Efficacy of subthalamic deep brain stimulation programming strategies for gait disorders in Parkinson's disease: a systematic review and meta-analysis.

Patients with advanced Parkinson's disease often suffer from severe gait and balance problems, impacting quality of live and persisting despite optimization of standard therapies. The aim of this review was to systematically review the efficacy of STN-DBS programming techniques in alleviating gait disturbances in patients with advanced PD. Searches were conducted in PubMed, Embase, and Lilacs databases, covering studies published until May 2024. The review identified 36 articles that explored five distinct STN-DBS techniques aimed at addressing gait and postural instability in Parkinson's patients: low-frequency stimulation, ventral STN stimulation for simultaneous substantia nigra activation, interleaving, asymmetric stimulation and a short pulse width study. Among these, 21 articles were included in the meta-analysis, which revealed significant heterogeneity among studies. Notably, low-frequency STN-DBS demonstrated positive outcomes in total UPDRS-III score and FOG-Q, especially when combined with dopaminergic therapy. The most favorable results were found for low-frequency STN stimulation. The descriptive analysis suggests that unconventional stimulation approaches may be viable for gait problems in patients who do not respond to standard therapies.

Persistence of Basal Ganglia Oscillatory Activity During Tremor Attenuation by Movement in Parkinson's Disease Patients.

BACKGROUND: One of the characteristics of parkinsonian tremor is that its amplitude decreases with movement. Current models suggest an interaction between basal ganglia (BG) and cerebello-thalamo-cortical circuits in parkinsonian tremor pathophysiology. OBJECTIVE: We aimed to correlate central oscillation in the BG with electromyographic activity during re-emergent tremor in order to detect changes in BG oscillatory activity when tremor is attenuated by movement. METHODS: We performed a prospective, observational study on consecutive parkinsonian patients who underwent deep brain stimulation surgery and presented re-emergent tremor. Coherence analysis between subthalamic nucleus/globus pallidus internus (STN/GPi) tremorous activity measured by microrecording (MER) and electromyogram (EMG) from flexor and extensor wrist muscles during rest, posture, and re-emergent tremor pause was performed during surgery. The statistical significance level of the MER-EMG coherence was determined using surrogate data analysis, and the directionality of information transfer between BG and muscle was performed using entropy transfer analysis. RESULTS: We analyzed 148 MERs with tremor-like activity from 6 patients which were evaluated against the simultaneous EMGs, resulting in 296 correlations. Of these, 26 presented a significant level of coherence at tremor frequency, throughout rest and posture, with a complete EMG stop in between. During the pause, all recordings showed sustained MER peaks at tremor frequency (±1.5 Hz). Information flows preferentially from BG to muscle during rest and posture, with a loss of directionality during the pause. CONCLUSIONS: Our results suggest that oscillatory activity in STN/GPi functionally linked to tremor sustains firing frequency during re-emergent tremor pause, thus suggesting no direct role of the BG circuit on tremor attenuation due to voluntary movements. © 2024 International Parkinson and Movement Disorder Society.

Possible mechanisms involved in subthalamotomy-induced dyskinesia in patients with Parkinson's disease.

BACKGROUND/AIMS: Operation-induced dyskinesia (OID) occurs in approximately 10% of patients submitted to subthalamotomy. The goal of the authors was to determine the possible causes of this feared complication. METHODS: The 54 patients who underwent unilateral subthalamotomy were divided into two groups: the OID group (OIDG), composed of 6 patients who developed dyskinesia following the operation, and the control group (CG), consisting of 48 patients who did not present this complication. The two groups were compared regarding age; sex; presence of levodopa-induced dyskinesia (LID) and/or stimulation-induced dyskinesia (SID); side of the operation; territories of the subthalamic nucleus (STN) involved by the lesion, and degree of lesion extension towards the zona incerta (ZI). RESULTS: The lesion involved the dorsolateral territory of the STN and was almost completely restricted to this nucleus in all patients of the OIDG, while it spread to the ZI in all but 1 patient of the CG. SID was significantly (p < 0.05) more frequent in the OIDG. There was also a strong trend favoring LID (p = 0.055). CONCLUSIONS: Damage to the dorsolateral territory of the STN and sparing of the ZI seem to be essential for the development of OID. SID and, to a lesser extent, LID are apparently significant risk factors for the development of this complication.

Antinociceptive effect of stimulating the zona incerta with glutamate in rats.

The zona incerta (ZI) is a subthalamic nucleus connected to several structures, some of them known to be involved with antinociception. The ZI itself may be involved with both antinociception and nociception. The antinociceptive effects of stimulating the ZI with glutamate using the rat tail-flick test and a rat model of incision pain were examined. The effects of intraperitoneal antagonists of acetylcholine, noradrenaline, serotonin, dopamine, or opioids on glutamate-induced antinociception from the ZI in the tail-flick test were also evaluated. The injection of glutamate (7 µg/0.25 µl) into the ZI increased tail-flick latency and inhibited post-incision pain, but did not change the animal performance in a Rota-rod test. The injection of glutamate into sites near the ZI was non effective. The glutamate-induced antinociception from the ZI did not occur in animals with bilateral lesion of the dorsolateral funiculus, or in rats treated intraperitoneally with naloxone (1 and 2 m/kg), methysergide (1 and 2 m/kg) or phenoxybenzamine (2 m/kg), but remained unchanged in rats treated with atropine, mecamylamine, or haloperidol (all given at doses of 1 and 2 m/kg). We conclude that the antinociceptive effect evoked from the ZI is not due to a reduced motor performance, is likely to result from the activation of a pain-inhibitory mechanism that descends to the spinal cord via the dorsolateral funiculus, and involves at least opioid, serotonergic and α-adrenergic mechanisms. This profile resembles the reported effects of these antagonists on the antinociception caused by stimulating the periaqueductal gray or the pedunculopontine tegmental nucleus.

NEUROZONE: on-line recognition of brain structures in stereotactic surgery--application to Parkinson's disease.

The success of stereotactic surgery for Deep Brain Stimulation depends critically on the exact positioning of a microelectrode recording in a target area of the brain. This paper presents the software system NEUROZONE composed of two main applications: first, it allows online recognition of brain structures by the analysis of signals from microelectrode recordings (MER), and second, it processes and analyses off-line databases allowing the inclusion of new trained classifiers for automatic identification. The software serves as a support to the analysis done by a medical specialist during surgery, and seeks to reduce the adverse side effects that may occur because of inadequate identification of the target areas. The software also allows the specialists to label recordings obtained during surgery, in order to generate a new off-line database or increase the amount of records in an already existing off-line database. NEUROZONE has been tested for Deep Brain Stimulation performed at the Institute for Epilepsy and Parkinson of the Eje Cafetero (Colombia), achieving positive identifications of the Subthalamic Nucleus (STN) over to 85% using a naive Bayes classifier.

Neuronal discharge patterns in the globus pallidus pars interna in a patient with Parkinson's disease and hemiballismus secondary to subthalamotomy.

Alterations in the basal ganglia-thalamocortical "motor" circuit activity, have been proposed to explain many features associated with hypokinetic and hyperkinetic movement disorders. We describe the firing pattern of the globus pallidus pars interna in a Parkinson disease's patient who developed Hemichorea-Ballismus subsequent to ipsilateral subthalamotomy, and compare findings to those from PD patients submitted to pallidotomy while in the OFF-medication state. Single units obtained from extracellular recordings were extracted and mean discharge frequency, interspike interval and coefficient of variation (defined as Tonicity Score) were computed. Discharge density histograms, analysis of distribution and spectral analysis were also performed. Mean firing frequency showed no significant difference between PD patients in the OFF state and the patient we report. However, a significant difference in tonicity was found for this patient characterized by a regular, non-bursting firing pattern. The findings indicate that in HB caused by lesions to STN in the parkinsonian state, GPi firing rates can be similar to and firing pattern more regular than those observed in GPi of PD patients OFF-medication with intact STN.

El núcleo subtalámico en la fisiopatología de la enfermedad de Parkinson y su rol como diana quirúrgica / The subthalamic nucleus in the pathophysiology of Parkinson's disease and its role as a surgical target

Parkinson's disease is one of the most common causes of neurological disability, it caused by selective loss of neurons at the substantia nigra, which causes an imbalance in the functioning of the basal ganglia. In the pathophysiological events underlying this disease, hyperactivity of the subthalamic nucleus is more often associated with major clinical manifestations; this structure also plays a fundamental role in motor control, making it an excellent surgical target.

La enfermedad de Parkinson es una de las causas más frecuentes de discapacidad neurológica, se produce por la pérdida selectiva de neuronas a nivel de la sustancia nigra, lo que genera un desbalance en el funcionamiento de los ganglios basales. De los eventos fisiopatológicos subyacentes en esta enfermedad, la hiperactividad del núcleo Subtalámico es el que más se relaciona con las principales manifestaciones clínicas, además esta estructura juega un papel fundamental en el control motor, lo que la convierte en una excelente diana quirúrgica.

Automatic identification of various nuclei in the basal ganglia for Parkinson's disease neurosurgery.

Stereotactic neurosurgery for Parkinson's disease (PD) is one of the most used treatments for relief symptoms of this degenerative disorder. Current methods include ablation and deep brain stimulation (DBS) that can be applied to the various nuclei in the basal ganglia (BG), for instance to the Subthalamic nucleus (STN) or the Ventral medial nucleus (Vim). Identification of thus regions must be rigorous and within a minimum position error. Usually, skilled specialist identifies the brain area by comparing and listening to the rhythm created by the temporal and spatial aggregation of action potentials presented in microelectrode recordings (MER). We present a novel system for automatic identification of the various nuclei in the BG which addresses the limitations of the subjectivity and the non-stationary nature of MER signals. This system incorporates the time-frequency analysis using the Hilbert-Huang Transform (HHT), which is a recent tool for processing nonlinear and non-stationary data, with a dynamic classifier based on Hidden Markov Models (HMM). Classification accuracy in two different databases is compared to validate the performance of the proposed method. Results show that system can recognize selected nuclei with a mean accuracy of 90%.

Kinematic evaluation of gestural and repetitive single joint movements of the arm after posteroventral pallidotomy, subthalamotomy or both procedures combined in two Parkinson's disease patients: two case studies.

Two patients with severe Parkinson's disease undergoing partial or complete ablative interruption of basal ganglia (BG) output are presented. One patient who underwent bilateral subthalamotomy, and a second who underwent unilateral posteroventral pallidotomy, followed 7 years later by a bilateral subthalamotomy because of contralateral disease progression, were studied. In addition to the usual clinical evaluation, changes in joint kinematics observed during unconstrained, skilled multi-joint movement and repetitive single joint (RSJ) movement of the wrist were studied. Clinical UPDRS items referred to hand movements contralateral to the procedure, and instrumental measurement of RSJ improved in both patients after either pallidotomy or subthalamotomy. When both BG outflow paths were interrupted as was the case in the second patient (bilateral subthalamotomy after the initial pallidotomy), no added clinical improvement was observed, RSJ even deteriorated slightly. Instrument-based studies for movement alteration detection after simultaneous ablation of the globus pallidus and the subthalamic nucleus of these two patients showed greater sensitivity than clinical evaluation alone. Complex gestural movement performance remained unaffected after partial (subthalamotomy or pallidotomy) or complete interruption of BG outflow (case 2), indicating BG compensatory capacity after total outflow interruption remained intact.

Neuromodulation of prelemniscal radiations in the treatment of Parkinson's disease.

In patients with Parkinson's disease (PD), tetrapolar electrodes were implanted in the prelemniscal radiations (RAPRL) to treat tremor, rigidity and bradykinesia. Fifteen patients were implanted unilaterally and five patients bilaterally and followed-up for one year. The selection criteria included the presence of unilateral pronounced tremor and rigidity in patients implanted unilaterally or bilateral symptoms including severe bradykinesia in patients implanted bilaterally. In the operating room, the tremor decreased significantly or was abolished following the insertion of the electrode in the RAPRL. This effect was temporary and subsided when the stimulation was off. However, when the stimulator was turned on, the severity of the symptoms and signs decreased significantly. The post-implantation MRI confirmed that the electrode contacts used for stimulation were inserted in RAPRL, a group of fibers located between the red nucleus and subthalamic nucleus, above the substantia nigra, medially to the zona incerta and below the thalamus. The patients were evaluated using the UPDRS part III, before implantation and every 3 months during the first year. Global scores decreased significantly. The pre- and postoperative median values (range in round brackets) were as follows: tremor improved from 3 (2-16) to 1 (2-3) (p<0.001); rigidity was either abolished or decreased markedly from 2 (1-16) to 0 (0-4) (p< 0.001); bradykinesia improved from 2 (0-4) to 1 (0-2) (p<0.001). We conclude that RAPRL, an area anatomically different from STN, is a good target for electrical stimulation in order to treat effectively all the main symptoms of PD.

Neuronal activity of the zona incerta in Parkinson's disease patients.

The objective of this study was to describe the firing characteristics of the zona incerta (ZI) in Parkinson's disease patients. The ZI constitutes a band of gray matter lying dorsal to the subthalamic nucleus, whose firing properties have not been well defined in humans yet. ZI proved to become hyperactive in 6-OHDA-lesioned rats as compared to normal rats, and regarding these noticeable changes in the discharge patterns it was suggested that ZI could be a putative target for the surgical treatment of Parkinson's disease. Twelve patients who underwent microrecording-guided subthalamic surgery consented to the study. Neurons from different tracts were classified as belonging to the ZI according to their firing features, background extracellular activity, anatomical mapping of trajectories, and atlas confirmation. Fifty-nine neurons were classified as belonging to ZI. The mean firing rate proved to be 29.5 Hz, with a broad dispersion band, even covering subthalamic nucleus (STN) frequency ranges. Pattern analysis showed heterogeneous neuronal signals ranging from tonic to burst and paused neurons. A decrease in extracellular background activity in the defined ZI was also observed. Five of the recorded neurons showed rhythmical spike trains with oscillations of 8 to 14 Hz, and two units were found to discharge trains at 4 Hz. None of the recorded ZI neurons responded to proprioceptive maneuvers. ZI presented firing activities with a broad spectrum in terms of frequency and tonicity. It is differentiated from STN recordings in Parkinson's disease patients mainly because of absent proprioceptive-related units and diminished extracellular background activity.

Imagens de ressonância magnética funcional em pacientes com doença de Parkinson submetidos à estimulação cerebral profunda / Functional Magnetic Resonance Imaging in patients with Parkinson’s disease with deep brain stimulation

A estimulação cerebral profunda (ECP) é usada para tratar a doença de Parkinson (DP) avançada. A estimulação do núcleo subtalâmico (NST) melhora o sintomas de parkinsonismo, mas seu mecanismo de ação permanece pouco compreendido. Dados comportamentais durante o exame e a evolução clínica foram analisados. RESULTADOS: Os pacientes não apresentaram complicações decorrentes dos exames de RMf. Com o estímulo elétrico ligado, nas sequências BL houve maior atividade em relação às RE, na área sensitivo-motora primária (SM1) esquerda. Durante o repouso, quando a estimulação elétrica foi ligada houve maior atividade das seguintes áreas: cerebelo direito, SM1 esquerda, Cgp, pM bilateral, mesencéfalo esquerdo e Cga. Houve melhora clínica dos pacientes e tanto a avaliação motora na primeira semana pós-operatória, na fase sem medicação, bem como a avaliação global em seis meses estiveram correlacionadas com os parâmetros motores aferidos durante os exames de RMf / Deep brain stimulation (DBS) is used to treat advanced Parkinson's disease (PD). Stimulation of the subthalamic nucleus (STN) is effective to improve the symptoms related to parkinsonism, but its mechanism of action remains poorly understood. Functional magnetic resonance imaging (fMRI) can be applied to study brain areas involved in motor activity, as a mean to better understand the effects of DBS. In this work we aimed to develop and test fMRI techniques to study DP patients treated with DBS. METHODS: We have initially performed tests to check the interference of the DBS in image quality and made adaptations that minimized the artifacts. After this initial phase PD patients were examined by fMRI in four different phases: during right hand movement (before surgery to implant DBS electrodes, after the surgery with the electrical stimulation turned off, and after the surgery with the electrical stimulation turned on the STN) and at rest with electrical stimulation turned on. In total, ten patients were examined, eight of them paired to matched normal volunteers...

Anatomic and neurophysiological methods for the targeting and lesioning of the subthalamic nucleus: Cuban experience and review.

OBJECTIVE: To develop a method to place a lesion precisely in the subthalamic nucleus (STN) and evaluate its effectiveness. METHODS: A retrospective study of targeting data collected during stereotactic planning to lesion the STN in 31 patients with Parkinson's disease and of results in more than 50 procedures was performed. The targeting method was based on computed tomographic imaging together with semimicroelectrode recording digital processing and electrical stimulation. Two statistical methods were used to correlate initial with final target coordinates and assess the efficacy of the targeting procedure. RESULTS: The anatomic target based on computed tomographic imaging data showed electrical activity in the subthalamus in the first pass in 82% of the procedures. In the remaining 18%, the STN was an average of 1.93 mm away from the nearest trajectory that recorded the STN (range, 1.41-2.24 mm). The average number of trajectories per procedure was 7.2; the location of the first trajectory relative to the center of the nucleus determined by electrical and physiological means (P < 0.01, analysis of variance, Student's t test) was as follows: in the lateral direction, 1.25 +/- 1.15 mm; in the anteroposterior direction, 1.53 +/- 1.31 mm; and in the vertical direction, 0.67 +/- 0.51 mm. The average number of tracts necessary to lesion the STN was two. CONCLUSION: The combination of computed tomographic imaging, semimicroelectrode recording, and microstimulation provides an effective method to identify the STN lesion in parkinsonian patients. The method used for anatomic localization and electrophysiological mapping of the subthalamus was found to be effective in reaching the sensorimotor region of the nucleus. We carried out an accurate determination of the subthalamus location and its volume in the lesioning.

[Deep brain stimulation of subthalamic nucleous in Parkinson's disease]. / Estimulação cerebral profunda no núcleo subtalâmico para doença de Parkinson.

UNLABELLED: We present the preliminary results in patients well selected to be implanted by deep brain stimulation (DBS) for Parkinsons's disease (PD). METHODS: 8 PD patients with disabled tremor, akinetic/bradikinetic and rigidity, in spite of best therapeutic assay with poor response were referred to surgery. It was implanted DBS Itrell 2. Theses patients were evaluated by the following scales: UPDRS, Schwab and England. RESULTS: The preliminary results in 6 months showed significant improvement of motor performance and it is shown by the scores. There were no complications so far with these procedures. CONCLUSION: The preliminary results indicate that DBS is highly effective, with benefit to those patients and it is according to literature.