Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression.

Depression is usually associated with alterations in the monoaminergic system. However, new evidences suggest the involvement of the glutamatergic system in the aetiology of depression. Here we explored the glutamatergic system in a rat model of depression (i.e., the flinders sensitive line (FSL)) to reveal the mechanism underlying the emotional and cognitive aspects associated with the disease. We showed a dramatically elevated level of baseline glutamatergic synaptic transmission by whole-cell recordings as well as impairment in long-term potentiation induced by high-frequency stimulation in hippocampal slices from FSL rats compared with Sprague-Dawley rats. At behavioural level, FSL rats displayed recognition memory impairment in the novel object recognition test. Enantioselective chromatography analysis revealed lower levels of D-serine in the hippocampus of FSL rats and both synaptic plasticity and memory impairments were restored by administration of D-serine. We also observed dysfunctional astrocytic glutamate regulation including downregulation of the glia glutamate transporter GLAST as shown by western blot. One possibility is that the dysfunctional astrocytic glutamate reuptake triggers a succession of events, including the reduction of D-serine production as a safety mechanism to avoid NMDA receptor overactivation, which in turn causes the synaptic plasticity and memory impairments observed. These findings open up new brain targets for the development of more potent and efficient antidepressant drugs.

Estimulación cerebral profunda: 12 años de experiencia y 250 pacientes intervenidos con un seguimiento de más de un año / Deep brain stimulation: 12 years experience and 150 patients treated with a follow-up of over a year

Introduction. Deep brain stimulation (DBS) is a widely accepted clinical technique. The main motor symptoms are significantly reduced. The success of the technique depends on the experience of the neurosurgeon, neurologist and neurophysiologist who carry it out. The presentation of extensive series is needed to confirm and further currently held knowledge. Aim. To demonstrate the clinical benefits of a long series of patients treated by a single group with a minimum follow-up of one year and to report new neurophysiological data. Patients and methods. The study examined a total of 250 patients with different diagnoses: most of them with Parkinson’s disease, tremor and dystonia. The nuclei that were chosen were located by magnetic resonance imaging, computerised axial tomography and neurophysiological registers. Neurophysiological exclusion criteria, such as reflex control of heart rate, sympathetic skin response and auditory startle reflex, are employed in order to exclude patients with Parkinson-plus. Results. The motor sub-scale (part III) of the Unified Parkinson’s Disease Rating Scale improves by 64% in the off-medication status with sub-thalamic stimulation at one year after surgery. One year after DBS, patients with dystonia show a significant decrease on the Burke-Fahn-Marsden dystonia scale. The improvement on the scales continues, with a mean descent of 65% in the second year after surgery. Conclusions. DBS is a suitable technique for the treatment of movement disorders. The neuronal activity of the sub-thalamus and the internal globus pallidus presents its own characteristics that reflect the motor symptoms of the patients. Surface electromyography proves to be useful for quantifying the patients’ improvement (AU)

Introducción. La estimulación cerebral profunda (ECP) es una técnica de gran aceptación clínica. Los principales síntomas motores se reducen significativamente. El éxito de la técnica radica en la experiencia del neurocirujano, neurólogo y neurofisiólogo que lo llevan a cabo. La presentación de series extensas es necesaria para confirmar y extender los actuales conocimientos. Objetivo. Demostrar los beneficios clínicos de una larga serie de pacientes intervenidos por un único grupo con un seguimiento mínimo de un año y presentar nuevos datos neurofisiológicos. Pacientes y métodos. Se han estudiado 250 pacientes con diversos diagnósticos; la mayoría con enfermedad de Parkinson, temblor y distonía. Los núcleos elegidos se localizan por resonancia magnética, tomografía axial computarizada y registros neurofisiológicos. Se utilizan criterios de exclusión neurofisiológicos, como el control reflejo de la frecuencia cardíaca, la respuesta simpaticocutánea y el reflejo de sobresalto auditivo, para excluir pacientes con Parkinson-plus. Resultados. La subescala motora (parte III) de la Unified Parkinson’s Disease Rating Scale mejora un 64% en situación off de medicación con la estimulación del subtálamo al año de la cirugía. Los pacientes con distonía muestran, un año después de la ECP, en la escala de distonía Burke-Fahn-Marsden, un descenso significativo. La mejoría en las escalas persiste, con un descenso medio del 65% en el segundo año después de la cirugía. Conclusiones. La ECP es una técnica apropiada para el tratamiento de los trastornos del movimiento. La actividad neuronal del subtálamo y del globo pálido interno presenta características propias que reflejan la sintomatología motora de los pacientes. La electromiografía superficial demuestra ser útil para cuantificar la mejoría de los pacientes (AU)

[Deep brain stimulation: 12 years' experience and 150 patients treated with a follow-up of over a year]. / Estimulación cerebral profunda: 12 años de experiencia y 250 pacientes intervenidos con un seguimiento de más de un año.

INTRODUCTION: Deep brain stimulation (DBS) is a widely accepted clinical technique. The main motor symptoms are significantly reduced. The success of the technique depends on the experience of the neurosurgeon, neurologist and neurophysiologist who carry it out. The presentation of extensive series is needed to confirm and further currently held knowledge. AIM: To demonstrate the clinical benefits of a long series of patients treated by a single group with a minimum follow-up of one year and to report new neurophysiological data. PATIENTS AND METHODS: The study examined a total of 250 patients with different diagnoses: most of them with Parkinson's disease, tremor and dystonia. The nuclei that were chosen were located by magnetic resonance imaging, computerised axial tomography and neurophysiological registers. Neurophysiological exclusion criteria, such as reflex control of heart rate, sympathetic skin response and auditory startle reflex, are employed in order to exclude patients with Parkinson-plus. RESULTS: The motor sub-scale (part III) of the Unified Parkinson's Disease Rating Scale improves by 64% in the off-medication status with sub-thalamic stimulation at one year after surgery. One year after DBS, patients with dystonia show a significant decrease on the Burke-Fahn-Marsden dystonia scale. The improvement on the scales continues, with a mean descent of 65% in the second year after surgery. CONCLUSIONS: DBS is a suitable technique for the treatment of movement disorders. The neuronal activity of the sub-thalamus and the internal globus pallidus presents its own characteristics that reflect the motor symptoms of the patients. Surface electromyography proves to be useful for quantifying the patients' improvement.

Deep brain stimulation in the globus pallidus to treat dystonia: electrophysiological characteristics and 2 years' follow-up in 10 patients.

Deep brain stimulation (DBS) was applied in the internal segment of the globus pallidus (GPi) to treat dystonia in 10 patients. One year after surgery the Burke-Fahn-Marsden movement scores were significantly lower than preoperative values (P=0.01). Two years after surgery the mean decrease reached 65% (P=0.001) with no motor symptoms worsening. Single unity activity was recorded in the operating room: GPi cells discharged with tonic (n=19; 29%), irregular (n=32; 48%), or burst-like activity (n=15; 23%) and fired with a mean discharge rate of 39 Hz+/-22. Some neurons demonstrated an oscillatory activity with periods lasting several seconds. Pairs of pallidal cells (n=8) recorded simultaneously displayed discharge synchronization. Movement modulated 64.4% of the cells tested, with increases in firing in 89% of cells and decreases in firing in 10% of cells. GPi cells responded to flexion and extension movements and to several passive manipulations indicating an important sensory role in dystonia. GPi neurons fired in advance of the electromyography (EMG) when the surface EMG was recorded simultaneously with the neuronal activity. Spectral analysis of the co-contracting muscles during dystonia demonstrated prominent high peaks at a low frequency band (20 Hz) during involuntary and voluntary movements. The high amplitude EMG profile recorded at rest diminished to very low values with GPi stimulation, allowing an ease of voluntary contractions. We conclude that DBS in the GPi is a reliable surgical technique for dystonia. GPi cells discharge with distinct electrophysiological characteristics that may explain some of the symptoms in dystonia. EMG recording in the operating room helps to determine which DBS contacts produce the best benefit.

Pallidal stimulation relieves myoclonus-dystonia syndrome.

A patient with myoclonus-dystonia syndrome was treated by implanting electrodes in the internal segment of the globus pallidus (GPi) and applying deep brain stimulation. Surgery was done in two sessions. The most affected limb was treated first and the other limb one year later. Neuronal recordings showed that most pallidal neurones discharged in bursts at a relatively low firing rate (mean (SD), 46 (18) Hz) compared with cells in the GPi in patients with Parkinson's disease. Neurones modified the rate and mode of discharge with dystonic postures and rapid involuntary contractions of limb muscles. Neurological examination at 24 months after surgery showed a decline of 47.8% and 78.5% in the Burke-Fahn-Marsden and disability rating scales, respectively.