Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function including gait and stability in people with PD, but differences in DBS contact locations within the STN may contribute to variability in the degree of improvement. Based on anatomic connectivity, dorsal STN may be preferentially involved in motor function and ventral STN in cognitive function. To determine whether dorsal DBS affects gait and balance more than ventral DBS, we conducted a double-blind evaluation of 23 PD patients with bilateral STN DBS. Each participant underwent gait analysis and balance testing off Parkinson medication in three DBS conditions (unilateral DBS in dorsal STN region, unilateral DBS in ventral STN region, and both stimulators off) on one day. For UPDRS-III scores and velocity for Fast and Pref gait, as well as stride length for Fast and Pref gait, dorsal and ventral stimulation improved gait, compared to the off condition (post hoc tests, p<0.05). However, there were no differences with dorsal compared to ventral stimulation. Balance, assessed using a multi-item clinical balance test (mini-BESTest), was similar across conditions. Absence of differences in gait and balance between dorsal and ventral conditions suggests motor connections involved in gait and balance may be more diffusely distributed in STN than previously thought, as opposed to neural connections involved in cognitive processes, such as response inhibition, which are more affected by ventral stimulation.
Parkinson Disease; Gait; Balance; Deep Brain Stimulation; Subthalamic Nucleus
Objective: High frequency stimulation of the subthalamic nucleus (STN) dramatically decreases motor disability in patients with Parkinson"s disease (PD), but has been reported to aggravate apathy. The aim of this study was to analyse the effect of STN stimulation on motivation and reward sensitivity in a consecutive series of PD patients.
Methods: Apathy and reward sensitivity (Apathy Scale, Stimulus-Reward Learning, Reversal, Extinction, and Gambling tasks) were assessed in 18 PD patients treated by bilateral STN stimulation ("on" and "off" conditions) compared with 23 matched patients undergoing long term treatment with levodopa ("on" and "off" conditions).
Results: Apathy decreased under both STN stimulation and levodopa treatment, whereas explicit and implicit stimulus reward learning was unchanged.
Conclusions: Bilateral STN stimulation in PD patients does not necessarily have a negative effect on motivation and reward sensitivity and can even improve apathy provided patients have been appropriately selected for neurosurgery.
It is now well established that subthalamic nucleus high-frequency stimulation (STN HFS) alleviates motor problems in Parkinson's disease. However, its efficacy for cognitive function remains a matter of debate. The aim of this study was to assess the effects of STN HFS in rats performing a visual attentional task. Bilateral STN HFS was applied in intact and in bilaterally dopamine (DA)-depleted rats. In all animals, STN HFS had a transient debilitating effect on all the variables measured in the task. In DA-depleted rats, STN HFS did not alleviate the deficits induced by the DA lesion such as omissions and latency to make correct responses, but induced perseverative approaches to the food magazine, an indicator of enhanced motivation. In sham-operated controls, STN HFS significantly reduced accuracy and induced perseverative behaviour, mimicking partially the effects of bilateral STN lesions in the same task. These results are in line with the hypothesis that STN HFS only partially mimics inactivation of STN produced by lesioning and confirm the motivational exacerbation induced by STN inactivation.
basal ganglia; cognitive functions; deep brain stimulation; dopamine
Background: Long term effects of subthalamic nucleus (STN) stimulation on cognition, mood, and behaviour are unknown.
Objective: This study evaluated the cognitive, mood, and behavioural effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) followed up for three years.
Methods: A consecutive series of 77 PD patients was assessed before, one, and three years after surgery. Mean (SD) age at surgery was 55 (8). Seven patients died or were lost for follow up. Neuropsychological assessment included a global cognitive scale, memory, and frontal tests. Depression was evaluated using the Beck depression inventory. Assessment of thought disorders and apathy was based on the unified Parkinson's disease rating scale. Reports of the behavioural changes are mainly based on interviews done by the same neuropsychologist at each follow up.
Results: Only two cognitive variables worsened (category fluency, total score of fluency). Age was a predictor of decline in executive functions. Depression improved whereas apathy and thought disorders worsened. Major behavioural changes were two transient aggressive impulsive episodes, one suicide, four suicide attempts, one permanent apathy, one transient severe depression, four psychoses (one permanent), and five hypomania (one permanent).
Conclusions: Comparing baseline, one year, and three year postoperative assessments, STN stimulation did not lead to global cognitive deterioration. Apathy scores mildly increased. Depression scores mildly improved. Behavioural changes were comparatively rare and mostly transient. Single case reports show the major synergistic effects of both medication and stimulation on mood and behaviour, illustrating the importance of a correct postoperative management.
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
Background: The short term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced levodopa responsive Parkinson's disease (PD) are well documented, but long term benefits are still uncertain.
Objectives: This study provides a 5 year follow up of PD patients treated with stimulation of the STN.
Methods: Thirty seven consecutive patients with PD treated with bilateral STN stimulation were assessed prospectively 6, 24, and 60 months after neurosurgery. Parkinsonian motor disability was evaluated with and without levodopa treatment, with and without bilateral STN stimulation. Neuropsychological and mood assessments included the Mattis Dementia Rating Scale, the frontal score, and the Montgomery-Asberg Depression Rating Scale (MADRS).
Results: No severe peri- or immediate postoperative side effects were observed. Six patients died and one was lost to follow up. Five years after neurosurgery: (i) activity of daily living (Unified Parkinson Disease Rating Scale (UPDRS) II) was improved by stimulation of the STN by 40% ("off" drug) and 60% ("on" drug); (ii) parkinsonian motor disability (UPDRS III) was improved by 54% ("off" drug) and 73% ("on" drug); (iii) the severity of levodopa related motor complications was decreased by 67% and the levodopa daily doses were reduced by 58%. The MADRS was unchanged, but cognitive performance declined significantly. Persisting adverse effects included eyelid opening apraxia, weight gain, addiction to levodopa treatment, hypomania and disinhibition, depression, dysarthria, dyskinesias, and apathy.
Conclusions: Despite moderate motor and cognitive decline, probably due to disease progression, the marked improvement in motor function observed postoperatively was sustained 5 years after neurosurgery.
Dopaminergic medication for motor symptoms in Parkinson’s disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.
Parkinson’s disease; pathological gambling; impulse control disorders; decision-making; dopamine
Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson’s disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal control, and whether these changes were correlated with limb function and stimulation settings.
Seventeen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when STN DBS was on, and again 1 h after STN DBS was turned off, and included aerodynamic measures during syllable production, and standard neurological ratings of limb function.
We found that PD participants exhibited changes with STN DBS, primarily consistent with increased intraoral pressure (n = 7) and increased velopharyngeal closure (n = 5). These changes were modestly correlated with measures of limb function, and were correlated with stimulation frequency.
Our findings suggest that STN DBS may change velopharyngeal control during syllable production in PD, with greater benefit associated with low frequency stimulation. However, DBS demonstrates a more subtle influence on speech-related velopharyngeal control than limb motor control. This distinction and its underlying mechanisms are important to consider when assessing the impact of STN DBS on PD.
Aerodynamic; Air flow; Air pressure; Frequency; Speech; Velopharyngeal area
Excessive burst firing in the dopamine-depleted basal ganglia correlates with severe motor symptoms of Parkinson's disease that are attenuated by high frequency electrical stimulation of the subthalamic nucleus (STN). Here we test the hypothesis that pathological bursts in dopamine-deprived basal ganglia are generated within the STN and transmitted to globus pallidus neurons. To answer this question we recorded excitatory synaptic currents and potentials from subthalamic and pallidal neurons in the basal ganglia slice (BGS) from dopamine-depleted mice while continuously blocking GABAA receptors. In control mice, a single electrical stimulus delivered to the internal capsule or the rostral pole of the STN evoked a short duration, small amplitude, monosynaptic EPSC in subthalamic neurons. In contrast, in the dopamine-depleted BGS, this monosynaptic EPSC was amplified and followed by a burst of polysynaptic EPSCs that eventually reverberated three to seven times, providing a long lasting response that gave rise to bursts of EPSCs and spikes in GP neurons. Repetitive (10–120 Hz) stimulation delivered to the STN in the dopamine-depleted BGS attenuated STN-evoked bursts of EPSCs in pallidal neurons after several minutes of stimulation but only high frequency (90–120 Hz) stimulation replaced them with small amplitude EPSCs at 20 Hz. We propose that the polysynaptic pathway within the STN amplifies subthalamic responses to incoming excitation in the dopamine-depleted basal ganglia, thereby transforming the STN into a burst generator and entraining pallidal neurons in pathogenic bursting activities. High frequency stimulation of the STN prevents the transmission of this pathological activity to globus pallidus and imposes a new glutamatergic synaptic noise on pallidal neurons.
basal ganglia; subthalamic nucleus; Parkinson; high frequency stimulation; burst firing; basal ganglia slice
The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson’s disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson’s disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson’s disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go–No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go–No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson’s disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions.
subthalamic nucleus; deep brain stimulation; response inhibition; Parkinson’s disease
Objectives: Bilateral chronic high frequency stimulation of the subthalamic nucleus (STN), through the stereotactical placement of stimulating electrodes, effectively improves the motor symptoms of severe Parkinson's disease. Intraoperative neurophysiological and clinical monitoring techniques (neuronal electrical activity recording and intraoperative stimulation) may improve and refine the localisation of the nucleus. The objective of this work was to compare the preoperative CT and MRI localisation with the intraoperative neurophysiological identification of STN. The relation between the localisation of the STN and the position of the most effective contact of the permanent quadripolar electrode at a 3 month and 1 year follow up was also studied.
Methods: Fourteen consecutive parkinsonian patients were submitted to bilateral implant for STN stimulation. All the patients underwent a standard MRI and stereotactic CT to obtain, by image fusion and localisation software, the stereotactical coordinates of STN. The STN extension and boundaries were identified by a semimicrorecording of the neuronal electrical activity. The definitive quadripolar electrode was positioned to locate at least two contacts within the STN recording area. Intraoperative macrostimulation was performed to confirm the correct position of the electrode. Postoperative clinical evaluation of the effects of stimulation was checked for each contact of the quadripolar electrode testing the improvement on contralateral rigidity to select the best contact. This evaluation was repeated at 3 months and 1 year after surgery.
Results: In 35.7% of the procedures it was necessary to perform more than one track to get a recording of neuronal activity consistent with STN.
The mean position of the central point of all the 28 STN recording areas in respect of the AC-PC line midpoint was 2.7 mm posterior (SD 0.7), 3.8 mm inferior (SD 1.1), and 11.6 mm lateral (SD 0.9), and the mean distance between the anatomical target and the central point of the STN as defined by intraoperative recording was 0.5 mm (SD 0.5) on the anteroposterior plane, 0.7 mm (SD 0.7) on the lateral plane, and 0.9 mm (SD 0.6) on the vertical plane. At 1 year the mean position of the central point of the most effective contact of the electrode in respect of the AC-PC line midpoint was 1.7 mm posterior (SD 0.9), 1.7 mm inferior (SD 1.5), and 12.3 mm lateral (SD 0.9).
Conclusion: The results highlight the role of the intraoperative recording to get a more accurate localisation of the STN in surgery for Parkinson's disease, allowing the identification of the boundaries and of the extension of the nucleus. The most effective contact of the quadripolar electrode was always in the upper part of the STN recording area or immediately above it, suggesting a role of this region in the clinical effectiveness of the STN electrical stimulation.
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.
We compared the surgical outcome with electrode positions after bilateral subthalamic nucleus (STN) stimulation surgery for Parkinson's disease. Fifty-seven patients treated with bilateral STN stimulations were included in this study. Electrode positions were determined in the fused images of preoperative MRI and postoperative CT taken at six months after surgery. The patients were divided into three groups: group I, both electrodes in the STN; group II, only one electrode in the STN; group III, neither electrode in the STN. Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage, and activities of daily living scores significantly improved at 6 and 12 months after STN stimulation in both group I and II. The off-time UPDRS III speech subscore significantly improved (1.6 ± 0.7 at baseline vs 1.3 ± 0.8 at 6 and 12 months, P < 0.01) with least L-dopa equivalent daily dose (LEDD) (844.6 ± 364.1 mg/day at baseline; 279.4 ± 274.6 mg/day at 6 months; and 276.0 ± 301.6 mg/day at 12 months, P < 0.001) at 6 and 12 months after STN deep brain stimulation (DBS) in the group I. Our findings suggest that the better symptom relief including speech with a reduced LEDD is expected in the patients whose electrodes are accurately positioned in both STN.
Parkinson Disease; Bilateral STN Stimulation; Clinical Outcome; Electrode Position; Fused Images
investigate the relation between the variation of the parameters of
stimulation and the clinical effectiveness in parkinsonian patients
treated with deep brain stimulation of the subthalamic nucleus (STN),
to provide information on the electrical parameter setting and the
mechanism of action of deep brain stimulation.
with Parkinson's disease bilaterally implanted in the STN were
studied. For every patient the intensity of the stimulus necessary to
obtain the disappearance of contralateral wrist rigidity (required
clinical effect, RCE) and the side effect threshold in 20 different
conditions of stimulation, coupling four pulse width values (60, 120, 210, 450 µs) with five rate values (10, 50, 90, 130, 170 Hz) were
determined. All the patients were tested after a 12 hour withdrawal of
antiparkinsonian drugs, and the clinical evaluation was double blind.
RESULTS—In all the
patients it was impossible to obtain the RCE using 10 and 50 Hz
stimulus rates. For all the other stimulus rate values, the
intensity-pulse width curves (IPWCs) for the RCE and for the side
effect threshold showed a hyperbolic trend. For every pulse width
value, increasing the rate from 90 to 130 and to 170Hz progressively
decreased the intensity of the stimulus necessary to reach the RCE, but
the differences were not significant. Within the same rate value, the
progressive reduction of the stimulus intensity necessary to obtain the
RCE, obtained with the lengthening of the pulse width was significant
(p<0.05) only comparing 60with 210 µs and 60 with 450 µs.
findings give some useful indications for the electrical parameter
setting in deep brain stimulation of the STN, and some information
about the mechanism of action of deep brain stimulation.
The short-term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced Parkinson’s disease (PD) are well documented, but long-term benefits are still uncertain. The aim of this study is to evaluate the outcome of 8 years of bilateral STN stimulation to PD patients.
In this study, 31 consecutive PD patients were treated with bilateral STN stimulation. Their functional status was measured using the Activities of Daily Living section of the Unified Parkinson’s Disease Rating Scale (UPDRS-ADL) at drug on (with medication) and drug off (without medication) states preoperatively and at 1, 5, and 8 years postoperatively. In addition, Levodopa equivalent doses and stimulation parameters were also assessed.
After 8 years of STN stimulation, the UPDRS-ADL scores were improved by 4% at drug off status (P > 0.05) and 22% at drug on status (P < 0.05) compared with baseline; the levodopa daily doses were reduced by 28% (P < 0.05) compared with baseline; the stimulation voltage and pulse width were not changed, but the stimulation frequency was decreased remarkably compared with the 5 years of follow-up. Adverse events were observed in 6 patients, including misplacement of the electrode and skin erosion requiring further surgery. All events were resolved without permanent sequelae. 2 patients died of aspiration pneumonia 6 and 7 years after surgery.
The marked improvement in UPDRS-ADL scores were still observed after 8 years of bilateral STN stimulation with medication.
Deep brain stimulation; Long-term effects; Parkinson’s disease; Subthalamic nucleus
To evaluate how bilateral subthalamic nucleus deep brain stimulation (STN-DBS) affects visuo-motor coordination (VMC) in patients with Parkinson’s disease (PD).
VMC involves multi-sensory integration, motor planning, executive function and attention. VMC deficits are well-described in PD. STN-DBS conveys marked motor benefit in PD, but pyscho-cognitive complications are recognized and the effect on VMC is not known.
Thirteen PD patients with bilateral STN-DBS underwent neurological, cognitive, and mood assessment before VMC testing with optimal DBS stimulation parameters (‘on-stimulation’) and then, on the same day without any medication changes, after DBS silencing and establishing motor function deterioration (‘off-stimulation’). Twelve age-matched healthy controls performed 2 successive VMC testing sessions, with a break of similar duration to that of the PD group. The computer cursor was controlled with a dome-shaped ‘mouse’ hidden from view that minimized tremor effects. Movement duration, hand velocity, tracking continuity, directional control variables, and feedback utilization variables were measured. MANOVA was performed on (1) clinically measured motor function, (2) VMC performance and (3) mood and attention, looking for main and interaction effects of: (1) group (controls/PD), (2) test-order (controls: first/second, PD: on-stimulation/off-stimulation), (3) path (sine/square/circle) and (4) hand (dominant/non-dominant).
Unified PD Rating Scale (UPDRS) Part III worsened off-stimulation versus on-stimulation (mean: 42.3 versus 21.6, p = 0.02), as did finger tapping (p = 0.02), posture-gait (p = 0.01), upper limb function (p<0.001) and backwards digit span (p = 0.02). Stimulation state did not affect mood. PD patients performed worse in non-velocity related VMC variables than controls (F(5,18) = 8.5, p<0.001). In the control group there were significant main effects of hand (dominant/non-dominant), path (sine/square/circle) and test-order (Test_1/Test_2). In the PD group, hand and path effects, but no test-order (on-stimulation/off-stimulation), were found.
‘Low-level’ clinically-measured motor function responds to STN-DBS but ‘high-level’ motor and cognitive functions relating to VMC may be unresponsive to STN-DBS.
The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson’s disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.
PMID: 19741594 CAMSID: cams1534
fMRI; impulse control disorder; dopamine agonist; reward; addiction; reinforcement
Objectives: Current models of basal ganglia dysfunction in Parkinson's disease suggest a pivotal role of subthalamic nucleus (STN) hyperactivity. There is a direct excitatory output to the globus pallidus internus (GPi), which in turn hyperinhibits the motor thalamus and leads to a lack of cortical facilitation. The model, however, does not address the reciprocal influence of GPi on STN activity.
Methods: Measurement of immediate changes in STN single cell activity after GPi deep brain stimulation (DBS).
Results: An opposite effect of GPi DBS in the dorsal versus ventral STN was found. There was an almost exclusive reduction of firing rate in the dorsal region of the STN, whereas the cells in the ventral region exhibited facilitation similar to the recordings from the substantia nigra pars reticulata.
Conclusion: Although these findings require confirmation, they suggest that the current theories of GPi DBS action, which do not include a GPi-STN modulation, are most likely incomplete.
Deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson disease (PD) improves motor function but has variable effects on mood. Little is known about the relationship between electrode contact location and mood response. We identified the anatomical location of electrode contacts and measured mood response to stimulation with the Visual Analog Scale in 24 STN DBS PD patients. Participants reported greater positive mood, decreased anxiety and apathy with bilateral and unilateral stimulation. Left DBS improved mood more than right DBS. Right DBS-induced increase in positive mood was related to more medial and dorsal contact locations. These results highlight the functional heterogeneity of the STN.
Parkinson disease; deep brain stimulation; mood
Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN) improves motor symptoms in Parkinson's disease (PD), but can exert detrimental effects on impulsivity. These effects are especially related to the inability to slow down when high-conflict choices have to be made. However, the influence that DBS has on delay aversion is still under-investigated. Here, we tested a group of 21 PD patients on and off stimulation (off medication) by using the Cambridge Gamble Task (CGT), a computerized task that allows the investigation of risk-related behaviours and delay aversion, and psychological questionnaires such as the Barratt Impulsiveness Scale (BIS), the Sensitivity to Punishment and to Reward Questionnaire (SPSRQ), and the Quick Delay Questionnaire (QDQ). We found that delay aversion scores on the CGT were no higher when patients were on stimulation as compared to when they were off stimulation. In contrast, PD patients reported feeling more impulsive in the off stimulation state, as revealed by significantly higher scores on the BIS. Higher scores on the sensitivity to punishment subscale of the SPSRQ highlighted that possible punishments influence patients' behaviours more than possible rewards. Significant correlations between delay aversion scores on the CGT and QDQ delay aversion subscale suggest that these two instruments can be used in synergy to reach a convergent validity. In conclusion, our results show that not all impulsivities are detrimentally affected by DBS of the STN and that the joint use of experimental paradigms and psychological questionnaires can provide useful insights in the study of impulsivity.
Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case–control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode.
Bilateral; deep brain stimulation; Parkinson's disease; subthalamic; unilateral; weight
Balance impairment is one of the most distressing symptoms in Parkinson's disease (PD) even with pharmacological treatment (levodopa). A complementary treatment is high frequency stimulation in the subthalamic nucleus (STN). Whether STN stimulation improves postural control is under debate. The aim of this study was to explore the effects of STN stimulation alone on balance performance as assessed with clinical performance tests, subjective ratings of fear of falling and posturography.
Ten patients (median age 66, range 59–69 years) with bilateral STN stimulation for a minimum of one year, had their anti-PD medications withdrawn overnight. Assessments were done both with the STN stimulation turned OFF and ON (start randomized). In both test conditions, the following were assessed: motor symptoms (descriptive purposes), clinical performance tests, fear of falling ratings, and posturography with and without vibratory proprioceptive disturbance.
STN stimulation alone significantly (p = 0.002) increased the scores of the Berg balance scale, and the median increase was 6 points. The results of all timed performance tests, except for sharpened Romberg, were significantly (p ≤ 0.016) improved. The patients rated their fear of falling as less severe, and the total score of the Falls-Efficacy Scale(S) increased (p = 0.002) in median with 54 points. All patients completed posturography when the STN stimulation was turned ON, but three patients were unable to do so when it was turned OFF. The seven patients with complete data showed no statistical significant difference (p values ≥ 0.109) in torque variance values when comparing the two test situations. This applied both during quiet stance and during the periods with vibratory stimulation, and it was irrespective of visual input and sway direction.
In this sample, STN stimulation alone significantly improved the results of the clinical performance tests that mimic activities in daily living. This improvement was further supported by the patients' ratings of fear of falling, which were less severe with the STN stimulation turned ON. Posturography could not be performed by three out of the ten patients when the stimulation was turned OFF. The posturography results of the seven patients with complete data showed no significant differences due to STN stimulation.
Adequate respiratory and laryngeal motor control are essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on respiratory and laryngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of respiratory and laryngeal control, and whether these changes were correlated with limb function and stimulation parameters. Eighteen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when DBS was on, and again 1 h after DBS was turned off, and included aerodynamic measures during syllable production, and standard clinical ratings of limb function. We found that PD participants exhibited changes with DBS, consistent with increased respiratory driving pressure (n = 9) and increased vocal fold closure (n = 9). However, most participants exceeded a typical operating range for these respiratory and laryngeal control variables with DBS. Changes were uncorrelated with limb function, but showed some correlation with stimulation frequency and pulse width, suggesting that speech may benefit more from low-frequency stimulation and shorter pulse width. Therefore, high-frequency STN DBS may be less beneficial for speech-related respiratory and laryngeal control than for limb motor control. It is important to consider these distinctions and their underlying mechanisms when assessing the impact of STN DBS on PD.
Aerodynamics; Air pressure; Air flow; High frequency; Laryngeal resistance; Voice
stimulation of the basal ganglia has become a promising treatment
option for patients with Parkinson's disease who have side effects
from drugs. Which is the best target—globus pallidus internus (GPi) or
subthalamic nucleus (STN)—is still a matter of discussion. The aim of
this prospective study is to compare the long term effects of GPi and
STN stimulation in patients with severe Parkinson's disease.
METHODS—Bilateral deep brain stimulators were
implanted in the GPi in six patients and in the STN in 12 patients with
severe Parkinson's disease. Presurgery and 3, 6, and 12 months
postsurgery patients were scored according to the CAPIT protocol.
the STN increased best Schwab and England scale score significantly
from 62 before surgery to 81 at 12 months after surgery; GPi
stimulation did not have an effect on the Schwab and England scale.
Stimulation of the GPi reduced dyskinesias directly whereas STN
stimulation seemed to reduce dyskinesias by a reduction of medication.
Whereas STN stimulation increased the unified Parkinson's disease
rating scale (UPDRS) motor score, GPi stimulation did not have a
significant effect. Fluctuations were reduced only by STN stimulation
and STN stimulation suppressed tremor very effectively.
of the GPi reduces medication side effects, which leads to a better
drug tolerance. There was no direct improvement of bradykinesia or
tremor by GPi stimulation. Stimulation of the STN ameliorated all
parkinsonian symptoms. Daily drug intake was reduced by STN
stimulation. The STN is the target of choice for treating patients with
severe Parkinson's disease who have side effects from drugs.
Deep brain stimulation of the subthalamic nucleus (STN-DBS) is efficacious in treating the motor symptoms of Parkinson’s disease (PD). However, the impact of STN-DBS on the progression of PD is unknown. Previous preclinical studies have demonstrated that STN-DBS can attenuate the degeneration of a relatively intact nigrostriatal system from dopamine (DA)-depleting neurotoxins. The present study examined whether STN-DBS can provide neuroprotection in the face of prior significant nigral DA neuron loss similar to PD patients at the time of diagnosis. STN-DBS between two and four weeks after intrastriatal 6-hydroxydopamine (6-OHDA) provided significant sparing of DA neurons in the SN of rats. This effect was not due to inadvertent lesioning of the STN and was dependent upon proper electrode placement. Since STN-DBS appears to have significant neuroprotective properties, initiation of STN-DBS earlier in the course of PD may provide added neuroprotective benefits in addition to its ability to provide symptomatic relief.
Deep Brain Stimulation; Subthalamic Nucleus; Parkinson’s disease; Neuroprotection; 6-hydroxydopamine; Stereology