NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience.

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

This corrects the article DOI: 10.1038/mp.2016.144.

Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress.

The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress.

Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.

Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.

[Current management of arteriovenous malformations. Retrospective study of 31 cases and literature review]. / Manejo actual de las malformaciones arteriovenosas. Estudio retrospectivo de 31 casos y revisión de la literatura.

OBJECTIVE: To establish some therapeutic criteria about the treatment of AVMs of III, IV and V grade of Spetzler and Martin and to analyse the results in the subgroup of preoperative embolization plus surgery. METHODS: We perform a retrospective analysis of a group of 31 patients with arteriovenous malformations (AVMs) treated in our center between 1999 and 2004. There were 19 women and 12 men, with a mean age of 31.6 years old (range, 1-62a). Their symptoms upon admission were intracranial hemorrhage in 77.4%, seizures in 12.9%, headache, ischemic event and incidental finding in 3.2% each group. Diagnostic angiography was performed in 29 cases and anatomopathologic diagnostic in 2 cases. The malformations were classified with Spetzler and Martin Grading Scale, in 10.3% grade I, 24.1% grade II, 37.9% grade III, 24.1% grade IV and 3.4% grade V. Patients were classified in 6 subgroups of treatment (surgery, embolization, radiosurgery, embolization plus surgery, embolization plus radiosurgery and conservative treatment). RESULTS: AVMs grade III, IV and V (19 patients) were treated with surgery (6 cases), embolization plus surgery (5 cases), but also other kind of treatments (embolization alone, radiosurgery and conservative) were used. Functional results in these groups of patients were 36.8% (7 cases) with no symptoms or slights symptoms (modified Rankin 0-1), 52.6% (10 cases) minor disability (mRankin 2), 5.3% (1 case) moderate disability and 5.3% (1 case) mortality. We observe a high rate of postembolization hemorrhage in the group of patients in which the combination of preoperative embolization plus surgery was used. In these cases, early surgery was performed with a good functional recovery. There was one case of postoperative mortality. CONCLUSION: We should consider some factors like the natural history, clinical presentation (hemorrhage), angiographic features (deep arterial supply, aneurisms), Spetzler and Martin Grading and the clinical condition of the patient before treating a cerebral AVM. In the subgroup of treatment with embolization plus surgery, we recommend to achieve a subtotal preoperative embolization > 50%, not to obliterate more than 50% in one session, to perform staged embolization waiting from 4 to 6 weeks between procedures, and from 1 to 3 weeks between the last embolization and surgery.

The usefulness of 18F-fluorocholine PET/CT in the detection of recurrence of central nervous system primary neoplasms. / Valor de la PET/TC cerebral con 18F-fluorocolina en la detección de recurrencias de neoplasias primarias del sistema nervioso central.

AIM: To study the usefulness of 18F-fluorocholine (FCH) in detecting the recurrence of primary brain tumours. MATERIAL AND METHODS: A prospective study was conducted on brain PET/CT with FCH for compassionate use in 21 patients with suspected recurrence of a primary brain tumour. The distribution by pathology was: three grade ii astrocytomas, three grade iii astrocytomas, one grade ii oligodendroglioma, three grade iii oligodendrogliomas, one grade iii oligoastrocytoma, four glioblastoma multiform, one gliomatosis cerebri, and five meningiomas. Studies in which there was a visually significant uptake in the brain parenchyma were classified as positive. RESULTS: A total of 17 patients were classified as positive, with the results being confirmed by histology (10 cases) or clinical follow-up and imaging, with no false positives or negatives. The mean SUVmax for positive patients was 8.02 and 0.94 for the negative ones, which was significantly different (P=.003) CONCLUSION: PET/CT with FCH shows encouraging results in the evaluation of patients with suspected recurrence of primary brain neoplasms.

Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up.

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome.

Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Across evolution, maternal care is a key source of environmental sensory signals to the developing brain, and a vast body of work has linked quantitative and qualitative aspects of maternal care to emotional outcome in children and animals. However, the fundamental properties of maternal signals, that promote advantageous vs pathological outcomes in the offspring, are unknown and have been a topic of intense study. We studied emotional outcomes of adolescent rats reared under routine or impoverished environments, and used mathematical approaches to analyze the nurturing behaviors of the dams. Unexpectedly, whereas the quantity and typical qualities of maternal care behaviors were indistinguishable in the two environments, their patterns and rhythms differed drastically and influenced emotional outcomes. Specifically, unpredictable, fragmented maternal care patterns translated into high-entropy rates of sensory signals to the offspring in the impoverished cages. During adolescence, these offspring had significant reductions in sucrose preference and in peer-play, two independent measures of the ability to experience pleasure. This adolescent anhedonia, often a harbinger of later depression, was not accompanied by measures of anxiety or helplessness. Dopaminergic pleasure circuits underlying anhedonia are engaged by predictable sequences of events, and predictable sensory signals during neonatal periods may be critical for their maturation. Conversely, unpredictability maternal-derived signals may disrupt these developmental processes, provoking anhedonia. In sum, high-entropy and fragmented patterns of maternal-derived sensory input to the developing brain predicts, and might promote, the development of anhedonia in rodents, with potential clinical implications.

[Intraoperative neurophysiological monitoring of brain stem in a case of cavernoma in the pons]. / Monitorización neurofisiológica intraoperatoria del tronco del encéfalo en un caso de cavernoma en protuberancia.

Neurophysiological monitoring during surgery to avoid damaging of eloquent brain areas is a useful tool. We are performing intraoperative neurophysiological test to locate motor, sensitive and speech areas with cortical stimulation and cranial nerves during cerebellopontine cranial base surgery. Neurophysiological monitoring during brain stem surgery has been less described. Brain stem surgery implies a careful selection of patients for surgery given the high risk of morbidity and mortality. For this reason, conservative treatment is usually indicated when an asymptomatic cavernoma is incidentally found. Instead, when bleeding or neurological deficit appear, operative treatment may be indicated and then the goal of surgery is to avoid the disability linked to the natural history. We present the case of a 29 year old woman with diagnosis of multiple cavernomas. She was admitted at our hospital because she presented weakness and sensitive disturbance of left limbs and dizziness. The CT scan and MRI showed a pontine haemorrhage caused by a cavernous hemangioma. We operated her on using neurophysiological monitoring of VII, VIII, X and XII cranial nerves with electromyographic recordings. Postoperative disability could be reduced with a better knowledge of entry zone into the brain stem and early physiotherapy.

Primer ensayo clínico empleando la estimulación cerebral profunda en pacientes con esquizofrenia resistente / Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial

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Mania following deep brain stimulation for Parkinson's disease.

Three patients with PD developed manic behavior after bilateral implantation of electrodes for deep-brain stimulation (DBS). Common to all three patients were manic symptoms unremitting after levodopa reduction or stimulation "off," lower electrodes positioning caudal to the subthalamic nucleus area, postoperative DBS with the lower contacts (0) of the quadripolar electrodes, and resolution of the manic episodes coinciding with stimulation through higher contacts.

The role of prefrontal regions in the Stroop task.

The Stroop is a classical paradigm that presumably involves the inhibition of automatic responses and is frequently used to assess the frontal lobe functions. We investigated the effect of discrete prefrontal lesions in a Stroop task. A sample of 32 patients with frontal lesions were matched with normal controls by sex, age and years of education. Significant differences between patients and controls were found for errors but not for reaction time. Regression analysis showed that the region most related to errors was the right prefrontal lateral cortex. Left lobectomies did not impair the Stroop performance. Our results favour the role of the right prefrontal cortex in sustained attention, and disagree with the conception of the left prefrontal cortex having a role in the inhibition of verbal automatic responses.

Radiotherapy for supratentorial low-grade gliomas: results and prognostic factors with special focus on tumour volume parameters.

From 1973 to 1990, 67 patients with a diagnosis of low-grade glioma were treated in our hospital. Overall survival was analysed as well as the influence of patient, tumour- and treatment-related factors with special focus on tumour volume parameters. Our study group included 49 patients treated by surgery and post-operative radiotherapy (RT) (40 patients) or post-biopsy irradiation alone (9 patients). Total or almost total resection was performed in 16 patients; partial excision was done in 24. With the available pre-surgery and pre-RT CT-scan and/or MRI images we were able to calculate tumour volumes by measuring the largest tumour dimensions in the three axes D1, D2, D3 and by assuming an ellipsoidal growth (i.e., tumour volume = D1D2D3 pi/6). RT was delivered to involved regions: either the residual tumour volume or the tumour bed. The median RT dose was 56 Gy (45-60, range). The 60- and 90-month overall survival (Kaplan-Meier) was 79% and 67%, respectively. Female sex, > 70% Karnofsky (Kf) score, oligodendroglioma and < 71 cm3 (approximately 5 cm diameter sphere) tumour residuals before RT were associated with better overall survival rates (p < 0.05, log-rank). However, a Cox proportional hazards model showed that only the histological subtype and Kf significantly determined the patients' outcome: 60-month overall survival of 100%, 62%, 83% and 64% for oligodendrogliomas, mixed oligo-astrocytomas and grade-I and grade-II astrocytomas, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous thrombosis of an intracranial aneurysm.

A case of spontaneous thrombosis of a previously ruptured anterior communicating artery aneurysm is reported. The patient was referred by another hospital to our service 4 months after the bleeding episode. He had developed a symptomatic normal pressure hydrocephalus, successfully treated by ventriculoperitoneal shunt. Follow-up angiographies, the first performed 4 months and the second 1 year after the bleeding, did not show the aneurysm. Furthermore, the parent artery was not occluded. The literature relative to the subject is reviewed and the possible mechanisms of spontaneous thrombosis are discussed.

Surgical management of aortic coarctation associated with ruptured cerebral artery aneurysm.

We report two patients with coarctation of the aorta who were admitted to the hospital with ruptured cerebral artery aneurysms. In both patients, we surgically treated the coarctation and later repaired the intracranial lesion. One patient, a 34-year-old woman, is alive and well after 3 years; whereas, the other, a 19-year-old man, did not survive. We discuss the sequence for surgery, which continues to be subjected to debate.

[Cranioencephalic trauma in adults: clinical and radiologic features]. / Traumatismo craneoencefálico del adulto: aspectos clínicos y radiológicos.

BACKGROUND: To analyse extracranial complications and basic variables in head-injury patients, such as Glasgow coma score (GCS), intracranial pressure (ICP) and cranial computerized tomography (CT), in relation to the outcome of these patients. PATIENTS AND METHODS: 64 consecutive patients (47 males and 17 females) with head injury, admitted from January 1992 to May 1994, were studied in this prospective study. Mean age was 37 +/- 18 years. Overall mortality was 23% (15/64). Student-t and Chi-square tests were used for statistical analysis, and p < 0.05 was considered statistical significant. RESULTS: Overall GCS was 7 +/- 3, survivors presenting GCS of 7.7 +/- 2.9 and non-survivors 4.7 +/- 1.5 (p = 0.04). CT were classified as follows: diffuse injury, 4 patients (7%); focal injury, 32 (53%), and mixed injury 24 (40%). Depending on the presence or absence of mesencephalic cisterns in the CT, GSC was 7.6 +/- 2.8 and 4.3 +/- 1.4, respectively (p = 0.04). Subarachnoid hemorrhage (SAH) was associated to a GCS of 6.3 +/- 2.5 and its absence to 8 +/- 3.3 (p = 0.03). The absence of mesencephalic cisterns and SAH were more frequent in the non-survivors, 72% and 32% (p = 0.01 and 0.04), respectively. ICP was recorded in 42 patients. Regarding to ICP, mortality was: 6.7% with ICP < or = 20 mmHg, 37% with ICP 21-30, 44% with ICP 31-40 and 67% with ICP > 50 mmHg (p = 0.03). Diabetes insipidus, cardiorespiratory arrest, shock, prolonged mechanical ventilation, SDRA and sepsis were the most frequent extracranial complications in non-survivors. CONCLUSIONS: There is an association between the outcome of head-injury patients with the GCS and ICP values. Absence of mesencephalic cisterns and SAH were radiologic signs of poor prognosis. Patients who died had more extracranial complications.

[Delayed central pain associated with a sub-insular hematoma followed by parieto-occipital tumor. Favorable effects of chronic stimulation of the ventral posterior thalamic nucleus]. / Dolor central retardado asociado a hematoma subinsular seguido por tumor parietoccipital. Efecto favorable de la estimulación crónica del núcleo VPL talámico.

INTRODUCTION: Déjerine and Roussy reported thalamic syndrome, chronic pain after a vascular lesion in the thalamus, in 1906. Posterior clinical observations allowed know that the same clinical picture can be observed after lesions in other parts of the central nervous system. Due to the fact that the more frequent etiology is vascular, nowadays the term central poststroke pain syndrome is preferred. CLINICAL CASE: We report a patient who suffered a left subinsular hematoma when he was 62 years old. Four years later he started complaining burning constant pain in the right side of the body with crisis of lancinating pain. Also allodynia was observed in the face and right arm. MRI disclosed a necrotic lesion at the level of the left subinsular region. CONCLUSIONS: The lancinating pain and the allodynia were properly controlled by deep brain stimulation with an electrode placed stereotactically at the level of VPL nucleus of the left thalamus. Five months later there was a recurrence of the pain, a CT disclosed a tumour in the parietal region with an important shift of the midline and migration of the electrode out the thalamus. A biopsy disclosed tumoral necrosis. The pathophysiology of the central poststroke pain and effectivity of the deep brain stimulation in this cases are discussed.

[Anesthesia in surgery for epilepsy]. / Anestesia en la cirugía de la epilepsia.

OBJECTIVES: To evaluate the efficacy of general anesthesia during epileptic surgery. MATERIAL AND METHODS: A retrospective study of 64 patients who received general anesthesia during epileptic surgery. In the preoperative period, anticonvulsive medication was adjusted in accordance with plasma levels and withdrawn entirely 8 hours before surgery. After premedication with droperidol and fentanyl, a balanced anesthetic technique was applied, based on pentothal, pancuronium (or vecuronium), fentanyl, N2O and isoflurane. Continuous monitoring of ECG, arterial blood pressure, pulse oximetry, ET CO2 and neuromuscular function. Isoflurane was stopped for 10 min after the opening of the duramadre so that ECoG could be recorded and methohexital or propofol was given in some cases in order to activate the epileptogenic focus. Muscular relaxation was restored intraoperatively following the study of somatosensory evoked potentials. Immediate and later complications related to anesthesia or surgery were recorded. RESULTS: The surgical procedure performed in most cases was temporal or frontal resection, with a mean duration for anesthesia of 377 +/- 50 min and for surgery of 318 +/- 50 min. Only one patient received local anesthesia and no hemodynamic changes were observed. Perioperative complications were cerebral edema (4 cases), arrhythmia (2 cases) and bronchospasm (1 case). Postoperative complications were as follows: 3 of 9 patients undergoing callosotomy required mechanical ventilation for 24 hours, 4 patients experienced language alterations, 3 wounds were infected, 2 cases of hemiplegia were observed, 1 status epilepticus occurred after administration of propofol and there was 1 case of respiratory distress. Anticonvulsive medication was given parenterally after surgery. CONCLUSIONS: General anesthesia is a safe and effective method for epileptic surgery, with local anesthesia providing additional sedation for isolated cases. Appropriate treatment requires an understanding of the pharmacokinetics and pharmacodynamics of the drugs used, as well as knowledge of the condition and the anticonvulsive medications used.