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Optogenetics is widely used in fundamental neuroscience. Its potential clinical translation for brain neuromodulation requires a careful assessment of the safety and efficacy of repeated, sustained optical stimulation of large volumes of brain tissues. This study was performed in rats and not in non-human primates for ethical reasons. We studied the spatial distribution of light, potential damage, and non-physiological effects in vivo, in anesthetized rat brains, on large brain volumes, following repeated high irradiance photo-stimulation. We generated 2D irradiance and temperature increase surface maps based on recordings taken during optical stimulation using irradiance and temporal parameters representative of common optogenetics experiments. Irradiances of 100 to 600 mW/mm 2 with 5 ms pulses at 20, 40, and 60 Hz were applied during 90 s. In vivo electrophysiological recordings and post-mortem histological analyses showed that high power light stimulation had no obvious phototoxic effects and did not trigger non-physiological functional activation. This study demonstrates the ability to illuminate cortical layers to a depth of several millimeters using pulsed red light without detrimental thermal damages.

Pharmacological dopamine replacement therapies provide the most well-established treatments for Parkinson's disease (PD). However, these long-term treatments can lead to motor complications and off-target effects. ProSavin(®), a lentiviral vector (LV)-based gene therapy approach aimed at restoring local and continuous dopamine production, through delivery of three enzymes in the dopamine biosynthesis pathway, was demonstrated to be safe and well-tolerated in a phase I/II clinical study of patients with advanced PD. Although improvements in motor behaviour were observed, the data indicated that higher levels of dopamine replacement might be required to maximize benefit. We attempted to increase production of dopamine, and its precursor L-Dopa in LV-transduced cells, by optimizing the gene order in the ProSavin expression cassette, and by creating fusions of two or three of the transgenes, using linker sequences. In vitro analysis showed that several gene arrangements provided significantly increased dopamine and/or L-Dopa production compared with ProSavin, and that LV titers and transgene expression were not affected by introducing gene fusions. One vector, equine infectious anemia virus (EIAV)-TCiA, was selected for further characterization and showed significant improvements in dopamine and L-Dopa production compared with ProSavin, in human neuronal cells. Further characterization of EIAV-TCiA demonstrated expression of all three dopamine enzymes in vivo and faithful delivery and integration of the expected gene expression cassette within the genome of target cells, as assessed by Northern and Southern blotting. In conclusion, we have developed a novel LV vector with an increased capacity for L-Dopa and dopamine production compared with the current ProSavin vector. Clinical evaluation of this vector will be performed to assess the benefits in patients with PD.

OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established therapy for motor symptoms in patients with pharmacoresistant Parkinson's disease (PD). However, the procedure, which requires multimodal perioperative exploration such as imaging, electrophysiology, or clinical examination during macrostimulation to secure lead positioning, remains challenging because the STN cannot be reliably visualized using the gold standard, T2-weighted imaging (T2WI) at 1.5 T. Thus, there is a need to improve imaging tools to better visualize the STN, optimize DBS lead implantation, and enlarge DBS diffusion. METHODS Gradient-echo sequences such as those used in T2WI suffer from higher distortions at higher magnetic fields than spin-echo sequences. First, a spin-echo 3D SPACE (sampling perfection with application-optimized contrasts using different flip angle evolutions) FLAIR sequence at 3 T was designed, validated histologically in 2 nonhuman primates, and applied to 10 patients with PD; their data were clinically compared in a double-blind manner with those of a control group of 10 other patients with PD in whom STN targeting was performed using T2WI. RESULTS Overlap between the nonhuman primate STNs segmented on 3D-histological and on 3D-SPACE-FLAIR volumes was high for the 3 most anterior quarters (mean [± SD] Dice scores 0.73 ± 0.11, 0.74 ± 0.06, and 0.60 ± 0.09). STN limits determined by the 3D-SPACE-FLAIR sequence were more consistent with electrophysiological edges than those determined by T2WI (0.9 vs 1.4 mm, respectively). The imaging contrast of the STN on the 3D-SPACE-FLAIR sequence was 4 times higher (p < 0.05). Improvement in the Unified Parkinson's Disease Rating Scale Part III score (off medication, on stimulation) 12 months after the operation was higher for patients who underwent 3D-SPACE-FLAIR-guided implantation than for those in whom T2WI was used (62.2% vs 43.6%, respectively; p < 0.05). The total electrical energy delivered decreased by 36.3% with the 3D-SPACE-FLAIR sequence (p < 0.05). CONCLUSIONS 3D-SPACE-FLAIR sequences at 3 T improved STN lead placement under stereotactic conditions, improved the clinical outcome of patients with PD, and increased the benefit/risk ratio of STN-DBS surgery.

Introduction: The aims of this study were to validate the French version of the SCales for Outcomes in Parkinson's Disease-PsychoSocial (SCOPA-PS) in individuals with Parkinson's disease (PD) who underwent deep brain stimulation of the subthalamic nucleus (DBS-STN), to confirm the unifactorial structure of this questionnaire, and to establish its psychometric properties., Methods: Routinely used psychological questionnaires (BDI-II, STAI-Y, PDQ-39, UPDRS III) and the SCOPA-PS were used for a cross-sectional observational study of 154 PD patients. SCOPA-PS acceptability, scaling assumption, reliability, ordinal confirmatory factor analysis and validity were assessed., Results: The ICC for two-week test-retest reliability was 0.88. SEM was 8.42. In confirmatory factor analysis, the one-factor model showed an acceptable fit to the data (Chi(2)/df=2.130; CFI=0.976; RMSEA=0.086). No floor or ceiling effects were observed. Skewness was 0.33. Item-total correlation coefficients ranged from 0.47 to 0.71. Cronbach's alpha was 0.86. SCOPA-PS SI correlated with PDQ-39 SI (rs=0.83) and with state-anxiety and depression (rs=0.56 and 0.69 respectively). The SCOPA-PS SI was higher in more depressed patients and in those with the most severe PD motor symptoms., Conclusion and Discussion: SCOPA-PS French version is a one-factor scale with satisfactory psychometric properties consistent with other language versions. This short scale can be used to evaluate the psychosocial component of QoL in PD patients treated with DBS-STN., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

This paper develops a new closed-loop firing rate regulation strategy for a population of neurons in the subthalamic nucleus, derived using a model-based analysis of the basal ganglia. The system is described using a firing rate model, in order to analyse the generation of beta-band oscillations. On this system, a proportional regulation of the firing rate reduces the gain of the subthalamo-pallidal loop in the parkinsonian case, thus impeding pathological oscillation generation. A filter with a well-chosen frequency is added to this proportional scheme, in order to avoid a potential instability of the feedback loop due to actuation and measurement delays. Our main result is a set of conditions on the parameters of the stimulation strategy that guarantee both its stability and a prescribed delay margin. A discussion on the applicability of the proposed method and a complete set of mathematical proofs is included.

Several disorders are related to pathological brain oscillations. In the case of Parkinson's disease, sustained low-frequency oscillations (especially in the β-band, 13-30 Hz) correlate with motor symptoms. It is still under debate whether these oscillations are the cause of parkinsonian motor symptoms. The development of techniques enabling selective disruption of these β-oscillations could contribute to the understanding of the underlying mechanisms, and could be exploited for treatments. A particularly appealing technique is Deep Brain Stimulation (DBS). With clinical electrical DBS, electrical currents are delivered at high frequency to a region made of potentially heterogeneous neurons (the subthalamic nucleus (STN) in the case of Parkinson's disease). Even more appealing is DBS with optogenetics, which is until now a preclinical method using both gene transfer and deep brain light delivery and enabling neuromodulation at the scale of one given neural network. In this work, we rely on delayed neural fields models of STN and the external Globus Pallidus (GPe) to develop, theoretically validate and test in silico a closed-loop stimulation strategy to disrupt these sustained oscillations with optogenetics. First, we rely on tools from control theory to provide theoretical conditions under which sustained oscillations can be attenuated by a closed-loop stimulation proportional to the measured activity of STN. Second, based on this theoretical framework, we show numerically that the proposed closed-loop stimulation efficiently attenuates sustained oscillations, even in the case when the photosensitization effectively affects only 50% of STN neurons. We also show through simulations that oscillations disruption can be achieved when the same light source is used for the whole STN population. We finally test the robustness of the proposed strategy to possible acquisition and processing delays, as well as parameters uncertainty.

Optogenetic neuromodulation techniques, which have emerged during the last 15 years, have considerably enhanced our ability to probe the functioning of neural circuits by allowing the excitation and inhibition of genetically-defined neuronal populations using light. Having gained tremendous popularity in the field of fundamental neuroscience, these techniques are now opening new therapeutic avenues. Optogenetic neuromodulation is a method of choice for studying the physiopathology of neurological and neuropsychiatric disorders in a range of animal models, and could accelerate the discovery of new therapeutic strategies. New therapeutic protocols employing optogenetic neuromodulation may also emerge in the near future, offering promising alternative approaches for disorders which lack appropriate treatments, such as pharmacoresistant epilepsy and inherited retinal degeneration., (© 2015 médecine/sciences – Inserm.)

Study Objectives: To explore the influence of acute bilateral ventral intermediate thalamic nucleus (VIM) stimulation on sleep., Design: Three consecutive full-night polysomnography recordings were made in the laboratory. After the habituation night, a random order for night ON-stim and OFF-stim was applied for the second and third nights., Setting: Sleep disorders unit of a university hospital., Patients: Eleven patients with bilateral stimulation of the ventral intermediate nucleus of the thalamus (VIM) for drug-resistant tremor., Measurements: Sleep measures on polysomnography., Results: Total sleep time was reduced during night ON-stim compared to OFF- stim, as well as rapid eye movement sleep percentage while the percentage of N2 increased. Wakefulness after sleep onset time was increased., Conclusion: Our results show that bilateral stimulation of the VIM nuclei reduces sleep and could be associated with insomnia., (© 2015 Associated Professional Sleep Societies, LLC.)

Background/Aims: Evaluation of tremor constitutes a crucial step from the diagnosis to the initial treatment and follow-up of patients with essential tremor. The severity of tremor can be evaluated using clinical rating scales, accelerometry, or electrophysiology. Clinical scores are subjectively given, may be affected by intra- and interevaluator variations due to different experience, delays between consultations, and subtle changes in tremor severity. Existing medical devices are not routinely used: they are expensive, time-consuming, not easily accessible. We aimed at showing that a smartphone application using the accelerometers embedded in smartphones is effective for quantifying the tremor of patients presenting with essential tremor. Methods: We developed a free iPhone/iPod application, Itremor, and evaluated different parameters on 8 patients receiving deep brain stimulation of the ventral intermediate nucleus of the thalamus: average and maximum accelerations, time above 1 g of acceleration, peak frequency, typical magnitude of tremor, for postural and action tremors, on and off stimulation. Results: We demonstrated good correlations between the parameters measured with Itremor and clinical score in all conditions. Itremor evaluation enabled higher discriminatory power and degree of reproducibility than clinical scores. Conclusion: Itremor can be used for routine objective evaluation of essential tremor, and may facilitate adjustment of the treatment. © 2015 S. Karger AG, Basel.

The introduction of robotics into surgery represents progression in the field of minimally invasive surgery. Its use has been reported in coronary artery bypass graft along with repair of other major vascular structures. We report the first case of robot-assisted resection of a large hepatic artery aneurysm. Robotic surgery is safe and feasible and is a significant advance in the field of aneurismal repair. It offers significant advantages in the degrees of freedom of movement compared to laparoscopic surgery.

Epidural spinal cord stimulation (SCS) is currently proposed to treat intractable neuropathic pain. Since the 1970s, isolated cases and small cohorts of patients suffering from dystonia, tremor, painful leg and moving toes (PLMT), or Parkinson’s disease were also treated with SCS in the context of exploratory clinical studies. Despite the safety profile of SCS observed in these various types of movement disorders, the degree of improvement of abnormal movements following SCS has been heterogeneous among patients and across centers in open-label trials, stressing the need for larger, randomized, double-blind studies. This article provides a comprehensive review of both experimental and clinical studies of SCS application in movement disorders.

Background: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease., Methods: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439., Findings: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline., Interpretation: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients., Funding: Oxford BioMedica., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Patients with Parkinson's disease frequently complain of sleep disturbances and loss of muscle atonia during rapid-eye-movement (REM) sleep is not rare. The orexin-A (hypocretin-1) hypothalamic system plays a central role in controlling REM sleep. Loss of orexin neurons results in narcolepsy-cataplexy, a condition characterized by diurnal sleepiness and REM sleep without atonia. Alterations in the orexin-A system have been also documented in Parkinson's disease, but whether these alterations have clinical consequences remains unknown., Methods: Here, we measured orexin-A levels in ventricular cerebrospinal fluid from eight patients with Parkinson's disease (four males and four females) who underwent ventriculography during deep brain-stimulation surgery and performed full-night polysomnography before surgery., Results: Our results showed a positive correlation between orexin-A levels and REM sleep without muscle atonia., Conclusion: Our results suggest that high levels of orexin-A in Parkinson's disease may be associated with loss of REM muscle atonia.

Objective: Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS., Methods: Clinical, morphologic (brain MRI, (123)I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women., Results: A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal (123)I-ioflupane SPECT. Unified Parkinson's Disease Rating Scale motor score was correlated to abnormal (123)I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04)., Conclusions: We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.

Background and Purpose: Despite the rapid development of neuropharmacotherapy, medical treatment of neuropathic pain (NP) still constitutes a significant socioeconomic problem. The authors herein present a group of patients treated with motor cortex stimulation (MCS) for NP of various types and aetiologies., Material and Methods: Our cohort included 12 female and 11 male NP patients aged 53 ± 16 treated with MCS. Eleven patients were diagnosed with neuropathic facial pain (NFP), 8 with hemi-body neuropathic pain (HNP), and 4 with deafferentation pain (DP). Prior to surgery, 16 out of 23 patients were treated with repetitive transcranial magnetic stimulation (rTMS), with a positive response in 10 cases. Pain intensity in our group was evaluated with the visual analogue scale (VAS) one month before and three months after MCS implantation., Results: Improvement on the VAS was reported in the whole group of patients (p < 0.001). The best results were reported in the NFP group (p < 0.001) while the worst ones were noted in the DP group (p = 0.04). Anamnesis duration positively correlated with outcome. Infection forced the authors to permanently remove the system in one case. There were no other complications in the group., Conclusions: Minimally invasive, safe neuromodulative treatment with MCS permits neuropathic pain control with good efficacy. The type of neuropathic pain might be a prognostic factor.

Background: Deep brain stimulation improves motor function and quality of life in patients with Parkinson's disease. The impact of these changes on patients' spouses is largely unknown., Methods: Twenty-six spouses of patients undergoing surgery were evaluated before and 12 months after surgery, using the 36-Item Short Form Health Survey for quality of life, the Beck Depression Inventory, and the Zarit Burden Inventory., Results: The spouses' mean mood and quality of life scores changed little, while burden improved in younger spouses. There was no significant change in the spouses' overall status. However, at the individual level the effect of surgery was more frequently negative than positive. Changes in psychological status and quality of life in the spouses did not correlate with changes in the patients' motor status or quality of life., Conclusions: Spouses' experience of neurostimulation for Parkinson's disease is variable and complex. The improvement in burden experienced by younger spouses may reflect a greater capacity to cope with new situations., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Surgical options of multiple sclerosis (MS) tremor treatment are limited and narrowed to thalamotomy or deep brain stimulation of the thalamic nucleus ventralis intermedius. Lack of qualification protocol frequently results in poor outcome., Objective: To determine prospectively the efficacy and safety of unilateral ventralis intermedius deep brain stimulation as a tool to control disabling kinetic arm tremor related to MS., Methods: Neurological and neuropsychological evaluations were performed 1 month and 1 day before surgery and 1, 3, and 6 months after surgery. The evaluation included measurement of tremor and dexterity, Extended Disability Status Scale, Mini Mental State Examination, and quality-of-life assessment. Nine consecutive patients were enrolled in the group. Mean age at the time of surgery was 38.9 ± 9 years; median Extended Disability Status Scale at baseline was 7.1. Mean MS duration was 11.7 years, and mean tremor duration was 6.11 years. Mean postural and kinetic scores and hand capacity were measured., Results: One month after surgery, median scores off and on stimulation were 12 and 6 for postural tremor, 12 and 10.5 for kinetic tremor score, 12 and 7.5 for manual capacity, and 22 and 20 for functional handicap, respectively. Similar results were 10 and 4, respectively, at the 3-month follow-up. Six months after surgery, median scores off and on stimulation were 10.4 and 4 for postural tremor and 12 and 7.8 for kinetic tremor, respectively., Conclusion: This prospective study confirms the value and safety of ventralis intermedius deep brain stimulation for treatment of kinetic tremor related to MS. Accurate and precise presurgical qualification plays a key role in successful treatment.

Supporting the hypothesis that proteasome dysfunction is involved in Parkinson's disease (PD), McNaught et al. (2004) reported that the systemic administration of the proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde (PSI) in rats led to the degeneration of the nigrostriatal pathway. However, several groups could not reproduce this finding. We herein attempted to improve the reliability of the PSI model by chronically delivering the inhibitor using osmotic minipumps in aged mice. We also tested whether PSI co-administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could act synergistically to induce toxicity. We found that PSI produced a significant reduction in locomotor activity that was mildly exacerbated by MPTP. However, PSI alone produced no sign of degeneration of the nigrostriatal dopaminergic pathway and did not exacerbate MPTP toxicity. To conclude, PSI administration does not provide a reliable phenotypic model of PD., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Subcortical nuclei are increasingly targeted for deep brain stimulation (DBS) and for gene transfer to treat neurological and psychiatric disorders. For a successful outcome in patients, it is critical to place DBS electrodes or infuse viral vectors accurately within targeted nuclei. However current MRI approaches are still limited to localize brainstem and basal ganglia nuclei accurately. By combining ultra-high resolution structural MRI and contrast-enhanced MRI using iron oxide nanoparticles at high field (3T and 7T), we could precisely locate the subcortical nuclei, in particular the subthalamic nucleus in macaques, and validate this location by intracranial electrophysiological mapping. The present data pave the way to a clinical application., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Over the last few years, deep brain stimulation (DBS) with targets such as the subthalamic nucleus or the pallidum were found to be beneficial in the treatment of Parkinson's disease and dystonia. The investigation of the mechanisms of action of DBS by recording concomitant neural activities in basal ganglia is hampered by the large stimulus artefacts (SA). Approaches to remove the SA with conventional filters, or other conventional digital methods, are not always effective due to the significant overlap between the spectral contents of the neuronal signal and the SA. Thus, such approaches may produce a significant residual SA or alter the neuronal signal dynamics by removing its frequency contents. In this work, we propose a method based on an on-line SA template extraction and on the Ensemble empirical mode decomposition (EEMD) to automatically detect and remove the dynamics of the SA without altering the embedded dynamics of the neuronal signal during stimulation. The results, based on real signals recorded in the subthalamic nucleus during Motor cortex stimulation (MCS) experiments, show that this technique, which may be applied on-line, effectively identifies, separates and removes the SA, and uncovers neuronal potentials superimposed on the artefact., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: This study examined changes in motor function and quality of life (QoL) after subthalamic nuclei deep brain stimulation (STN-DBS) in patients with Parkinson disease (PD) and the role of psychosocial predictors on individual changes., Methods: Forty-one patients with advanced PD (29 men and 12 women; mean age: 62.0 ± 8.0; disease duration: 14.5 ± 5.7) completed self-report questionnaires before surgery and at 6 and 12 months after surgery. Psychosocial measures assessed coping strategies (Ways of Coping Checklist-Revised), symptoms of depression (Beck Depression Inventory version II), anxiety (State-Trait Anxiety Inventory), and QoL (Parkinson Disease Questionnaire 39 Items, Medical Outcomes Study 36-Item Short-Form Health Survey)., Results: After surgery, motor function (Unified Parkinson Disease Rating Scale III and IV), global QoL (Parkinson Disease Questionnaire 39 Items) and Physical Component Summary of the Medical Outcome Study Short Form 36-items Health Survey improved, whereas the Mental Component Summary tended to deteriorate. Depression and anxiety were stable. Improvements in motor function and QoL were associated with younger age, shorter duration of illness, higher baseline distress (depression and anxiety), and changes in problem-focused coping. Improvements in mental QoL were associated with a less frequent use of coping focused on seeking social support., Conclusions: STN-DBS is associated with major positive changes in PD affecting motor function and QoL. These changes are related to psychological variables, including emotional distress and coping. A better focus on these individual characteristics is necessary to improve care of patients with PD who undertake STN-DBS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The authors describe the case of a 35-year-old woman with a history of an addiction to cigarette smoking who presented with an intracerebral hemorrhage from a ruptured arteriovenous malformation. The patient reported an immediate and complete disruption of her addiction to cigarette smoking following her stroke. Structural MR imaging revealed a lesion of the posterior cingulate cortex. Neuropsychological tests showed intact cognitive functioning. This observation suggests that the posterior cingulate cortex may play a role in the addiction to cigarette smoking.

In Parkinson's disease, degeneration of specific neurons in the midbrain can cause severe motor deficits, including tremors and the inability to initiate movement. The standard treatment is administration of pharmacological agents that transiently increase concentrations of brain dopamine and thereby discontinuously modulate neuronal activity in the striatum, the primary target of dopaminergic neurons. The resulting intermittent dopamine alleviates parkinsonian symptoms but is also thought to cause abnormal involuntary movements, called dyskinesias. To investigate gene therapy for Parkinson's disease, we simulated the disease in macaque monkeys by treating them with the complex I mitochondrial inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which induces selective degeneration of dopamine-producing neurons. In this model, we demonstrated that injection of a tricistronic lentiviral vector encoding the critical genes for dopamine synthesis (tyrosine hydroxylase, aromatic L-amino acid decarboxylase, and guanosine 5'-triphosphate cyclohydrolase 1) into the striatum safely restored extracellular concentrations of dopamine and corrected the motor deficits for 12 months without associated dyskinesias. Gene therapy-mediated dopamine replacement may be able to correct Parkinsonism in patients without the complications of dyskinesias.

The survival outcome of patients suffering from gliomas is directly linked to the complete surgical resection of the tumour. To help the surgeons to delineate precisely the boundaries of the tumour, we developed an intraoperative positron probe with background noise rejection capability. The probe was designed to be directly coupled to the excision tool such that detection and removal of the radiolabelled tumours could be simultaneous. The device consists of two exchangeable detection heads composed of clear and plastic scintillating fibres. Each head is coupled to an optic fibre bundle that exports the scintillating light to a photodetection and processing electronic module placed outside the operative wound. The background rejection method is based on a real-time subtraction technique. The measured probe sensitivity for (18)F was 1.1 cps kBq(-1) ml(-1) for the small head and 3.4 cps kBq(-1) ml(-1) for the large head. The mean spatial resolution was 1.6 mm FWHM on the detector surface. The gamma-ray rejection efficiency measured by realistic brain phantom modelling of the surgical cavity was 99.4%. This phantom also demonstrated the ability of the probe to detect tumour discs as small as 5 mm in diameter (20 mg) for tumour-to-background ratios higher than 3:1 and with an acquisition time around 4 s at each scanning step. These results indicate that our detector could be a useful complement to existing techniques for the accurate excision of brain tumour tissue and more generally to improve the efficiency of radio-guided cancer surgery.

A higher than expected frequency of suicide has been reported among patients undergoing subthalamic nucleus deep brain stimulation (STN DBS) for advanced Parkinson's disease (PD). We conducted a retrospective survey of 200 patients with PD who underwent STN DBS. Two patients (1%) committed suicide and four (2%) attempted suicide, despite clear motor improvements. Suicidal patients did not differ from non-suicidal patients with respect to age, disease duration or preoperative depressive and cognitive status. Suicidal behaviour was associated with postoperative depression and/or altered impulse regulation. Suicidal behaviour is a potential hazard of STN DBS, calling for careful preoperative assessment and close postoperative psychiatric and behavioural follow-up.

Huntington's disease (HD) is a neurological disorder characterized by striatal degeneration, motor symptoms and complex neuropsychiatric alterations. There is currently no genetic model of HD in non-human primates (NHPs). In this study we investigated neuropathological and behavioral changes following injections of lentiviral vectors encoding a fragment of mutated huntingtin (Htt171-82Q) into the dorsolateral sensorimotor putamen of macaques. In the first study, we injected Htt171-82Q into one hemisphere and a lentiviral vector encoding Htt171-19Q or saline into the other, and studied the animals for 9 weeks. During this period, when apomorphine was administered into Htt171-19Q/82Q animals, it induced progressive chorea, dystonia and ipsilateral turning behavior, whereas animals infected with Htt171-19Q/19Q showed no abnormal behavior. After 9 weeks, the putamen of animals infected with Htt171-82Q presented neuritic and nuclear Htt aggregates, reactive astrocytes and loss of the neuronal marker NeuN. In a second study, we injected Htt171-82Q bilaterally into the dorsolateral putamen. From week 15 after infection, these animals progressively developed spontaneous dyskinesia of the legs, arms, and trunk and, in one case, tics that persisted for up to 30 weeks. The present study constitutes a proof-of-principle for the development of a genetic model of HD in NHP.

Aging is the most prominent risk factor for Parkinson's disease. Yet, consensus of how advancing age may predispose the dopamine (DA) system to parkinsonism is lacking. Three age ranges of female rhesus monkeys, 8-9, 15-17, and 21-31 years, received unilateral DA depletion with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Morphological and biochemical analyses of DA-depleted and intact hemispheres revealed three primary findings: (1) The intact striatum exhibited age-related declines in dopamine (DA) and homovanillic acid (HVA) that were present by middle age; (2) In the MPTP-treated striatum, the compensatory increase in DA activity was absent in old monkeys; and (3) Age-associated morphological changes included declines in the density of tyrosine hydroxylase (TH) positive fibers in striatum, decreased nigral soma size, and optical density of TH, but no significant loss of neurons. These findings suggest that aging produces changes in the nigrostriatal DA system that approach the threshold for expression of parkinsonian features, and that progressive impairment of plasticity may be central to the role of aging in development of parkinsonism.

Objective: Pain management in patients having a subarachnoid haemorrhage was assessed in French intensive care unit of neurosurgical centres., Study Design: Nationwide survey., Methods: A standardized postal questionnaire was sent to senior doctor of every neurosurgical centres in France inquiring pain scores assessment, analgesics used and their routes of administration, centre's opinion about efficacy of pain management., Results: Of the 34 centres, 24 returned completed questionnaires. Fifty four per cent of the centres evaluated pain intensity with a non valid pain score. In the case of patients in the comatose, pain was not evaluated in fifty four per cent of the centres. Paracetamol and morphine were the most currently used analgesics drugs. Morphine was administered subcutaneously by 75% of the centres. Six centres used also PCA. Thirty-seven percent of the centres were reluctant to use opioids and 75% to use NSAIDS., Conclusion: The majority of the centres considered pain management in patient suffering from subarachnoid haemorrhage (SAH) was not optimal and stressed the need to establish a well validated pain rating scale dedicated to SAH patients.

Background: Gliomas are "intraparenchymally metastatic" tumors, invading the brain in a non-destructive way that suggests cooperation between glioma cells and their environment. Recent studies using an engineered rodent C6 tumor cell line have pointed to mechanisms of invasion that involved gap junctional communication (GJC), with connexin 43 as a substrate. We explored whether this concept may have clinical relevance by analyzing the participation of GJC in human glioblastoma invasion., Results: Three complementary in vitro assays were used: (i) seeding on collagen IV, to analyze homocellular interactions between tumor cells (ii) co-cultures with astrocytes, to study glioblastoma/astrocytes relationships and (iii) implantation into organotypic brain slice cultures, that mimic the three-dimensional parenchymal environment. Carbenoxolone, a potent blocker of GJC, inhibited cell migration in the two latter models. It paradoxically increased it in the first one. These results showed that homocellular interaction between tumor cells supports intercellular adhesion, whereas heterocellular glioblastoma/astrocytes interactions through functional GJC conversely support tumor cell migration. As demonstrated for the rodent cell line, connexin 43 may be responsible for this heterocellular functional coupling. Its levels of expression, high in astrocytes, correlated positively with invasiveness in biopsied tumors., Conclusions: our results underscore the potential clinical relevance of the concept put forward by other authors based on experiments with a rodent cell line, that glioblastoma cells use astrocytes as a substrate for their migration by subverting communication through connexin 43-dependent gap junctions.

A concept in Parkinson's disease postulates that motor cortex may pattern abnormal rhythmic activities in the basal ganglia, underlying the genesis of observed motor symptoms. We conducted a preclinical study of electrical interference in the primary motor cortex using a chronic MPTP primate model in which dopamine depletion was progressive and regularly documented using 18F-DOPA positron tomography. High-frequency motor cortex stimulation significantly reduced akinesia and bradykinesia. This behavioral benefit was associated with an increased metabolic activity in the supplementary motor area as assessed with 18-F-deoxyglucose PET, a normalization of mean firing rate in the internal globus pallidus (GPi) and the subthalamic nucleus (STN), and a reduction of synchronized oscillatory neuronal activities in these two structures. Motor cortex stimulation is a simple and safe procedure to modulate subthalamo-pallido-cortical loop and alleviate parkinsonian symptoms without requiring deep brain stereotactic surgery.

Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.

Diffuse invasion of the brain, an intrinsic property of gliomas, renders these tumours incurable, and is a principal determinant of their spatial and temporal growth. Knowledge of the invasive potential of gliomas is highly desired in order to understand their behaviour in vivo. Comprehensive ex vivo invasion studies including tumours of different histological types and grades are however lacking, mostly because reliable physiological invasion assays have been difficult to establish. Using an organotypic rodent brain slice assay, we evaluated the invasiveness of 42 grade II-IV glioma biopsy specimens, and correlated it with the histological phenotype, the absence or presence of deletions on chromosomes 1p and 19q assessed by fluorescent in situ hybridisation, and proliferation and apoptosis indices assessed by immunocytochemistry. Oligodendroglial tumours with 1p/19q loss were less invasive than astrocytic tumours of similar tumour grade. Correlation analysis of invasiveness cell proliferation and apoptosis further suggested that grade II-III oligodendroglial tumours with 1p/19q loss grow in situ as relatively circumscribed compact masses in contrast to the more infiltrative and more diffuse astrocytomas. Lower invasiveness may be an important characteristic of oligodendroglial tumours, adding to our understanding of their more indolent clinical evolution and responsiveness to therapy.

Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor with restorative effects in a variety of rodent and primate models of Parkinson's disease (PD), could be of therapeutic value to PD. In this study, we show that intraventricular chronic infusion of low doses of GDNF using encapsulated genetically engineered C2C12 cells can exert: (1) transient recovery of motor deficits (hypokinesia); (2) significant protection of intrinsic striatal dopaminergic function in the immediate vicinity of the site of implantation of the capsule in the caudate nucleus, and (3) significant-long-lasting-neurotrophic properties at the nigral level with an increase volume of the cell bodies. These observations confirm the potent neurorestorative potential of GDNF in PD and the safety/efficacy of the encapsulation technology as a means to deliver in situ this neurotrophic cytokine even using an intraventricular approach.

Huntington's disease is a hereditary disease in which degeneration of neurons in the striatum leads to motor and cognitive deficits. Foetal striatal allografts reverse these deficits in phenotypic models of Huntington's disease developed in primates. A recent open-label pilot study has shown some clinical improvement or stabilization in three out of five Huntington's disease patients who received bilateral striatal grafts of foetal neurons. We show here that the clinical changes in these three patients were associated with a reduction of the striatal and cortical hypometabolism, demonstrating that grafts were able to restore the function of striato-cortical loops. Conversely, in the two patients not improved by the grafts, striatal and cortical hypometabolism progressed over the 2-year follow-up. Finally, detailed anatomical-functional analysis of the grafted striata, enabled by the 3D fusion of MRI and metabolic images, revealed considerable heterogeneity in the anatomic and metabolic profiles of grafted tissue, both within and between Huntington's disease patients. Our results demonstrate the usefulness of PET measurements of brain glucose metabolism in understanding the effects of foetal grafts in patients with Huntington's disease.

Three cases of bacterial brain abscesses, in immunocompetent patients, are reported. In all these cases, the diffusion-weighted magnetic resonance (MRI) with apparent diffusion coefficient (ADC) map has permitted an early diagnosis and a rapid treatment. This emergency MRI showed in the three cases a low signal on TI-weighted images, a high signal on T2-weighted and echo-planar images, and a decrease of ADC (0.36- 0.49 x 10(-3) mm2/s). So, this new MRI technique provides an available and rapid element in the brain abscess diagnosis which often remains a complex clinical and radiological diagnosis.

Object: The reliable assessment of the invasiveness of gliomas in vitro has proved elusive, because most invasion assays inadequately model in vivo invasion in its complexity. Recently, organotypical brain cultures were successfully used in short-term invasion studies on glioma cell lines. In this paper the authors report that the invasiveness of human glioma biopsy specimens directly implanted into rodent brain slices by using the intraslice implantation system (ISIS) can be quantified with precision. The model was first validated by the demonstration that, in long-term studies, established glioma cells survive in the ISIS and follow pathways of invasion similar to those in vivo., Methods: Brain slices (400 microm thick) from newborn mice were maintained on millicell membranes for 15 days. Cells from two human and one rodent glioblastoma multiforme (GBM) cell lines injected into the ISIS were detected by immunohistochemistry or after transfection with green fluorescent protein-containing vectors. Preferential migration along blood vessels was identified using confocal and fluorescent microscopy. Freshly isolated (< or = 24 hours after removal) 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-prelabeled human glioma biopsy specimens were successfully implanted in 19 (83%) of 23 cases, including 12 GBMs and seven lower grade gliomas (LGGs). Morphometric quantification of distance and density of tumor cell invasion showed that the GBMs were two to four times more invasive than the LGGs. Heterogeneity of invasion was also observed among GBMs and LGGs. Directly implanted glioma fragments were more invasive than spheroids derived from the same biopsy specimen., Conclusions: The ISIS combines a high success rate, technical simplicity, and detailed quantitative measurements and may, therefore, be used to study the invasiveness of biopsy specimens of gliomas of different grades.

The primate striatum contains tyrosine hydroxylase (TH)-immunoreactive (ir) neurons, the numbers of which are augmented after dopamine depletion. Glial cell line-derived neurotrophic factor (GDNF) strongly modulates the viability and phenotypic expression of dopamine ventral mesencephalic neurons. The effect of GDNF on TH-ir neurons intrinsic to the striatum has yet to be investigated. In the present study, stereological counts of TH-ir striatal neurons in aged and parkinsonian nonhuman primates revealed that GDNF delivered via a lentiviral vector (lenti-) further increased the number of these cells. Aged monkeys treated with lenti-GDNF displayed an eightfold increase in TH-ir neurons relative to lenti-beta-galactosidase-treated monkeys. Unilateral 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine treatment alone in young monkeys resulted in a bilateral eightfold increase in TH-ir striatal cells. This effect was further magnified sevenfold on the side of lenti-GDNF treatment. These cells colocalized with the neuronal marker neuronal-specific nuclear protein. Some of these cells colocalized with GDNF-ir, indicating that an alteration in phenotype may occur by the direct actions of this trophic factor. Thus, GDNF may mediate plasticity in the dopamine-depleted primate brain, which may serve to compensate for cell loss by converting striatal neurons to a dopaminergic phenotype.

Objective: Huntington's disease is a progressive neurodegenerative disease characterized by movement disorder, cognitive deterioration, and selective striatal degeneration. No effective treatment exists, and thus stable primate models could aid in the development of novel therapies., Methods: Two primate models of Huntington's disease were analyzed: bilateral stereotactic intrastriatal injections of quinolinic acid (QA), and daily systemic intramuscular administration of 3-nitropropionic acid (3-NP) for up to 8 weeks in male Cebus apella monkeys. The animals' behavior was evaluated before, during, and 3 months after administration of the neurotoxin. Magnetic resonance imaging scans of the brain were obtained before and after treatment., Results: Frontal cognitive function as evaluated by object retrieval-detour task test demonstrated a marked deterioration in successful responses, with an increase in barrier reaches in both groups. No significant change in performance of fine motor tasks was observed. QA-treated animals displayed hyperactivity at night. Animals in both groups demonstrated abnormal posture, and the 3-NP-treated group showed spontaneous and apomorphine-induced dystonia and dyskinesia. The QA-treated group displayed large areas of increased signal on T2-weighted images in the caudate and putamen bilaterally. Treatment with 3-NP resulted in smaller lesions. Immunohistochemistry and morphometric analyses revealed that both groups had lesions in the striatum. A large area of neuronal loss with glial sparing was observed in the QA-treated group, including the caudate and putamen bilaterally. The 3-NP-treated group displayed smaller lesions restricted to the dorsolateral putamen., Conclusion: These results suggest that both QA and 3-NP induce behavioral and morphological features that resemble the juvenile and akinetic-rigid variants of Huntington's disease, with the group with 3-NP-induced lesions displaying smaller lesions and spontaneous dyskinesia.

Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.

The neuroprotective properties of cyclosporin A (CsA) are mediated by its ability to prevent mitochondrial permeability transition during exposure to high levels of calcium or oxidative stress. By using the mitochondrial toxin 3-nitropropionic acid (3NP), the present study assessed whether CsA could protect striatal neurons in vitro and in vivo. In vitro, 3NP produced a 20-30% reduction of striatal glutamic acid decarboxylase-immunoreactive (GAD-ir) neurons. A single treatment with CsA protected GAD-ir neurons from 3NP toxicity at lower (0.2 or 1.0 microM), but not at higher (5.0 microM) doses. Similar findings were seen when the cultures were treated twice with cyclosporin. In vivo experiments used the Lewis rat model of Huntington's disease (HD) in which a low 3NP dose was delivered subcutaneously through an osmotic minipump. Rats received unilateral or bilateral intrastriatal saline injections to disrupt the blood-brain barrier (BBB) and facilitate CsA reaching vulnerable neurons. In the first experiment, CsA treated 3NP-lesioned rats displayed significantly more dopamine-and adenosine-3;, 5;-monophosphate-regulated phosphoprotein (DARPP32-ir) neurons ipsilateral to BBB disruption compared to the contralateral intact striatum, indicating that disruption of the BBB maybe necessary for CsA's neuroprotective effects. In the second experiment, stereological counts of DARPP32-ir neurons revealed that CsA protected striatal neurons in a dose-dependent manner following bilateral disruption of the striatal BBB. Rats treated with the higher (15 or 20 mg/kg) but not lower (5 mg/kg) doses of CsA displayed greater numbers of DARRP32-ir striatal neurons relative to vehicle-treated 3NP-lesioned rats. Thus, under conditions in which CsA can gain access to striatal neurons, significant protection from 3NP toxicity is observed. Therefore, CsA or more lipophilic analogues of this compound, may be of potential therapeutic benefit by protecting vulnerable neurons from the primary pathological event observed in HD., (Copyright 2000 Wiley-Liss, Inc.)

Since its description by Dandy in 1922, several techniques have been used to perform third ventriculostomy under endoscopic control. Except for the blunt technique, in which the endoscope is used by itself to create the opening in the floor of the third ventricle, the other techniques require more than one instrument to perforate the floor of the ventricle and enlarge the ventriculostomy. The new device described is a sterilizable modified forceps that allows both the opening of the floor and the enlargement of the ventriculostomy in a simple and effective way. The new device has the following characteristics: 1) the tip of the forceps is thin enough to allow the easy perforation of the floor of the ventricle; 2) the inner surface of the jaws is smooth to avoid catching vessels of the basal cistern; and 3) the outer surface of the jaws has indentations that catch the edges of the opening to prevent them from slipping along the instrument's jaws. The ventricle floor is opened by gentle pressure of the forceps, which is slowly opened so that the edges of the aperture are caught by the distal outer indentation of the jaws, leading to an approximately 4-mm opening of the floor. This device has been used successfully in 10 consecutive patients. This new device allows surgeons to perform third ventriculostomy under endoscopic control in a very simple, quick, and effective way, avoiding the need for additional single-use instruments.

The endoscopic approach of the tumors of the third ventricle interests mainly the colloid cysts but also offers the possibilities of biopsies. Twenty two patients (16 men and 6 women, average age 41 years) presenting with hydrocephalus related to a tumor of the pineal area were treated by a ventriculostomy with attempt at biopsy : they are outside of the limits of this report. Twenty two other patients (15 men, 7 women, average age 39 years) were operated on from 1994 to 1999 for a colloid cyst, and 2 of them were admitted in emergency in sudden coma. The CT scan showed a colloid cyst (hyperdense in 16 patients) associated with an hydrocephalus, except for a patient previously shunted. The diameter of the cyst varied from 4 to 50 mm (average of 20 mm). All the patients were operated on using a rigid endoscope. Among the 20 patients presenting a tumor of the pineal area, a biopsy was possible only in 4 cases (20%). There were no hemorrhage nor neurological disorders. In all the cases, the size and the number of the specimens were sufficient to allow the histological diagnosis. For the patients presenting with colloid cyst, the average follow-up is 2 years. All the preoperative symptoms disappeared except for the memory disorders which were improved. The post-operative Evans index decreased significantly. No residual cyst was observed on the post-operative MRI in 14 patients (63%). Among these patients, an asymptomatic recurrence was observed and remained stable after 44 months of follow-up. A residual cyst was observed in 8 patients (36%), with a diameter from 5 to 25 mm (average 9 mm). No patient required a shunt procedure, and no patient presented hemorrhagic complication. Endoscopy is especially useful in the first line treatment of the colloid cysts of the third ventricle.