Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Magnetic Resonance-Guided Focused Ultrasound (MRgFUS)-Thalamotomy for Essential Tremor: Lesion Location and Clinical Outcomes.

BACKGROUND: Factors predicting clinical outcomes after MR-guided focused ultrasound (MRgFUS)-thalamotomy in patients with essential tremor (ET) are not well known. OBJECTIVE: To examine the clinical outcomes and their relationship with patients' baseline demographic and clinical features and lesion characteristics at 6-month follow-up in ET patients. METHODS: A total of 127 patients were prospectively evaluated at 1 (n = 122), 3 (n = 102), and 6 months (n = 78) after MRgFUS-thalamotomy. Magnetic resonance imaging (MRI) was obtained at 6 months (n = 60). Primary outcomes included: (1) change in the Clinical Rating Scale of Tremor (CRST)-A+B score in the treated hand and (2) frequency and severity of adverse events (AEs) at 6 months. Secondary outcomes included changes in all subitems of the CRST scale in the treated hand, CRST-C, axial tremor (face, head, voice, tongue), AEs, and correlation of primary outcomes at 6 months with lesion characteristics. Statistical analysis included linear mixed, standard, and logistic regression models. RESULTS: Scores for CRST-A+B, CRST-A, CRST-B in the treated hand, CRST-C, and axial tremor were improved at each evaluation (P < 0.001). Five patients had severe AEs at 1 month that became mild throughout the follow-up. Mild AEs occurred in 71%, 45%, and 34% of patients at 1, 3, and 6 months, respectively. Lesion volume was associated with the reduction in the CRST-A (P = 0.003) and its overlapping with the ventralis intermedius nucleus (Vim) nucleus with the reduction in CRST-A+B (P = 0.02) and CRST-B (P = 0.008) at 6 months. CONCLUSIONS: MRgFUS-thalamotomy improves hand and axial tremor in ET patients. Transient and mild AEs are frequent. Lesion volume and location are associated with tremor reduction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Unilateral Magnetic Resonance-Guided Focused Ultrasound Lesion of the Subthalamic Nucleus in Parkinson's Disease: A Prospective Study.

BACKGROUND: Unilateral subthalamic nucleus (STN) ablation using magnetic resonance-guided focused ultrasound (MRgFUS) is being explored as a new treatment for asymmetric Parkinson's disease (PD). OBJECTIVES: The aims were to study the efficacy and safety of this treatment in asymmetric PD patients and to characterize the lesions. METHODS: This prospective, single-center, open-label study evaluated asymmetric PD patients at 6 (n = 20) and 12 months (n = 12) after MRgFUS lesion of the STN. The primary outcome was the change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III), score in off medication on the treated side and the adverse events (AEs) at 6-month follow-up. We also evaluated cognitive-neuropsychological changes, self-assessment of clinical improvement, and the correlation of the lesion volume with the motor outcomes. RESULTS: On the treated side, the MDS-UPDRS III score (mean difference = 13.8) and the scores in rigidity, bradykinesia, and tremor improved (P < 0.001) throughout the follow-up compared to baseline (at 6 months: rigidity mean difference = 2.8, improvement: 83.5%; bradykinesia mean difference = 6.0, improvement: 69.4%; tremor mean difference = 4.7, improvement: 91.5%). One patient had severe weakness in the treated hemibody, 1 had moderate dyskinesia, and 1 was in moderate confusional state that became mild (weakness) or completely resolved (dyskinesia and confusional state) at 6 months. The rest of the AEs were mild. We observed no clinically relevant changes in cognitive-neuropsychological tests. The percentage of ablation of the STN correlated with the improvement in the total MDS-UPDRS III and contralateral tremor scores (P < 0.05). CONCLUSION: Unilateral MRgFUS lesion of the STN resulted in a significant motor improvement. We observed no persistent severe AEs, although mild, mostly transient AEs were frequent. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

3-T MR-guided focused ultrasound thalamotomy for tremor in patients with a cardiac pacemaker: case series and review of the literature.

MR-guided focused ultrasound (MRgFUS) has proven its efficacy and safety for the treatment of essential tremor (ET) and/or Parkinson's disease (PD). However, having a cardiac pacemaker has been considered an exclusion criterion for the use of MRgFUS. Only 2 patients with a cardiac pacemaker treated with MRgFUS have been previously reported, both treated using 1.5-T MRI. In this paper, the authors present their experience performing 3-T MRgFUS thalamotomy in 4 patients with an implanted cardiac pacemaker. Treatments were uneventful regarding complications or severe side effects. MRgFUS using 3-T MRI was found to be an efficient and safe treatment for ET and/or PD in patients with an MRI-compatible pacemaker.

Effects of dexmedetomidine on subthalamic local field potentials in Parkinson's disease.

BACKGROUND: Dexmedetomidine is frequently used for sedation during deep brain stimulator implantation in patients with Parkinson's disease, but its effect on subthalamic nucleus activity is not well known. The aim of this study was to quantify the effect of increasing doses of dexmedetomidine in this population. METHODS: Controlled clinical trial assessing changes in subthalamic activity with increasing doses of dexmedetomidine (from 0.2 to 0.6 µg kg-1 h-1) in a non-operating theatre setting. We recorded local field potentials in 12 patients with Parkinson's disease with bilateral deep brain stimulators (24 nuclei) and compared basal activity in the nuclei of each patient and activity recorded with different doses. Plasma levels of dexmedetomidine were obtained and correlated with the dose administered. RESULTS: With dexmedetomidine infusion, patients became clinically sedated, and at higher doses (0.5-0.6 µg kg-1 h-1) a significant decrease in the characteristic Parkinsonian subthalamic activity was observed (P<0.05 in beta activity). All subjects awoke to external stimulus over a median of 1 (range: 0-9) min, showing full restoration of subthalamic activity. Dexmedetomidine dose administered and plasma levels showed a positive correlation (repeated measures correlation coefficient=0.504; P<0.001). CONCLUSIONS: Patients needing some degree of sedation throughout subthalamic deep brain stimulator implantation for Parkinson's disease can probably receive dexmedetomidine up to 0.6 µg kg-1 h-1 without significant alteration of their characteristic subthalamic activity. If patients achieve a 'sedated' state, subthalamic activity decreases, but they can be easily awakened with a non-pharmacological external stimulus and recover baseline subthalamic activity patterns in less than 10 min. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002680-34; NCT-02982512.

Subthalamotomy for Parkinson's disease: clinical outcome and topography of lesions.

OBJECTIVE: Subthalamotomy is an effective alternative for the treatment of Parkinson's disease (PD). However, uncertainty about the optimal target location and the possibility of inducing haemichorea-ballism have limited its application. We assessed the correlation between the topography of radiofrequency-based lesions of the subthalamic nucleus (STN) with motor improvement and the emergence of haemichorea-ballism. METHODS: Sixty-four patients with PD treated with subthalamotomy were evaluated preoperatively and postoperatively using the Unified Parkinson's Disease Rating Scale motor score (UPDRSm), MRI and tractography. Patients were classified according to the degree of clinical motor improvement and dyskinesia scale. Lesions were segmented on MRI and averaged in a standard space. We examined the relationship between the extent of lesion-induced disruption of fibres surrounding the STN and the development of haemichorea-ballism. RESULTS: Maximum antiparkinsonian effect was obtained with lesions located within the dorsolateral motor region of the STN as compared with those centre-placed in the dorsal border of the STN and the zona incerta (71.3%, 53.5% and 20.8% UPDRSm reduction, respectively). However, lesions that extended dorsally beyond the STN showed lower probability of causing haemichorea-ballism than those placed entirely within the nucleus. Tractography findings indicate that interruption of pallidothalamic fibres probably determines a low probability of haemichorea-ballism postoperatively. CONCLUSIONS: The topography of the lesion is a major factor in the antiparkinsonian effect of subthalamotomy in patients with PD. Lesions involving the motor STN and pallidothalamic fibres induced significant motor improvement and were associated with a low incidence of haemichorea-ballism.

History and future challenges of the subthalamic nucleus as surgical target: Review article.

For many years the subthalamic nucleus had a poor reputation among neurosurgeons as a result of the acute movement disorders that develop after its lesion or manipulation through different surgical procedures. However, this nucleus is now considered a key structure in relation to parkinsonism, and it is currently one of the preferred therapeutic targets for Parkinson's disease. The implication of the subthalamic nucleus in the pathophysiology of chorea and in the parkinsonian state is thought to be related to its role in modulating the basal ganglia, a fundamental circuit in movement control. Indeed, recent findings have renewed interest in this anatomical structure. Accordingly, this review aims to present a history of the subthalamic nucleus, evolving from the classic surgical concepts associated with the avoidance of this structure, to our current understanding of its importance based on findings from more recent models. Future developments regarding the relationship of the subthalamic nucleus to neuroprotection are also discussed in this review. © 2018 International Parkinson and Movement Disorder Society.

Oscillatory activity in the basal ganglia and deep brain stimulation.

Over the past 10 years, research into the neurophysiology of the basal ganglia has provided new insights into the pathophysiology of movement disorders. The presence of pathological oscillations at specific frequencies has been linked to different signs and symptoms in PD and dystonia, suggesting a new model to explain basal ganglia dysfunction. These advances occurred in parallel with improvements in imaging and neurosurgical techniques, both of which having facilitated the more widespread use of DBS to modulate dysfunctional circuits. High-frequency stimulation is thought to disrupt pathological activity in the motor cortex/basal ganglia network; however, it is not easy to explain all of its effects based only on changes in network oscillations. In this viewpoint, we suggest that a return to classic anatomical concepts might help to understand some apparently paradoxical findings. © 2016 International Parkinson and Movement Disorder Society.

Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry.

BACKGROUND: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor. METHODS: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (≥48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications. RESULTS: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure. CONCLUSIONS: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society.

Effect of Dexmedetomidine and Propofol on Basal Ganglia Activity in Parkinson Disease: A Controlled Clinical Trial.

BACKGROUND: Deep brain stimulation electrodes can record oscillatory activity from deep brain structures, known as local field potentials. The authors' objective was to evaluate and quantify the effects of dexmedetomidine (0.2 µg·kg·h) on local field potentials in patients with Parkinson disease undergoing deep brain stimulation surgery compared with control recording (primary outcome), as well as the effect of propofol at different estimated peak effect site concentrations (0.5, 1.0, 1.5, 2.0, and 2.5 µg/ml) from control recording. METHODS: A nonrandomized, nonblinded controlled clinical trial was carried out to assess the change in local field potentials activity over time in 10 patients with Parkinson disease who underwent deep brain stimulation placement surgery (18 subthalamic nuclei). The relationship was assessed between the activity in nuclei in the same patient at a given time and repeated measures from the same nucleus over time. RESULTS: No significant difference was observed between the relative beta power of local field potentials in dexmedetomidine and control recordings (-7.7; 95% CI, -18.9 to 7.6). By contrast, there was a significant decline of 12.7% (95% CI, -21.3 to -4.7) in the relative beta power of the local field potentials for each increment in the estimated peak propofol concentrations at the effect site relative to the control recordings. CONCLUSIONS: Dexmedetomidine (0.2 µg·kg·h) did not show effect on local field potentials compared with control recording. A significant deep brain activity decline from control recording was observed with incremental doses of propofol.

[Neuroprotective subthalamotomy in Parkinson's disease. The role of magnetic resonance-guided focused ultrasound in early surgery]. / Subtalamotomía como neuroprotección en la enfermedad de Parkinson. El papel de los ultrasonidos guiados por resonancia como cirugía temprana.

Subthalamic nucleus hyperactivity in Parkinson's disease may be a very early phenomenon. Its start is not well known, and it may occur during the pre-symptomatic disease stage. Glutamatergic hyperactivity may be neurotoxic over the substantia nigra compacta dopaminergic neurons. If this occurred, the excitatory neurotransmitter, glutamate, should affect the neurons that maintain a high turnover as a compensatory mechanism. Would a subthalamic nucleus lesion decrease this hyperactivity and thus be considered as a neuroprotective mechanism for dopaminergic neurons? The authors hypothesise about the possibility to perform surgery on a subthalamic nucleus lesion at a very early stage in order to avoid the neurotoxic glutamatergic effect over the dopaminergic neurons, and therefore be considered as a neuroprotective surgery able to alter the progress of the disease during early motor symptoms. In this regard, magnetic resonance-guided focused ultrasound techniques open a new window in the stereotactic armamentarium.

Factors Associated with Tremor Changes during Sedation with Dexmedetomidine in Parkinson's Disease Surgery.

INTRODUCTION: Dexmedetomidine is an α2-agonist recently proposed as a potentially ideal drug for sedation during the surgical treatment of Parkinson's disease (PD). This report documents the incidence of changes in motor symptoms (especially tremor) in PD patients sedated with dexmedetomidine for deep brain stimulation or ablation procedures. METHODS: We reviewed a retrospective cohort of 22 patients who underwent surgery for PD with dexmedetomidine sedation at a single institution from 2010 to 2014. A logistic regression analysis was performed to analyze possible confounding factors. RESULTS: 14 cases of tremor reduction or suppression were recorded (cumulative incidence: 63.6%; 95% CI: 40.7-82.8). No association could be identified between loading dose, ß-blocker use and preoperative total Unified Parkinson's Disease Rating Scale III, with tremor changes. The maintenance dose of dexmedetomidine was higher in patients who did not experience changes [median and range for patients with and without tremor alteration 0.75 (0.2-1.0) and 1.0 µg × kg(-1) × h(-1) (0.7-1.4), respectively; p = 0.021]. CONCLUSION: Dexmedetomidine provides adequate sedation during surgery for PD, but it might affect motor signs making intraoperative testing difficult or even impossible. Dosage appears not to be the determining factor in motor changes, whose cause remains unclear.

High beta activity in the subthalamic nucleus and freezing of gait in Parkinson's disease.

OBJECTIVE: Oscillatory activity in the beta band is increased in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients. Rigidity and bradykinesia are associated with the low-beta component (13-20Hz) but the neurophysiological correlate of freezing of gait in PD has not been ascertained. METHODS: We evaluated the power and coherence of the low- and high-beta bands in the STN and cortex (EEG) of PD patients with (p-FOG) (n=14) or without freezing of gait (n-FOG) (n=8) in whom electrodes for chronic stimulation in the STN had been implanted for treatment with deep brain stimulation. RESULTS: p-FOG patients showed higher power in the high-beta band (F=11.6, p=0.002) that was significantly reduced after l-dopa administration along with suppression of FOG (F=4.6, p=0.042). High-beta cortico-STN coherence was maximal for midline cortical EEG electrodes, whereas the low-beta band was maximal for lateral electrodes (χ(2)=20.60, p<0.0001). CONCLUSIONS: The association between freezing of gait, high-beta STN oscillations and cortico-STN coherence suggests that this oscillatory activity might interfere in the frontal cortex-basal ganglia networks, thereby participating in the pathophysiology of FOG in PD.

[Brainstem metastasis from a prostate adenocarcinoma in the context of Muir-Torre syndrome]. / Metástasis de un adenocarcinoma prostático en tronco cerebral en el contexto de un síndrome de Muir-Torre.

INTRODUCTION: Muir-Torre syndrome is a genetic disease characterised by the association of sebaceous neoplasms with visceral neoplasms, mainly colorectal cancer and secondly urogenital tumours. Metastases from prostate tumours without systemic disease are rare in the brain and exceptional in the brainstem. CASE REPORT: We present a 48-year old male, with a single brainstem metastasis from a prostate adenocarcinoma, who had previously been diagnosed with Muir-Torre syndrome. Diagnostic stereotactic biopsy was performed. CONCLUSION: Single metastasis from a prostate adenocarcinoma in the brainstem without systemic disease is exceptional. Due to the different diagnostic possibilities, biopsy should be performed in order to obtain a diagnosis, especially in the context of Muir-Torre syndrome.

Development and Performance Evaluation of a Clinical Predictive Model to Estimate the Risk of Red Blood Cell Requirements in Brain Tumor Surgery.

BACKGROUND: The identification of factors associated with perioperative red blood cell (RBC) transfusion provides an opportunity to optimize the patient and surgical plan, and to guide perioperative crossmatch and RBC orders. We examined the association among potential bleeding risk factors and RBC requirements to develop a novel predictive model for RBC transfusion in patients undergoing brain tumor surgery. METHODS: This retrospective study included 696 adults who underwent brain tumor surgery between 2008 and 2018. Multivariable logistic regression with backward stepwise selection for predictor selection was used during modeling. Model performance was evaluated using area under the receiver operating characteristic curve, and calibration was evaluated with Hosmer-Lemeshow goodness-of-fit χ 2 -estimate. RESULTS: Preoperative hemoglobin level was inversely associated with the probability of RBC transfusion (odds ratio [OR]: 0.50; 95% confidence interval [CI]: 0.39-0.63; P <0.001). The need for RBC transfusion was also greater in patients who had a previous craniotomy (OR: 2.71; 95% CI: 1.32-5.57; P =0.007) and in those with larger brain tumor volume (OR: 1.01; 95% CI: 1.00-1.02; P =0.009). The relationship between number of planned craniotomy sites and RBC transfusion was not statistically significant (OR: 2.11; 95% CI: 0.61-7.32; P =0.238). A predictive model for RBC requirements was built using these 4 variables. The area under the receiver operating characteristic curve was 0.79 (95% CI: 0.70-0.87; P <0.001) showing acceptable calibration for predicting RBC transfusion requirements. CONCLUSIONS: RBC requirements in patients undergoing brain tumor surgery can be estimated with acceptable accuracy using a predictive model based on readily available preoperative clinical variables. This predictive model could help to optimize both individual patients and surgical plans, and to guide perioperative crossmatch orders.

Subthalamic activity during diphasic dyskinesias in Parkinson's disease.

BACKGROUND: Diphasic dyskinesias are a subtype of levodopa-induced dyskinesias that appear typically at the onset and end of levodopa antiparkinsonian action. The pathophysiology of diphasic dyskinesias is not well understood. METHODS: We analyzed local field potentials recorded from the subthalamic nucleus in 7 Parkinson's disease (PD) patients who showed typical diphasic dyskinesias during postoperative recordings through a deep brain stimulation electrode. The evolution of the different oscillatory activities related to the onset and end of diphasic dyskinesias was studied by windowed fast Fourier transforms. RESULTS: Typical "off"-state beta activity disappeared with the onset of diphasic dyskinesias, whereas gamma activity was absent or minimal until their end. Theta activity during diphasic dyskinesias was similar to that observed during peak-dose dyskinesias. CONCLUSIONS: From a neurophysiological viewpoint, patients exhibited oscillatory activity typical of the "on" medication state during diphasic dyskinesias. The minimal presence of gamma activity during diphasic dyskinesias, however, suggests that this "on" state might be incomplete or limited to dopaminergic mechanisms affecting the lower limbs.

Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson's disease.

Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinson's disease receive dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to the predominant clinical features of each patient, their Parkinson's disease was associated with impulse control disorders (n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients with impulse control disorders displayed theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that was generated 2-8 mm below the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency (mean: 8.38 Hz) and was generated 0-2 mm below the intercommissural line. No such activity was detected in patients that displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the 4-7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with dyskinesia it was in the 7.5-10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories.

Coupling between beta and high-frequency activity in the human subthalamic nucleus may be a pathophysiological mechanism in Parkinson's disease.

In Parkinson's disease (PD), the oscillatory activity recorded from the basal ganglia shows dopamine-dependent changes. In the "off" parkinsonian motor state, there is prominent activity in the beta band (12-30 Hz) that is mostly attenuated after dopaminergic therapy ("on" medication state). The on state is also characterized by activity in the gamma (60-80 Hz) and high-frequency (300 Hz) bands that is modulated by movement. We recorded local field potentials from a group of 15 PD patients (three females) treated with bilateral deep brain stimulation of the subthalamic nucleus, using a high sampling rate (2 kHz) and filters suitable to study high-frequency activity (0.3-1000 Hz). We observed high-frequency oscillations (HFOs) in both the off and on motor states. In the off state, the amplitude of the HFOs was coupled to the phase of the abnormal beta activity. The beta-coupled HFOs showed little or even negative movement-related changes in amplitude. Moreover, the degree of movement-related modulation of the HFOs correlated negatively with the rigidity/bradykinesia scores. In the on motor state, the HFOs were liberated from this beta coupling, and they displayed marked movement-related amplitude modulation. Cross-frequency interactions between the phase of slow activities and the amplitude of fast frequencies have been attributed an important role in information processing in cortical structures. Our findings suggest that nonlinear coupling between frequencies may not only be a physiological mechanism (as shown previously) but also that it may participate in the pathophysiology of parkinsonism.

Milestones in research on the pathophysiology of Parkinson's disease.

Progress in our understanding of the mechanisms underlying the cardinal motor abnormalities of Parkinson's disease (PD), in particular akinesia and bradykinesia and their treatment, has been remarkable. Notable accomplishments include insights into the functional organization of the basal ganglia and their place in the motor system as components of a family of parallel cortico-subcortical circuits that subserve motor and nonmotor functions and the development of models of the intrinsic organization of the basal ganglia, including delineation of the so-called direct, indirect, and hyperdirect pathways. Studies in primate models of PD have provided insight into the alterations of neuronal activity that are responsible for the motor features of PD, revealing both altered tonic levels of discharge and significant disturbances of the patterns of discharge throughout the motor circuitry and have led to the formulation of circuit models of PD, providing testable hypotheses for research and stimulating the development of new therapies. Most importantly, the discovery that lesions of the subthalamic nucleus, a key node of the indirect pathway, abolish the cardinal features of PD contributed to the renaissance in the use of surgical approaches to treating patients with PD, including ablation and deep brain stimulation.

Revisiting Forel Field Surgery.

BACKGROUND: Lesioning the Forel field or the subthalamic region is considered a possible treatment for tremoric patients with Parkinson disease, essential tremor, and other diseases. This surgical treatment was performed in the 1960s to 1970s and was an alternative to thalamotomy. Recently, there has been increasing interest in the reappraisal of stimulating and/or lesioning these targets, partly as a result of innovations in imaging and noninvasive ablative technologies, such as magnetic resonance-guided focused ultrasonography. OBJECTIVE: We wanted to perform a thorough review of the subthalamic region, both from an anatomic and a surgical standpoint, to offer a comprehensive and updated analysis of the techniques and results reported for patients with tremor treated with different techniques. METHODS: We performed a systematic review of the literature, gathering articles that included patients who underwent ablative or stimulation surgical techniques, targeting the pallidothalamic pathways (pallidothalamic tractotomy), cerebellothalamic pathway (cerebellothalamic tractotomy), or subthalamic area. RESULTS: Pallidothalamic tractotomy consists of a reduced area that includes pallidofugal pathways. It may be considered an interesting target, given the benefit/risk ratio and the clinical effect, which, compared with pallidotomy, involves a lower risk of injury or involvement of vital structures such as the internal capsule or optic tract. Cerebellothalamic tractotomy and/or posterior subthalamic area are other alternative targets to thalamic stimulation or ablative surgery. CONCLUSIONS: Based on the significant breakthrough that magnetic resonance-guided focused ultrasonography has meant in the neurosurgical world, some classic targets such as the pallidothalamic tract, Forel field, and posterior subthalamic area may be reconsidered as surgical alternatives for patients with movement disorders.