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Time-frequency analysis of transient neuromuscular events: dynamic changes in activity of the subthalamic nucleus and forearm muscles related to the intermittent resting tremor.

In order to investigate the dynamic change in transient neuromuscular events and the functional correlation between the neural and muscular activity, local field potentials (LFPs) of the subthalamic nucleus (STN) and surface electromyograms (sEMGs) over several episodes of transient resting tremor from a patient with Parkinson's disease were quantitatively characterised in time-frequency domain using short-time Fourier transform and continuous wavelet transform. Events of onset and cessation of the tremor-related activity in the STN and muscles were correlated to reveal the temporal relationship between the two signals. A significant suppression in the power of the STN LFPs in the beta band (10-30 Hz) preceded the onset of resting tremor, which was presented as the increases in the power at the tremor frequency (3.0-4.5 Hz) in both STN LFPs and surface EMGs. Over the episodes of the intermittent resting tremor, the power of the STN LFPs in the beta band and the power of sEMGs in the tremor frequency band change in an alternating pattern with a significant exponential correlation (P(STN) = 16.8+62.3 x exp(-P(EMG)/6270.7); R2 = 0.72; p < 0.05). Significant linear correlation in the power values at the tremor frequency appears between STN LFPs and sEMGs (P(STN) = 65.1 + 2.1 x 10(-4)P(EMG); R2 = 0.41; p < 0.05). In comparison with short-time Fourier transform, similar results could be achieved using continuous wavelet transform of an appropriate wavelet with a higher temporal resolution but larger distortion in the high frequency.

Electromyography↗

Effects of bilateral subthalamic nucleus stimulation on sleep, daytime sleepiness, and early morning dystonia in patients with Parkinson disease.

OBJECT: The aim of this study was to assess the long-term effects of bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) on sleep, daytime sleepiness, and early morning dystonia and to evaluate the relationship between total sleep time and motor function. METHODS: Patients who had undergone bilateral STN DBS and a follow-up evaluation of 6 months (89 patients), 12 months (83 patients), and 24 months (43 patients) were included in this study. The patients were preoperatively assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) in the medication-on and -off conditions, and they completed patient diaries. A subset of patients also completed the Epworth Sleepiness Scale. These assessments were repeated postoperatively with stimulation. The UPDRS activities of daily living (ADL) and motor scores as well as total sleep hours were significantly improved at 6, 12, and 24 months poststimulation and with no medication compared with baseline values. Increased sleep time was significantly correlated with improvements in bradykinesia but not with tremor or rigidity. Patient-reported sleep problems and early morning dystonia were reduced after STN DBS. Antiparkinsonian medications were significantly reduced after STN DBS; however, there were no changes in excessive daytime sleepiness 6, 12, or 24 months after surgery. CONCLUSIONS: Bilateral STN DBS increased total sleep time and reduced patient-reported sleep problems and early morning dystonia for up to 24 months posttreatment. These changes in sleep were related to improvements in functioning, specifically those affected by bradykinesia. Despite significant reductions in antiparkinsonian medications, STN DBS did not reduce excessive daytime sleepiness.

Activities of Daily Living↗

Effect of subthalamic nucleus stimulation on obsessive-compulsive disorder in a patient with Parkinson disease. Case report.

The authors report on a patient with Parkinson disease (PD) and severe obsessive-compulsive disorder (OCD), in whom bilateral stimulation of the subthalamic nucleus (STN) was used to treat both PD and OCD symptoms. This 49-year-old man had displayed symptoms of PD for 13 years. Progressively, his motor disability became severe despite optimal medical treatment. In parallel, he suffered severe OCD for 16 years, with obsessions of accumulation and compulsions of gathering and rubbing that lasted more than 8 hours per day. Bilateral high-frequency STN stimulation was performed to treat motor disability. After surgery (at 1-year follow up), motor and OCD symptoms were dramatically improved. The pre- and postoperative Yale-Brown Obsessive-Compulsive Scale scores were 32 and 1, respectively. No additional antiparkinsonian drugs were administered. This case and other recent reports indicate that OCD symptoms can be improved by deep brain stimulation, a finding that opens new perspectives in the surgical treatment of severe and medically intractable OCD.

Electric Stimulation Therapy↗

Effects of subthalamic nucleus stimulation on actual and imagined movement in Parkinson's disease : a PET study.

BACKGROUND: PET studies in moderately affected Parkinson's disease (PD) patients reveal abnormal cerebral activation during motor execution and imagery, but the effects of subthalamic nucleus (STN) stimulation are not well established. OBJECTIVES: to assess the effect of STN stimulation on cerebral activation during actual and imagined movement in patients with advanced PD. METHODS: seven severely affected PD patients treated with bilateral STN stimulation were studied with PET and H(2)(15)O. The following conditions were investigated: (1). rest; (2). motor execution of a sequential predefined joystick movement with the right hand and (3). motor imagery of the same task. Patients were studied with and without left STN stimulation while right stimulator remained off. RESULTS: Without STN stimulation, the primary motor cortex was activated only during motor execution whereas the dorsolateral prefrontal cortex (DLPFC) was activated only during motor imagery. An activation of the supplementary motor area (SMA) was seen during both motor execution and motor imagery. Left STN stimulation during motor execution increased the regional cerebral blood flow (rCBF) bilaterally in the prefrontal cortex including DLPFC, in the left thalamus and putamen. In addition, a reduction of rCBF was noted in the right primary motor cortex, inferior parietal lobe and SMA. Under left STN stimulation, during motor imagery, rCBF increased bilaterally in the DLPFC and in the left thalamus and putamen and decreased in the left SMA and primary motor cortex. CONCLUSION: STN stimulation during both motor execution and imagery tends to improve the functioning of the frontal-striatal-thalamic pathway and to reduce the recruitment of compensatory motor circuits notably in motor, premotor and parietal cortical areas.

Aged↗

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.

Aged↗

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: effects of variation in stimulation parameters.

OBJECTIVE: To 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. METHODS: Ten patients 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 micros) 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 170 Hz 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 60 with 210 micros and 60 with 450 micros. CONCLUSIONS: The 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.

Aged↗

Bilateral stimulation of the subthalamic nucleus in Parkinson's disease: surgical efficacy and prediction of outcome.

OBJECTIVE: Over the last decade neurosurgery has reemerged as a valid therapy for patients with advanced Parkinson's disease. Previously, we have addressed safety and efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS). In this study, we extended these observations and analyzed factors that affect surgical outcome and its predictive value. METHODS: Thirty-nine patients were enrolled in an open-label prospective protocol designed to evaluate safety and efficacy of bilateral STN DBS in patients with advanced Parkinson's disease between January 1999 and July 2002. Electrodes were stereotactically implanted with electrophysiological conformation of the target location. All patients were evaluated in the medication 'off' and 'on' state preoperatively and at 3, 6, and 12 months after surgery in medication 'on' and 'off' as well as in the stimulation 'off' and 'on' state. Tests included Unified Parkinson's Disease Rating Scales (UPDRS) as well as timed tests. All data was analyzed by means of Analysis of Variance. For outcome prediction, correlation and linear regression analyses were utilized. Stimulation produced significant improvements in all 'off' mediation conditions, resulting in a 42% improvement in UPDRS III score at 12 months compared to the preoperative status. Stimulation in conjunction with medication did not produce any significant change when compared to the preoperative medication 'on' state. Dyskinesia, motor fluctuations, and duration of 'off' periods were significantly reduced with stimulation. Significant outcome predictor variables were age, preoperative percent change of UPDRS III score from medication 'off' to medication 'on' state, and the duration of disease. CONCLUSIONS: Bilateral STN DBS produces robust improvements in parkinsonian motor symptoms. Surgical outcome can reliably be predicted.

Adult↗

High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor.

It has been hypothesized that in Parkinson's disease (PD) there is increased synchronization of neuronal firing in the basal ganglia. This study examines the discharge activity of 121 pairs of subthalamic nucleus (STN) neurons in nine PD patients undergoing functional stereotactic mapping. Four patients had a previous pallidotomy. A double microelectrode setup was used to simultaneously record from two neurons separated by distances as small as 250 micrometer. In the six patients who had limb tremor during the recording session (n = 76 pairs), the discharge pattern of 12 pairs of tremor cells (TCs) was found to be coherent at the frequency of the limb tremor. Both in-phase and out-of-phase relationships were observed between TCs. Interestingly, in these six patients, 63/129 single neurons displayed 15-30 Hz oscillations, whereas 36/76 pairs were coherent in this frequency range. Although the oscillatory frequencies were variable between patients, they were highly clustered within a patient. The phase difference between these pairs was found to be close to 0. High-frequency synchronization was observed during periods of limb tremor as well as during intermittent periods with no apparent limb tremor. In contrast, in the three patients without limb tremor during the recording session, only 1/84 neurons had high-frequency oscillatory activity, and no TCs or synchronous high-frequency oscillatory activity was observed (n = 45 pairs). These findings demonstrate that in PD patients with limb tremor, many STN neurons display high-frequency oscillations with a high degree of in-phase synchrony. The results suggest that high-frequency synchronized oscillatory activity may be associated with the pathology that gives rise to tremor in PD patients.

Action Potentials↗

Targeting the subthalamic nucleus for deep brain stimulation: technical approach and fusion of pre- and postoperative MR images to define accuracy of lead placement.

OBJECTIVES: To define the role of magnetic resonance imaging (MRI) and intraoperative electrophysiological recording in targeting the subthalamic nucleus (STN) in Parkinson's disease and to determine accuracy of electrode placement. PATIENTS AND METHODS: We implanted 54 electrodes into the STN in 27 patients. Target planning was done by coordinate guidelines and visualising the STN on MRI and defined in relation to the mid-point of the AC-PC line. Intraoperative microelectrode recording was used. We adjusted electrode positions for placement in the centre of the STN electrical activity and verified this on postoperative MRI in 16 cases, which were fused to the preoperative images to measure actual error in electrode placement in the three axes. RESULTS: Based on coordinate calculation and MRI localisation, the mean of the target was 11.5 mm lateral, 2.5 mm posterior and 4.1 mm inferior to the mid-point of the AC-PC line. Fifty good electrophysiological recordings of the STN (average length 4.65 mm) were achieved and target point adjusted in 90% of lead placements. The mean of the final target after electrophysiological correction was 11.7 mm lateral, 2.1 mm posterior, and 3.8 mm inferior to the mid-point. The distance from the centre of the electrode artefact to the final target used after electrophysiological recording on the fused images was 0.48 mm, 0.69 mm, and 2.9 mm in the x, y, and z axes, respectively. No postoperative MRI related complication was observed. CONCLUSION: Both direct visualisation of the STN on MRI and intraoperative electrophysiological recording are important in defining the best target. Individual variations exist in the location of the STN target. Fewer tracks were required to define STN activity on the side operated first. Our current stereotactic method of electrode placement is relatively accurate.

Adult↗

Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements.

Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity.

Animals↗

Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease.

This study examines the effect of apomorphine (APO), a nonselective D(1)- and D(2)-dopamine receptor agonist, on the firing activity of neurons in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) in patients with Parkinson's disease (PD). Single-unit microelectrode recordings were conducted in 13 patients undergoing implantation of deep brain stimulation electrodes in STN and 6 patients undergoing a pallidotomy. Doses of APO (2.5-8 mg) were sufficient to produce an ON state, but not intended to induce dyskinetic movements. Following baseline recordings from a single neuron, APO was administered and the activity of the neuron followed for an average of 15 min. The spontaneous discharge of neurons encountered before (n = 309), during (n = 146, 10-60 min), and after the effect of APO had waned (n = 127, >60 min) was also sampled, and the response to passive joint movements was noted. In both nuclei, APO increased the overall proportion of spikes in burst discharges (as detected with Poisson "surprise" analysis), and a greater proportion of cells with an irregular discharge pattern was observed. APO significantly decreased the overall firing rates of GPi neurons (P < 0.01), but there was no change in the overall firing rate of neurons in the STN (P = 0.68). However, the mean firing rates of STN neurons during APO-induced movements (choreic or dystonic dyskinesias) that occurred in four patients were significantly lower than OFF-period baseline values (P < 0.05). Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (TCs) was found to be significantly reduced from 19 to 6% in the STN and 14 to 0% in the GPi following APO administration. APO also decreased the firing rate of STN TCs (P < 0.05). During the OFF state, more than 15% of neurons tested (STN = 93, GPi = 63) responded to passive movement of two or more joints. After APO, this proportion decreased significantly to 7% of STN cells and 4% of GPi cells (STN = 28, GPi = 26). These findings suggest that the APO-induced amelioration of parkinsonian symptoms is not solely due to a decrease in overall activity in the GPi or STN as predicted by the current model of basal ganglia function in PD.

Action Potentials↗

Ten-Hertz stimulation of subthalamic nucleus deteriorates motor symptoms in Parkinson's disease.

Recently, a pathological oscillatory network at 10 Hz including several motor areas was described in patients with idiopathic Parkinson's disease (PD). In 7 PD patients, we tested the clinical effect of subthalamic nucleus (STN) stimulation at varying frequencies 1 to 3 years after implantation of electrodes. STN stimulation at 10 Hz induced significant worsening of motor symptoms, especially akinesia, compared with no stimulation and therapeutic stimulation (> or =130 Hz). This finding indicates the clinical relevance of pathological 10 Hz synchronization in PD.

Aged↗

Response to levodopa in parkinsonian patients with bilateral subthalamic nucleus stimulation.

The response to levodopa changes over time in Parkinson's disease, probably due to alterations in the dopaminergic system, progression of the disease and pulsatile oral intake of the drug. Bilateral high-frequency stimulation of the subthalamic nucleus (STN) allows a large reduction or the complete cessation of levodopa intake in patients with advanced Parkinson's disease. We studied variation in the motor short-duration response (SDR) during a levodopa challenge in bilaterally STN-stimulated patients. Twenty-eight consecutive patients with a mean duration of Parkinson's disease of 16.6 +/- 6.0 years at the time of surgery were enrolled. Fourteen patients were evaluated both before STN stimulation and 3 months after surgery (group 1) whereas the other 14 patients were assessed before implantation and after a mean of 3 years of STN stimulation (group 2). After drug withdrawal for one night, the hand-tapping test (TT) was carried out every 15 min, together with evaluation of dyskinesias using a modified Goetz scale. The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was assessed every 30 min. In operated patients, STN stimulation was stopped 15 min before starting the clinical evaluations. A suprathreshold oral levodopa dose was given after one motor evaluation and two TTs. The clinical evaluation was carried out until the TT score returned to the baseline. In group 1, six patients continued without levodopa after surgery and the other eight received a daily mean dose of 337 mg; in group 2, seven patients continued without levodopa and the other seven received a daily mean dose of 386 mg. The main change in the levodopa SDR was a significant reduction in levodopa-induced dyskinesias in both groups. In those patients of group 1 who did not receive levodopa after surgery, the motor UPDRS magnitude decreased and the 'on' UPDRS motor score worsened. In group 2, the results were similar, but in the patients who continued to receive levodopa after surgery the TT magnitude increased. On the whole, chronic bilateral STN stimulation tended to decrease the magnitude of the levodopa SDR without changing the duration and latency of the response. These results suggest that continuous STN stimulation induces long-term plastic changes of the dopaminergic system, with slow and partial desensitization. In addition, the persistence of levodopa intake after surgery might hinder this beneficial process.

Adult↗

Placement of deep brain stimulators into the subthalamic nucleus or Globus pallidus internus: technical approach.

Deep brain stimulation (DBS) represents a major advance in the treatment of Parkinson's disease (PD). As more neurosurgeons enter this field, technical descriptions of implantation techniques are needed. Here we present our technical approach to subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS implantation, based on 180 STN implants and 75 GPi implants. The essential steps in DBS implantation are magnetic resonance imaging (MRI)-guided stereotactic localization, confirmation of the motor territory of the target nucleus with microelectrode mapping, and intra-operative test stimulation to determine voltage thresholds for stimulation-induced adverse effects. Lead locations are documented by postoperative MRI in all cases.

Dystonia↗

The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease.

Depth recordings in patients with Parkinson's disease (PD) have demonstrated prominent oscillatory activity in the beta frequency (13-35 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesized to contribute to bradykinesia, it is unclear to what extent the LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded both LFPs and multi-neuronal activity from microelectrodes inserted into STN in six PD patients (8 sides) during functional neurosurgery. As microelectrodes passed from above STN into STN, there was a pronounced increase in beta frequency band LFP activity. Furthermore, spike-triggered averages of LFP activity suggested that the discharges of neurons in STN were locked to beta oscillations in the LFP. The LFP is therefore likely to represent synchronous activity in populations of neurons in the STN of patients with PD.

Action Potentials↗

Branched output neurons of the rat subthalamic nucleus: electrophysiological study of the synaptic effects on identified cells in the two main target nuclei, the entopeduncular nucleus and the substantia nigra.

The synaptic responses of entopeduncular and nigral cells to subthalamic stimulation were studied with extracellular recording techniques in rats with and without chronic lesions. Entopeduncular output cells were identified by antidromic activation from the lateral habenula, ventral anterior thalamic nucleus and tegmenti pedunculopontine nucleus. Nigral cells projecting to superior colliculus were identified by antidromic discharge. Stimulation of the subthalamic nucleus produced a short latency suppression of spontaneous activity (10-60 ms duration) of 89% of the entopeduncular cells tested in chronically lesioned rats. Of these cells, 50% were identified as projecting to lateral habenula. On the other hand, subthalamic nucleus stimulation produced a short latency excitation of 73% of the nigral cells tested (4.16 +/- 0.07 ms). Forty-eight percent of these cells projected to superior colliculus. The subthalamic fibres which terminate in entopeduncular nucleus and substantia nigra, come from the same neuronal population since the majority, if not all, rat subthalamic neurones send branched projections to both these nuclei. Therefore, the two different types of responses recorded in these nuclei are elicited by the activation of a single neuronal population. This dual effect could be easily explained if one of the responses is mediated by local interneurones. If not, the same transmitter induces the two responses. The entopeduncular nucleus and substantia nigra which are the main target nuclei of the subthalamic nucleus, are also the only known outputs of the striatum. The subthalamic efferent cells could thus modulate the activity of the entire striatal descending output. It is noteworthy that this subthalamic control is different in entopeduncular nucleus than in substantia nigra.

Animals↗

High-frequency electrical stimulation of the subthalamic nucleus in Parkinson's disease: kinetic and kinematic gait analysis.

In the advanced phase of Parkinson's disease (PD), gait disturbances represent one of the main causes of disability. Several studies demonstrated that high-frequency electrical stimulation (HFS) of the subthalamic nucleus (STN) significantly improves the motor symptoms of PD. This study was finalised to quantitatively analyze the effect of STN HFS on gait of PD patients, through a three-dimensional gait analysis system. Ten PD patients were studied, with and without STN HFS. The results demonstrated that STN HFS significantly improves all the main gait parameters in PD patients.

Biomechanical Phenomena↗

Olfactory function in patients with idiopathic Parkinson's disease: effects of deep brain stimulation in the subthalamic nucleus.

Decrease of olfactory function in patients with Parkinson's disease (PD) is a well-investigated fact. The present study aimed to investigate olfaction in PD patients with a specific focus on the effects of deep brain stimulation in the subthalamic nucleus. Eleven patients (age 42-67 years) participated in this study. Using the "Sniffin' Sticks", olfactory function was assessed based on butanol odor thresholds and the patients' ability to discriminate odors. Measures were taken with the stimulator being switched ON and OFF, respectively. While deep brain stimulation had no effect on odor thresholds, in hyposmic PD patients odor discrimination was found to be significantly higher during the ON period. This may indicate that deep brain stimulation has a positive effect on the cognitive processing of olfactory information in PD patients.

Adult↗