Effects of levodopa and subthalamic nucleus stimulation on cognitive and affective functioning in Parkinson's disease.

In Parkinson's disease (PD), levodopa and subthalamic nucleus (STN) stimulation lead to major improvement in motor symptoms. Effects of both treatments on cognition and affective status are less well understood. Motor, cognitive, and affective symptoms may relate to the dysfunctioning of parallel cortico-striatal loops. The aim of this study was to assess cognition, behavior, and mood, with and without both treatments in the same group of PD patients. A group of 22 nondemented PD patients was included in this study. Patients were tested twice before surgery (off and on levodopa) and twice 3 months after surgery (OFF and ON STN stimulation, off levodopa). Cognitive and affective effects of STN stimulation and levodopa had some common, but also different, effects. STN stimulation improved performance on the planning test, associated with the dorsolateral prefrontal cortex. However, the treatments had opposite effects on tests associated with the orbitofrontal cortex; specifically, levodopa impaired while STN stimulation improved performance on the extinction phase of a reversal/extinction task. Acutely, both treatments improved motivation and decreased fatigue and anxiety. On chronic treatment (3 months after surgery), depression improved, whereas apathy worsened 3 months after surgery. To conclude, there were significant but contrasting effects of levodopa and STN stimulation on cognition and affective functions.     

Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.     

Differential effects of levodopa and subthalamic nucleus deep brain stimulation on bradykinesia in Parkinson's disease

Cardinal symptoms of Parkinson's disease (PD) respond well to treatment with levodopa and deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, it has remained unclear whether levodopa and STN‐DBS have differential effects on bradykinesia. We investigated 8 PD‐patients with STN‐electrodes in four conditions: STN‐DBS and levodopa (ON_MED/ON_STIM), STN‐DBS only (OFF_MED/ON_STIM), levodopa only (ON_MED/OFF_STIM), without STN‐DBS/levodopa (OFF_MED/OFF_STIM). Fourteen volunteers served as controls. Subjects performed fastest possible (1) pronation/supination of the forearm (diadochokinesia) and (2) flexion and extension of the index finger (finger movements). Movements were recorded using a 3D‐ultrasound‐system. Maximum frequency, amplitude, and smoothness of movements were determined. During OFF_MED/OFF_STIM, all parameters were worser than in all other conditions. In proximal diadochokinesia, OFF_MED/ON_STIM significantly improved the amplitude and frequency, whereas ON_MED/OFF_STIM had no significant effect. In contrast, we found a stronger effect of levodopa (ON_MED/OFF_STIM) on amplitudes of distal finger movement than on amplitudes of diadochokinesia. Combination of treatments during ON_MED/ON_STIM further improved both movements. However, maximum frequency remained lower in PD‐patients during ON_MED/ON_STIM compared with controls. This study demonstrates a better effect of levodopa on distal finger movements and STN‐DBS on proximal diadochokinesia. Furthermore, a complementary effect of both therapies on brain areas involved in bradykinesia can be assumed. © 2007 Movement Disorder Society     

Effects of subthalamic nucleus stimulation and levodopa treatment on gait abnormalities in Parkinson disease

BACKGROUND: Stimulation of the subthalamic nucleus is proposed for the treatment of patients presenting with severe Parkinson disease. The effect on gait is not clearly established. OBJECTIVES: To evaluate objectively the influence of bilateral subthalamic nucleus stimulation on gait in Parkinson disease and to compare it with the effects of levodopa treatment. METHODS: Ten patients underwent bilateral subthalamic nucleus stimulation. The preoperative and postoperative (3 months after surgery) clinical gait disturbances, as well as spatial and temporal gait parameters, were analyzed in off and on-drug conditions. The gait analysis was performed using a video motion analysis system (optoelectronic VICON system; Oxford Metrics, Oxford, England). RESULTS: In the off condition, there was an improvement after surgery for the total motor score and the gait subscore. In the on-drug condition, there was an improvement in levodopa-induced dyskinesias and the motor score, whereas the gait subscore was unchanged. For the gait parameters measured by the video motion analysis system system, there was also an improvement in the off condition and to a lesser extent in the on-drug condition. CONCLUSIONS: Our method allowed exact quantification of the benefit of surgery on gait parameters. Compared with the levodopa treatment, the effect of stimulation on gait kinematic parameters seems to be qualitatively similar but quantitatively different with a lower benefit on gait velocity and stride length. Concerning the pathophysiology of gait troubles in Parkinson disease, the deficit in control of stride length would be the fundamental deficit. The study underlines the possible role of the subthalamic nucleus on the stride length regulation.     

Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson's disease

Excessive synchronization of basal ganglia neural activity at low frequencies is considered a hallmark of Parkinson's disease (PD). However, few studies have unambiguously linked this activity to movement impairment through direct stimulation of basal ganglia targets at low frequency. Furthermore, these studies have varied in their methodology and findings, so it remains unclear whether stimulation at any or all frequencies < or = 20 Hz impairs movement and if so, whether effects are identical across this broad frequency band. To address these issues, 18 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both subthalamic nuclei were stimulated bilaterally at 5, 10 and 20 Hz after overnight withdrawal of their medication and the effects of the DBS on a finger tapping task were compared to performance without DBS (0 Hz). Tapping rate decreased at 5 and 20 Hz compared to 0 Hz (by 11.8+/-4.9%, p=0.022 and 7.4+/-2.6%, p=0.009, respectively) on those sides with relatively preserved baseline task performance. Moreover, the coefficient of variation of tap intervals increased at 5 and 10 Hz compared to 0 Hz (by 70.4+/-35.8%, p=0.038 and 81.5+/-48.2%, p=0.043, respectively). These data suggest that the susceptibility of basal ganglia networks to the effects of excessive synchronization may be elevated across a broad low-frequency band in parkinsonian patients, although the nature of the consequent motor impairment may depend on the precise frequencies at which synchronization occurs.     

Effects of subthalamic nucleus stimulation on motor cortex excitability in Parkinson's disease

BACKGROUND: Transcranial magnetic stimulation (TMS) studies have found abnormalities in several excitatory and inhibitory circuits in the motor cortex in PD. These include motor evoked potential (MEP) recruitment curve, silent period duration (SP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI). METHODS: The authors studied the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on these circuits in 12 patients with PD treated with STN DBS. Data from nine patients who completed the study were analyzed. Patients remained on their usual medications. The stimulators were set at the optimal parameters (ON), half the optimal amplitude (HALF), and switched off (OFF) in random order. RESULTS: The Unified PD Rating Scale motor scores were significantly lower in the ON compared to the HALF and OFF conditions. Resting SICI, studied with paired-pulse TMS at interstimulus interval of 2 ms, was reduced in the OFF and HALF conditions compared to normal subjects. STN stimulation restored SICI to normal levels. STN stimulation had no effect on motor threshold, MEP recruitment curve, SP, active SICI, ICF, and LICI. CONCLUSIONS: Although restoration of short-interval intracortical inhibition by STN stimulation is similar to the effects of dopaminergic drugs, it has no effect on silent period duration and long-interval intracortical inhibition, which are also influenced by dopaminergic drugs. A previous study found that internal globus pallidus (GPi) stimulation reduced SP but did not change SICI. Thus, GPi and STN stimulation may affect different circuits in the motor cortex.     

Bilateral subthalamic nucleus stimulation for Parkinson's disease

High frequency stimulation of the subthalamic nucleus (STN) is known to ameliorate the signs and symptoms of advanced Parkinson's disease. AIM: We studied the effect of high frequency STN stimulation in 23 patients. METHOD: Twenty-three patients suffering from severe Parkinson's disease (Stages III-V on Hoehn and Yahr scale) and, particularly bradykinesia, rigidity, and levodopa-induced dyskinesias underwent bilateral implantation of electrodes in the STN. Preoperative and postoperative assessments of these patients at 1, 3, 6 and 12 months follow-up, in "on" and "off" drug conditions, was carried out using Unified Parkinson's Disease Rating Scale, Hoehn and Yahr staging, England activities of daily living score and video recordings. RESULTS: After one year of electrical stimulation of the STN, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III) off medication improved by 62% and 61% respectively (p<0.0005). The subscores for the akinesia, rigidity, tremor and gait also improved. (p<0.0005). The average levodopa dose decreased from 813 mg to 359 mg. The cognitive functions remained unchanged. Two patients developed device-related complications and two patients experienced abnormal weight gain. CONCLUSION: Bilateral subthalamic nucleus stimulation is an effective treatment for advanced Parkinson's disease. It reduces the severity of "off" phase symptoms, improves the axial symptoms and reduces levodopa requirements. The reduction in the levodopa dose is useful in controlling drug-induced dyskinesias.     

Effects of subthalamic nucleus deep brain stimulation on sweating function in Parkinson's disease

Purpose

To assess the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on the sweating function in patients with advanced Parkinson's disease (PD).

Methods

Nineteen patients with idiopathic PD (mean age ± SD, 61.58 ± 9.47) were examined immediately before and 6 months after DBS. Each examination session included registration of autonomic symptoms by means of a semi-structural questionnaire and recording of sympathetic skin response (SSR) from both palms and one sole. The neurophysiological measurements were compared to those of 19 matched for sex and age healthy controls.

Results

Six months post-DBS motor improvement was amounted to 65.9% and the daily levodopa equivalent dose was decreased by 36.4%. Post-operatively, dyshidrosis manifestations were reduced by 66.7% (pre-DBS sudomotor dysfunction in 47.4% of patients and sudomotor fluctuation in 57.1% of the above patients). There were no significant differences in-between pre- and post-DBS results of SSR study. However, the number of patients with at least one abnormal SSR pre-operative was reduced from 6 to 3 post-operative. No correlation was found between this neurophysiological finding and the change of clinical symptoms of hyperhidrosis or the DBS motor improvement.

Conclusions

These results, although based on a small sample, suggest that STN DBS, in addition to the effect to the mobility, might also favorably regulate sweat in idiopathic PD.     

Effects of subthalamic nucleus deep brain stimulation and L-DOPA on blinking in Parkinson's disease

In this study we asked whether subthalamic nucleus deep brain stimulation (STN-DBS) alone, or in combination with l-dopa, modifies voluntary, spontaneous and reflex blinking in patients with Parkinson's disease (PD). Sixteen PD patients who underwent STN-DBS were studied in four experimental conditions: without STN-DBS and without l-dopa, STN-DBS alone, l-dopa alone and STN-DBS plus l-dopa. The results were compared with those obtained in 15 healthy controls. Voluntary blinking was assessed by asking participants to blink as fast as possible; spontaneous blinking was recorded during two 60s rest periods; reflex blinking was evoked by electrical stimulation of the supraorbital nerve. Blinking were recorded and analysed with the SMART motion system. STN-DBS increased the peak velocity and amplitude for both the closing and opening voluntary blink phases, but prolonged the inter-phase pause duration. l-dopa had no effects on voluntary blinking but reversed the increased inter-phase pause duration seen during STN-DBS. Spontaneous blink rate increased after either STN-DBS or l-dopa. Reflex blinking kinematics were not modified by STN-DBS or l-dopa. The STN-DBS effects on voluntary blinking kinematics and spontaneous blinking rate may occur as results of changes of cortico-basal ganglia activity. The prolonged pause duration of voluntary blinking indicates that STN-DBS has detrimental effects on the cranial region. These results also shed light on the pathophysiology of eyelids opening apraxia following STN-DBS.     

Language recovery following subthalamic nucleus stimulation in Parkinson's disease

Neuropsychological consequences of stimulation of the subthalamic nucleus for treatment of drug-resistant Parkinson's disease (PD) have been studied previously. However, no detailed investigations of linguistic function modifications have been carried out. We studied four consecutive patients with PD who underwent chronic bilateral stimulation of the subthalamic nuclei. Neuropsychological and linguistic evaluations were performed before and 2 weeks after surgery. Linguistic abilities were studied also 1 year after surgery with stimulators both off and on. Intraphrasal hesitation pauses, phonemic paraphasias and morpho-syntactic errors were significantly reduced and lexical retrieval improved with stimulation of the subthalamic nuclei. Implicit linguistic phenomena, mainly occurring within basal ganglia circuitry, benefited by recovery of functional equilibrium within basal nuclei and between overall basal ganglia circuitry and cerebral cortex.     

Effect of subthalamic nucleus stimulation on levodopa-induced dyskinesia in Parkinson's disease

Article abstract-The authors studied the effect of bilateral subthalamic nucleus stimulation on levodopa-induced dyskinesias in 24 consecutive parkinsonian patients with disabling dyskinesias. The improvement in the three subtypes of levodopa-induced dyskinesias was significant from the third postoperative month and was mainly due to the decrease in the daily dose of levodopa allowed by the stimulation-induced improvement in the motor score.     

The effect of subthalamic nucleus stimulation on kinaesthesia in Parkinson's disease

BACKGROUND: Parkinson's disease is accompanied by deficits in passive motion and limb position sense. OBJECTIVE: To investigate whether deep brain stimulation of the subthalamic nucleus (STN-DBS) reverses these proprioceptive deficits. METHODS AND RESULTS: A passive movement task was applied to nine patients with Parkinson's disease and bilateral chronic STN-DBS and to seven controls. Thresholds for 75% correct responses were 0.9 degrees for controls, 2.5 degrees for Parkinson's disease patients when stimulation was OFF, and 2.0 degrees when stimulation was ON. CONCLUSIONS: STN-DBS improves kinaesthesic deficits in Parkinson's disease, but does not lead to a full recovery of proprioceptive function.     

Change of the melanocortin system caused by bilateral subthalamic nucleus stimulation in Parkinson's disease

Escamilla‐Sevilla F, Pérez‐Navarro MJ, Muñoz‐Pasadas M, Sáez‐Zea C, Jouma‐Katati M, Piédrola‐Maroto G, Ramírez‐Navarro A, Mínguez‐Castellanos A. Change of the melanocortin system caused by bilateral subthalamic nucleus stimulation in Parkinson’s disease.
Acta Neurol Scand: 2011: 124: 275–281.
© 2011 John Wiley & Sons A/S. Objectives – Determine whether bilateral subthalamic nucleus stimulation (STN–DBS) in Parkinson’s disease (PD) is associated with an increase in neuropeptide Y (NPY) and/or resistance to inhibition by leptin in relation to post‐surgery weight gain. Materials and Methods – This prospective study included 20 patients who underwent bilateral STN–DBS and 17 who refused surgery. Data were obtained at baseline, 3 and 6 months on neurological and nutritional status, including determination of body mass index (BMI) and serum NPY and leptin levels. Results – NPY and leptin levels changed over time, with a distinct pattern. The BMI increase at 6 months was greater in the surgical group (5.5 ± 6.3% vs 0.5 ± 3.5%; P = 0.035). Medical group exhibited a reduction in leptin level (−2.0 ± 4.3 ng/ml) and a consequent increase in NPY level (72.4 ± 58.7 pmol/ml). However, STN–DBS patients showed an increase in leptin (3.1 ± 5.0 ng/ml; P = 0.001 vs medical group) and also in NPY (12.1 ± 53.6 pmol/ml; P = 0.022 vs medical group) levels, which suggests resistance to inhibition by leptin. Rise in NPY level correlated with higher stimulation voltages. Conclusions – Bilateral STN–DBS causes disruption of the melanocortin system, probably related to diffusion of the electric current to the hypothalamus. This mechanism may in part explain the weight gain of patients with PD after surgery.     

Long-term follow up of subthalamic nucleus stimulation in Parkinson's disease

Twenty-two patients with PD received bilateral implants for high frequency stimulation of the subthalamic nucleus. The patients were treated for more than 1 year (up to 36 months). At the last visit, the Unified Parkinson Disease Rating Scale (UPDRS) motor score without medication improved by 50.2% (p < 0.001) and the UPDRS activities of daily living score improved by 68.4% (p < 0.001). The most common long-lasting adverse events were hypophonia and dysarthria; transient events were increased sexuality and mania. The surgical procedure induced transient intraoperative psychosis in seven patients.     

Bilateral subthalamic nucleus stimulation improves balance control in Parkinson's disease

BACKGROUND: Parkinson's disease (PD), the most common basal ganglia degenerative disease, affects balance control, especially when patients change balance strategy during postural tasks. Bilateral chronic stimulation of the subthalamic nucleus (STN) is therapeutically useful in advanced PD, and reduces the motor signs of patients. Nevertheless, the effects of STN stimulation on postural control are still debatable. AIMS: To assess the impact of bilateral STN stimulation on balance control in PD and to determine how basal ganglia related sensorimotor modifications act on neurosensorial organisation of balance and motor postural programming. METHODS: Twelve subjects aged 45-70 years underwent unified Parkinson's disease rating scale motor (part III) clinical tests, static and dynamic posturography, including sensory organisation and adaptation tests, shortly before and six months after bilateral implantation of electrodes into the STN. RESULTS: The postoperative static test showed an improvement in postural control precision both in eyes open and eyes closed conditions. The dynamic test highlighted the decreased number of falls and the ability of the patients to develop more appropriate sensorimotor strategies when stimulated. The sensory organisation test showed an improvement of equilibrium score and, thus, a better resolution of sensorial conflicts. CONCLUSIONS: STN stimulation allowed a reduction in rigidity and therefore an improvement in the ability to use muscular proprioception as reliable information, resulting in vestibulo-proprioceptive conflict suppression. STN stimulation has a synergistic effect with levodopa for postural control. Accordingly, non-dopaminergic pathways could be involved in postural regulation and STN stimulation may influence the functioning of these pathways.