Battery longevity of neurostimulators in Parkinson disease: A historic cohort study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for motor complications in Parkinson disease (PD). Since 2012, the nonrechargeable dual-channel neurostimulator available in France seems to have shorter battery longevity compared to the same manufacturer's previous model. OBJECTIVE: The aim of this study was to evaluate the battery longevity of older and more recent neurostimulators from the same manufacturer and to explore factors associated with battery life variations. MATERIALS AND METHODS: We retrospectively studied our cohort of PD patients who underwent STN DBS between 1987 and 2017. We collected data concerning neurostimulator replacements and parameters. We compared the survival of the first device available, Kinetra® and the current one, Activa-PC® (Medtronic Inc.) and estimated the factors that had an impact on battery longevity through a Cox logistic regression. RESULTS: Three hundred sixty-four PD patients received a total of 654 DBS STN neurostimulators: 317 Kinetra® and 337 Activa-PC®. The survival analysis, using the Kaplan-Meier estimator, showed a difference between the curves of the two devices (log-rank test; p < 0.001). The median survival of an Activa-PC® neurostimulator was 1666 days, while it was 2379 days for a Kinetra®. After adjustment, according to the multivariate analysis, the main factors associated with battery lifetime were: the neurostimulator type; the number of subsequent neurostimulator implantations; the total electrical energy delivered (TEED); and sex. CONCLUSION: The Kinetra® neurostimulator lifetime is 2.5 years longer than the Activa-PC®. The type of the device, the high TEED and the number of subsequent neurostimulator implantations influence battery longevity most. These results have medical-economic implications since the survival of PD patients with DBS increases over years.

Modulation of motor inhibition by subthalamic stimulation in obsessive-compulsive disorder.

High-frequency deep brain stimulation of the subthalamic nucleus can be used to treat severe obsessive-compulsive disorders that are refractory to conventional treatments. The mechanisms of action of this approach possibly rely on the modulation of associative-limbic subcortical-cortical loops, but remain to be fully elucidated. Here in 12 patients, we report the effects of high-frequency stimulation of the subthalamic nucleus on behavior, and on electroencephalographic responses and inferred effective connectivity during motor inhibition processes involved in the stop signal task. First, we found that patients were faster to respond and had slower motor inhibition processes when stimulated. Second, the subthalamic stimulation modulated the amplitude and delayed inhibition-related electroencephalographic responses. The power of reconstructed cortical current densities decreased in the stimulation condition in a parietal-frontal network including cortical regions of the inhibition network such as the superior parts of the inferior frontal gyri and the dorsolateral prefrontal cortex. Finally, dynamic causal modeling revealed that the subthalamic stimulation was more likely to modulate efferent connections from the basal ganglia, modeled as a hidden source, to the cortex. The connection from the basal ganglia to the right inferior frontal gyrus was significantly decreased by subthalamic stimulation. Beyond motor inhibition, our study thus strongly suggests that the mechanisms of action of high-frequency subthalamic stimulation are not restricted to the subthalamic nucleus, but also involve the modulation of distributed subcortical-cortical networks.

Low-frequency versus high-frequency stimulation of the pedunculopontine nucleus area in Parkinson's disease: a randomised controlled trial.

OBJECTIVE: To compare the influence of low-frequency (10-25 Hz) versus higher (60-80 Hz) frequency stimulation of the pedunculopontine nucleus area (PPNa) on akinaesia, freezing of gait and daytime sleepiness. METHOD: We included nine patients with Parkinson's disease (PD) and severe gait disorders. In this double-blind randomised cross-over study, patients were assessed after 24 h of PPNa stimulation. Assessments included the motor part of the Unified Parkinson's Disease Rating Scale, the Epworth Sleepiness Scale and a behavioural gait assessment. RESULTS: Compared with 60-80 Hz, 10-25 Hz PPNa stimulation led to decreased akinaesia, gait difficulties and daytime sleepiness in 7/9 patients. In one patient, these symptoms were aggravated under 10-25 Hz stimulation compared with 60-80 Hz. CONCLUSION: These results are in keeping with the benefits of chronic PPNa stimulation for gait and postural difficulties in patients with PD, and with regard to the influence of patients' clinical characteristics, differential neuronal loss in the PPNa and electrode location. We conclude that in patients with PPNa stimulation, low frequency provides a better outcome than high-frequency stimulation.

Effect of subthalamic nucleus stimulation on penicillin induced focal motor seizures in primate.

BACKGROUND: Drug-resistant motor epilepsies are particularly incapacitating for the patients. In a primate model of focal motor seizures induced by intracortical injection of penicillin, we recently showed that seizures propagated from the motor cortex towards the basal ganglia. OBJECTIVE: Using the same animal model here, we hypothesized that disruption of subthalamic nucleus (STN) activity by chronic high frequency stimulation (HFS) could modify pathological excessive cortical synchronisation occurring during focal motor seizures, and therefore could reduce seizure activity. METHODS: Two monkeys were chronically implanted with one electrode positioned into the STN. In each experiment, seizures were induced during 6 hours by injecting penicillin into the motor cortex. During stimulation sessions, HFS-STN was applied at the beginning of penicillin injection. RESULTS: Our results indicate that HFS-STN improved focal motor seizures by delaying the occurrence of the first seizure, by decreasing the number of seizures by 47% and therefore the total time spent seizing by 53% compared to control. These results argue for a therapeutic use of HFS-STN in motor seizures because they were obtained in a very severe primate model of motor status similar to that seen in human. Furthermore, HFS-STN was much more efficient than direct cortical HFS of the epileptic focus, which we already tested in the same primate model. CONCLUSIONS: The present study suggests that HFS-STN could be used as an experimental therapy when other therapeutic strategies are not possible or have failed in humans suffering from motor epilepsy but the present study still warrants controlled studies in humans.

Inhibitory control and error monitoring by human subthalamic neurons.

The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2-4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15-35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.

Neurological imaging of brain damages after radiotherapy and/or chimiotherapy.

Radiotherapy and chemotherapy may induce neurological toxicities with different appearances on CT and MRI scans. While optimized radiotherapy techniques have reduced some complications, new unwanted effects have occurred on account of therapeutic protocols involving the simultaneous use of radiotherapy and chemotherapy. Advances in radio-surgery, innovative anti-angiogenic therapies, as well as prolonged patient survival have led to the emergence of new deleterious side effects. In this report, we describe the early, semi-delayed, and late encephalic complications, while specifying how to identify the morphological lesions depending on the therapeutic protocol.

Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease.

We examined executive functioning in patients with Parkinson's disease exhibiting, or not, levodopa-resistant freezing of gait (L-FOG). 38 advanced-stage patients with L-FOG were identified in a consecutive series of 400 patients. They were matched with 38 patients without L-FOG. All patients underwent prospective evaluations of cognitive and motor functioning before subthalamic nucleus surgery, and 1 year after. A composite frontal score, a measure of executive functioning, was compared between the two groups. We also examined correlations between the frontal score and the score on the FOG item of the Unified Parkinson Disease Rating Scale II. Results show that after surgery, patients with L-FOG, as a group, were more impaired in executive functioning than control patients. However, individual data analysis showed preserved executive functions in 11 patients with L-FOG. In addition, there was no correlation between L-FOG severity and the degree of executive impairment. Therefore, frontal dysfunction may be one mechanism underlying L-FOG in a number of patients with Parkinson's disease. However, since some patients develop L-FOG despite the preservation of executive functions, lesions or dysfunction of other neuronal structures are likely to be involved.

[Mechanisms of action of high-frequency deep brain stimulation. A review of the literature and current concepts]. / Les mécanismes d'action de la stimulation cérébrale à haute fréquence. Revue de la littérature et concepts actuels.

High-frequency deep brain stimulation (HF-DBS) has become a widely used therapeutic method in the field of movement disorders for the treatment of Parkinson's disease, essential tremor or dystonia. New targets and indications are under evaluation in several other conditions such as cluster headache, obesity, epilepsy or psychiatric diseases (depression, OCD). However, the mechanisms of action of HF-DBS remain poorly understood. Herein we present a review of the literature and our current view of the question. The first part deals with the effects of stimulation itself on the different parts of the neuron and tries to answer the question of what is actually stimulated by DBS (cell bodies, dendrites or axons). The second part is devoted to the ortho- and antidromic effects of the stimulation. The third part more specifically focuses on the case of subthalamic nucleus stimulation. The target axons in the subthalamic area are discussed in the light of recent optogenetic studies. In conclusion, HF-DBS leads to a kind of functional deafferentation of the stimulated structure and to the modulation of cortical activity (both ortho and antidromically). Which effects are relevant to the therapeutic effects of DBS is still unclear. Further investigations are required especially regarding the corticosubthalamic pathways.

Body fat and body weight reduction following hypothalamic deep brain stimulation in monkeys: an intraventricular approach.

OBJECTIVE: The authors proposed an intraventricular 'floating' electrode inserted in the third ventricle (V3) adjacent to the ventromedian hypothalamus (VMH) in a freely moving Macaca fascicularis to modulate food intake (FI), body fat (BF), body weight (BW) and body mass index (BMI), as a potential treatment of obesity. METHODS: Five adult Macaca fascicularis monkeys were implanted stereotactically in the V3 contiguous to the VMH with one deep brain stimulation (DBS) electrode. The study was divided in two phases: (a) acute 24 h-fasting trials: different electrical stimulation parameters were applied to a fasting primate to determine the best combination in reducing FI; and (b) chronic 8-week stimulation trials: three cycles of intraventricular-VMH DBS lasting 8-10 weeks were performed at 130 Hz, 80 Hz (most effective frequency reducing FI) and 30 Hz, respectively. BMI, BW, BF content, skinfolds and hormones were measured during baseline and at the end of each session of stimulation. RESULTS: Acute 24 h-fasting trials: there was a decrease in FI in all subjects at 80 Hz, (11-19%, mean 15%). Chronic 8-week stimulation trials: a significant decrease in BW and BMI was observed in three out of four monkeys at 80 Hz (mean 8 ± 4.4%). Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. The sham monkey remained stable. No significant adverse effects were recorded. CONCLUSION: The stimulation of the VMH region through an intraventricular approach might acutely modulate FI and induce a sustained decrease in BW and fat mass in normal non-human primate.

A non-human primate model of bipedal locomotion under restrained condition allowing gait studies and single unit brain recordings.

For decades, several animal models of locomotion have allowed a better understanding of the basic physiological mechanisms of gait. However, unlike most of the mammals, the Order Primates is characterized by fundamental changes in locomotor behaviour. In particular, some primates use a specific pattern of locomotion and are able to naturally walk bipedally due possibly to a specific supra-spinal control of locomotion. These features must be taken into account when one considers to study the intrinsic properties of human gait. Thus, an experimental model of bipedal locomotion allowing precise and reproducible analysis of gait in non-human primate is still lacking. This study describes a non-human primate model of bipedal locomotion under restrained condition. We undertook a kinematic and biomechanic study in three Macaca fascicularis trained to walk bipedally on a treadmill. One of the primate was evaluated in complete head fixation. Gait visual analysis and electromyographic recordings provided pertinent description of the gait pattern. Step frequencies, step lengths, cycle and stance phase durations were correlated with Froude number (dimensionless velocity), whereas swing phase durations remained non-correlated. Gait patterns observed in our model were similar to those obtained in freely bipedal Macaca fuscata and to a lesser extend to Humans. Gait pattern was not modified by head fixation thereby allowing us to perform precise and repetitive micro electrode recordings of deep cerebral structures. Thus, the present model could provide a pertinent pre-clinical tool to study gait parameters and their neuronal control but also could be helpful to validate new therapeutics interventions.

Rationale for hypothalamus-deep brain stimulation in food intake disorders and obesity.

Appetite modulation in conjunction with enhancing metabolic rate with hypothalamic lesions has been widely documented in animal and even in humans. It appears these effects can be reproduced by DBS, and the titratability and reversibility of this procedure, in addition to well established safety profile, make DBS an appealing option for obesity treatment. Targeting the hypothalamus with DBS has already been shown to be feasible and potentially effective in managing patients with intractable chronic cluster headache [26]. The surgical risk however must be cautiously taken into account when targeting the hypothalamus, where some mortality cases have been reported when targeting the posterior part [34]. The development of new surgical approach will probably reduce this surgical risk. Moreover, the role of functional neurosurgery in obesity is not a new idea. In fact, LH was targeted in obese humans with electrocoagulation more than 30 years ago, resulting in significant yet transient appetite suppression and slight weight reduction [36]. All those elements have made possible the recent regain of interest in DBS for morbid obesity and open an exciting new area of research in neurosurgery and endocrinology.

Prognostic value of perfusion MR imaging in patients with oligodendroglioma: A survival study.

OBJECTIVE: The purpose of this study was to evaluate retrospectively whether cerebral blood volume measurement based on pretreatment perfusion MRI is a prognostic biomarker for survival in patients with oligodendroglioma or mixed oligoastrocytoma. PATIENTS AND METHODS: Between 1998 and 2004, 54 patients (23 females and 31 males), aged 21-73 years, with oligodendroglioma (or mixed tumour) were examined prior to beginning treatment with dynamic susceptibility-weighted contrast (DSC) perfusion MRI during gadolinium first-pass. The relative cerebral blood volume (rCBV) was calculated by dividing the measurement within the tumour by the measurement of the normal-appearing contralateral region. Patients were classified in two groups, grade A and grade B, according to the Saint-Anne Hospital classification and followed-up clinically and by means of MRI until their death or for a minimum of 5 years. Patients were also classified in grade II and grade III-IV, according to the World Health Organisation (WHO) classification, and were analysed with the same methods. Age, sex, treatment, tumour grade, contrast agent uptake, and rCBV were tested using survival curves with Kaplan-Meier's method, and their differences were analysed using the log-rank test. RESULTS: In this population, median survival was 3 years. A rCBV threshold value of 2.2 was validated as a prognostic factor, for survival in these patients with oligodendrogliomas. Age, sex, contrast uptake, and maximum rCBV were found to be prognostic factors in univariate analysis. Multivariate analysis revealed that tumour grade (grade A/grade B), rCBV, age, and sex were prognostic factors independent of the other factors. The tumour grade according to the WHO classification (II versus III-IV) was also detected as an independent prognostic factor. CONCLUSION: Pretreatment rCBV measured by DSC perfusion MRI was found to be a prognostic factor for survival in patients with oligodendroglioma or mixed tumour, by using the Saint-Anne Hospital classification, which separate the IIB from the IIA.

Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

Pedunculopontine nucleus stimulation induces monocular oscillopsia.

Two patients with Parkinson's disease with pedunculopontine nucleus (PPN) stimulation for gait impairments reported "trembling vision" during the setting of the electrical parameters, although there was no clinically observable abnormal eye movement. Oculomotor recordings revealed frequency locked voltage dependent vertical or oblique movements of the eye ipsilateral to the active contact, suggesting current spreading to the mesencephalic oculomotor fibres. These results emphasise the difficulty of stimulating this mesencephalic region.

Gait is associated with an increase in tonic firing of the sub-cuneiform nucleus neurons.

In animals, the pedunculopontine (PPN) and the sub-cuneiform (SCU) nuclei located in the upper brainstem are involved during the processing of gait. Similar functional nuclei are suspected in humans but their role in gait is unclear. Here we show that, using extra-cellular recordings of the PPN/SCU region obtained in two parkinsonian patients, the SCU neurons increased their firing rate without modifying their firing pattern during mimicked steps. We conclude that SCU neurons are activated during gait processes.

[Value of perfusion MRI in the study of pilocytic astrocytoma and hemangioblastoma: preliminary findings]. / Intérêt de l'imagerie de perfusion dans l'étude des astrocytomes pilocytiques et des hémangioblastomes : étude préliminaire.

PURPOSE: Pilocytic astrocytomas (PA) and hemangioblastomas (HB) can present the same morphological characteristics on conventional MRI sequences, most usually in the form of a cerebellar cystic mass with a mural nodule that strongly enhances on post-contrast T1 images. We discuss here the value of perfusion MRI in the differentiation of these two tumors, the diagnoses of which have already been histopathologically established. METHOD: Eleven patients with PA and eight with HB underwent first-pass perfusion MRI. The maximum relative cerebral blood volume (rCBV(max)), defined as the ratio between the CBV(max) in tumor tissue and the CBV in healthy, contralateral white matter, is considered to be indicative of the type of tumor. RESULTS: The difference between the rCBV(max) of PA (rCBV(max)=1.19+/-0.71, range 0.6-3.27) compared with that of HB (rCBV(max)=9.37+/-2.37, range 5.38-13) was significant (P<0.001). The first-pass curve crossed the baseline, corresponding to vascular permeability problems in both PA and HB. CONCLUSION: The first-pass method of perfusion MRI is a quick and useful way to differentiate between PA and HB.

[Epilepsy surgery in France]. / La chirurgie de l'épilepsie en France Evaluation de l'activité

We report here the results of the first survey on epilepsy surgery activity in France. Data from a questionnaire sent to 17 centers practicing epilepsy surgery were analyzed. All centers responded; however, all items were not completely documented. Over 50 years, more than 5000 patients have been operated on for drug-resistant epilepsy and more than 3000 patients underwent some invasive monitoring, most often SEEG. Currently, nearly 400 patients (including more than 100 children) are operated on yearly for epilepsy in France. Over a study period varying among centers (from two to 20 years; mean, 9.5 years), results from more than 2000 patients including one-third children were analyzed. Important differences between adults and children, respectively, were observed in terms of location (temporal: 72% versus 4.3%; frontal: 12% versus 28%; central: 2% versus 11%), etiology (hippocampal sclerosis: 41% versus 2%; tumors 20% versus 61%); and procedures (cortectomy: 50% versus 23%; lesionectomy: 8% versus 59%), although overall results were identical (seizure-free rates following temporal lobe surgery: 80.6% versus 79%; following extratemporal surgery: 65.9% versus 65%). In adults, the best results were observed following temporomesial (TM) resection associated with hippocampal sclerosis or other lesions (class I: 83% and 79%, respectively), temporal neocortical (TNC) lesional (82%), while resections for cryptogenic temporal resections were followed by 69% (TM) and 63% (TNC) class I outcome. Extratemporal lesional resections were associated with 71% class I outcome and cryptogenic 43%. In children, the best results were obtained in tumor-associated epilepsy regardless of location (class I: 80%). A surgical complication occurred in 8% after resective surgery - with only 2.5% permanent morbidity - and 4.3% after invasive monitoring (mostly hemorrhagic). Overall results obtained by epilepsy surgery centers were in the higher range of those reported in the literature, along with a low rate of major surgical complications. Growing interest for epilepsy surgery is clearly demonstrated in this survey and supports further development to better satisfy the population's needs, particularly children. Activity should be further evaluated, while existing epilepsy surgery centers as well as healthcare networks should be expanded.

[Basal ganglia deep-brain stimulation for treatment of drug-resistant epilepsy: review and current data]. / La stimulation cérébrale profonde des ganglions de la base comme traitement des épilepsies pharmacorésistantes: revue et données actuelles.

The surgical treatment of intractable epilepsies involving eloquent areas of the cortex is still challenging. Deep-brain stimulation could be an alternative to resective surgery because it can modulate the remote control systems of epilepsy, such as the thalamus and basal ganglia. The surgical experience acquired in the field of movement disorder surgery and the low morbidity of this technic could allow one to apply DBS to intractable epilepsies, such as generalized, motor and bitemporal epilepsies. Here we discuss the main experimental and clinical data reported so far in the literature and taken from our own experience.

Effects of subthalamic nucleus stimulation and levodopa on freezing of gait in Parkinson disease.

OBJECTIVE: We studied the effects of subthalamic nucleus (STN) stimulation vs levodopa on freezing of gait (FOG) and gait impairments in a large consecutive series of patients with Parkinson disease with bilateral STN stimulation. METHODS: One hundred twenty-three patients performed the Stand Walk Sit Test before and 1 year after surgery both off and on levodopa and off and on stimulation. RESULTS: Before surgery, 25 patients displayed FOG episodes and 48 were unable to complete the Stand Walk Sit Test when off levodopa. Both symptoms were alleviated by levodopa. After surgery, STN stimulation reproduced the improvement induced by levodopa before surgery in all but two patients with FOG and five others unable to walk. In 11 patients, FOG or inability to perform the test first occurred after surgery. In all patients but those experiencing FOG during the Stand Walk Sit Test before surgery, the benefit of STN stimulation did not reach that of levodopa before surgery. In patients with FOG before surgery, the effect of STN stimulation did not differ from that of levodopa either before or after surgery. CONCLUSIONS: Overall, subthalamic nucleus stimulation improved levodopa-responsive freezing of gait in most patients, although it was not always as effective as levodopa to improve gait impairments. In addition, surgery can induce gait problems in some patients.

[Presurgical evaluation of intractable epilepsy using stereo-electro-encephalography methodology: principles, technique and morbidity]. / Explorations préchirurgicales des épilepsies pharmacorésistantes par stéréo-électro-encéphalographie: principes, technique et complications.

In the stereo-electro-encephalography (SEEG) methodology developed by Talairach and Bancaud in Sainte-Anne Hospital in Paris, France, the objective of placing depth electrode recordings in presurgical evaluation is to study the spatial and temporal organization of a seizure. This defines for each patient the cortical onset zone, the propagation pattern of the seizure, and the possible involvement of eloquent areas of the cortex. This methodology requires a meticulous stereotactic surgical technique. We report here the SEEG methodology, surgical technique, and morbidity.