.3% at 5 years, possibly related to the reduction in medication requirement, direct STN stimulation effect or PD progression. STN-DBS alone significantly improved motor scores (37.2% at 3 years and 35.1% at 5 years) and activities of daily living scores (27.1% at 3 years and 19.2% at 5 years). Anti-PD drugs were significantly reduced by 47.9% at 3 years and 39.8% at 5 years. However, the magnitude of the preoperative response to levodopa did not predict DBS benefit at 3 and 5 years.     

Osteoporosis in Parkinson's disease.

There are few studies of osteoporosis in Parkinson's disease (PD). We assessed the prevalence of osteoporosis in a PD clinic cohort. All subjects with a confirmed diagnosis of PD attending a clinic were invited to participate. All consenting subjects had bone density measured by dual energy X-ray absorptiometry scanning. Further data, including demography, disease duration, and disease severity, were collected. One hundred five subjects participated; median age was 75 (54-92) years. Fifty-one (49%) patients were men. Of the men: median T score, -1.3 (range, -4.7 to 3.8); median Z score, 0.0 (-3.2 to 4.7); diagnostic categories: osteoporosis, 20%; osteopenia, 41%; normal, 39%. Of the women: median T score -2.7 (-4.7 to 1.4); median Z score, -0.25 (-2.6 to 4.2); diagnostic categories: osteoporosis, 63%; osteopenia, 28%; and normal, 9%. Whole sample: osteoporosis, 42%; osteopenia, 34%; and normal, 24%. There were associations between age, depression, disease duration, and osteoporosis but not with disease severity. Female gender was an independent predictor of osteoporosis. The prevalence of osteoporosis/osteopenia is considerable in PD patients but does not exceed that of other people of similar age. Osteoporosis/osteopenia was present in almost all women of this age group with PD.     

Long‐term outcomes of surgical therapies for Parkinson's disease

The surgical lesion of different brain structures has been used as a treatment for Parkinson's disease (PD) for several decades. More recently, the favored therapeutic approach has involved the administration of levodopa and the use of DBS. These two major therapeutic advances have greatly modified both the clinical condition of patients and the history of the disease. With the introduction of L ‐dopa in 1967, patients could regain mobility, because their akinesia, tremor, and rigidity were greatly improved, with consequent significant improvement in quality of life and increased life expectancy. However, after the so‐called “honeymoon” period in which the disease seemed to be controlled, motor fluctuations and L ‐dopa‐induced dyskinesias mitigated the initial enthusiasm. In the 1990s, unilateral pallidotomy and DBS of the globus palllidus internus and STN reduced these motor fluctuations and dyskinesias remarkably, thereby inaugurating a new era in the surgical treatment of PD. Short‐ and medium‐term follow‐up studies of patients who underwent surgery have documented sustained, significant motor benefits. However, given the progressive nature of PD and the purely symptomatic effects of pallidotomy and DBS, the long‐term clinical evolution of these surgical patients currently seems to be associated with a new PD phenotype, mainly characterized by axial motor problems and cognitive impairment. Here, we analyze the long‐term clinical outcomes of surgical PD patients with at least 5‐year follow‐up, focusing on the long‐term motor symptoms that were initially responsive to surgery. © 2012 Movement Disorder Society     

Applause sign in advanced Parkinson's disease

BackgroundThe ‘applause sign’ a tendency to continue applauding in response to instructions to clap three times was described in 1995 and was considered specific to degenerative disease, especially to atypical parkinsonian disorders. In early phase Parkinson's disease (PD) the sign has been reported positive as well. In late stage PD it is unknown whether and to what extent the sign may be elicited and it remains unknown if and to what degree the sign correlates to cognitive impairment and PD related dementia.MethodsNursing home residents with PD (MMSE >17) were included. All patients underwent the clapping test and were tested for cognitive disturbance by making use of accepted clinimetrics (MMSE and Scopa-cog). T-testing was performed with the hypothesis that patients expressing the applause sign would score lower on the MMSE or Scopa-cog.ResultsSeventy three nursing home residents (mainly Hoehn and Yahr 4/5) with a mean disease duration of 10 years and a mean age of 78.7 years were included. The applause sign was found positive in 15 of 73 residents (20.5%). Residents expressing the applause sign had significantly lower mean scores on the MMSE (25.1 vs 22.9 points, p < 0.006) and Scopa-cog (14.8 vs 12.0 points, p < 0.039).ConclusionsThe applause sign is present in late stage PD and correlates with a higher degree of cognitive impairment as established with accepted clinimetric tests. A higher degree of frontal lobe involvement explains the presence of the applause sign.     

Effect of daily repetitive transcranial magnetic stimulation on motor performance in Parkinson's disease.

Previous studies in patients with Parkinson's disease have reported that a single session of repetitive transcranial magnetic stimulation (rTMS) can improve some or all of the motor symptoms for 30 to 60 minutes. A recent study suggested that repeated sessions of rTMS lead to effects that can last for at least 1 month. Here we report data that both confirm and extend this work. Fifty-five unmedicated PD patients were classified into four groups: two groups (early and late PD) received 25 Hz rTMS bilaterally on the motor arm and leg areas; other groups acted as control for frequency (10 Hz) and for site of stimulation (occipital stimulation). All patients received six consecutive daily sessions (3,000 pulses for each session). The first two groups then received a further three booster sessions (3 consecutive days of rTMS) after 1, 2, and 3 months, while the third group had only one additional session after the first month. Unified Parkinson's Disease Rating Scale (UPDRS), walking time, key-tapping speed, and self-assessment scale were measured for each patient before and after each rTMS session and before and after the monthly sessions. Compared to occipital stimulation, 25 Hz rTMS over motor areas improved all measures in both early and late groups; the group that received 10 Hz rTMS improved more than the occipital group but less than the 25 Hz groups. The effect built up gradually during the sessions and was maintained for 1 month after, with a slight reduction in efficacy. Interestingly, the effect was restored and maintained for the next month by the booster sessions. We conclude that 25 Hz rTMS can lead to cumulative and long-lasting effects on motor performance.     

Effect of expectancy and personality on cortical excitability in Parkinson's disease

Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty‐six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO‐Five Factor Inventory, General Perceived Self‐Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor‐evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P < .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P < .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. © 2013 Movement Disorder Society     

Sleep disorders in Parkinson's disease.

We sought to estimate the frequency and nature of sleep disturbances in Indian Parkinson's disease (PD) patients. One hundred forty nine consecutive PD patients attending the Movement Disorders Clinic of the All India Institute of Medical Sciences, New Delhi, India and 115 age-matched healthy controls participated. After clinical evaluation, sleep assessment was done using a 23-question, validated sleep questionnaire. Mean age of PD patients and the duration of illness were 58.37 (S.D. 10.45) years and 5.7 (S.D. 3.85) years, respectively. The mean age of the controls was 56.50 (S.D. 11.45) years (P > 0.05). Sleep problems were seen in 63 (42%) PD patients compared to 12% of controls. These were: insomnia in 32%, nightmares in 32%, and excessive day time sleepiness in 15% of PD patients as compared with 5%, 5% and 6%, respectively, in controls (P < 0.025). Presence of nightmares was significantly associated with higher Hoehn and Yahr score (P < 0.002), high unified Parkinson's disease rating scale (UPDRS) Part I score (P < 0.000) and levodopa dose (P < 0.025). Excessive daytime sleepiness correlated with higher Hoehn and Yahr stage (P < 0.004), and levodopa dose (P < 0.040). The sleep latency was longer in PD patients as compared to controls (P < 0.000). Multiple logistic regression analysis showed association of sleep disturbances with UPDRS Part III, Schwab and England score, levodopa dose, rigidity score, and bradykinesia score. Sleep problems are much more common in PD patients compared to controls (P < 0.001), and correlate with increased severity of disease.     

Body weight gain rate in patients with Parkinson's disease and deep brain stimulation.

We evaluated body weight changes in patients with Parkinson's disease (PD) after electrode implantation for deep brain stimulation (DBS) in the subthalamic nucleus (STN) in relation to clinical improvement. Thirty PD patients who received STN DBS were included (22 men, 8 women; mean age, 60.0 +/- 7.1 years; mean PD duration, 13.5 +/- 3.7 years; mean body mass index [BMI], 21.6 +/- 3.0 kg/m2). Body weight, physical activity, and Unified Parkinson's Disease Rating Scale (UPDRS) scores were noted before and 3 and 12 months after the procedure. Significant weight gain occurred in 29 patients; the mean increase was 14.8 +/- 9.8% of initial body weight in 1 year. Of the patients, 46.5% reported weight gain in the first 3 months, 21.4% gradual weight gain in the first 6 months, and 32.1% a slow increase for 1 year. Mean BMI increased up to 24.7 +/- 3.7 kg/m2. After 1 year, mean UPDRS motor score improved significantly in off and in on; and therapy complications improved by 91.0 +/- 17.0%. BMI changes at 3 and 12 months were significantly correlated to dyskinesia score changes, and levodopa dosage was not. In PD, STN DBS produces not only symptom control, but also weight gain. DBS candidates should be given nutritional counseling before the intervention to prevent rapid and/or excessive weight gain.     

Primitive reflexes distinguish vascular parkinsonism from Parkinson's disease

OBJECTIVES: Although vascular parkinsonism (VP) occurs frequently in the elderly, its clinical features have not been investigated in detail, particularly in comparison with Parkinson's disease (PD). The goal of this study is to clarify the diagnostic value of pathological reflexes in differentiating between VP and PD. PATIENTS AND METHODS: In 132 patients with PD and 55 with VP, pathological reflexes, including snout reflex (SR), palmomental reflex (PMR), corneomandibular reflex (CMR), jaw reflex (JR), Hoffmann reflex (HR), and extensor plantar response (EPR), were evaluated. RESULTS: The percentage of each pathological reflex elicited in two groups (VP:PD) was as follows: SR (78:30), PMR (53:26), CMR (9:6), JR (33:12), HR (29:11), and EPR (25:8). The prevalence of pathological reflexes, except for CMR, was significantly higher in the VP patients than in the PD patients. In particular, SR and PMR were more frequent than upper motor neuron signs in the VP patients. The sensitivity and specificity of either SR or PMR for VP were 84% and 82%. CONCLUSION: Snout and palmomental reflexes are useful tools in the differentiation between VP and PD.