The renin-angiotensin system is upregulated in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis

Purpose: As reported by several authors, angiotensin II (AngII) is a proinflammatory molecule that stimulates the release of inflammatory cytokines and activates nuclear factor kappa B (NF kappa B), being also associated with the increase of cellular oxidative stress. Its production depends on the activity of the angiotensin converting enzyme (ACE) that hydrolyzes the inactive precursor angiotensin I (AngI) into AngII. It has been suggested that AngII underlies the physiopathological mechanisms of several brain disorders such as stroke, bipolar disorder, schizophrenia, and disease. The aim of the present work was to localize and quantify AngII AT1 and AT2 receptors in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis (MTS) submitted to corticoamygdalohippocampectomy for seizure control. Method: Immunohistochemistry, Western blot, and real-time PCR techniques were employed to analyze the expression of these receptors. Results: The results showed an upregulation of AngII AT1 receptor as well as its messenger ribonucleic acid (mRNA) expression in the cortex and hippocampus of patients with MTS. In addition, an increased immunoexpression of AngII AT2 receptors was found only in the hippocampus of these patients with no changes in its mRNA levels. Discussion: These data show, for the first time, changes in components of renin-angiotensin system (RAS) that could be implicated in the physiopathology of MTS.

Tailored resections for intractable rolandic cortex epilepsy in children: a single-center experience with 48 consecutive cases

A single-center experience with pediatric patients who underwent surgery for intractable rolandic epilepsy was reviewed with the aim of identifying putative factors that could influence postoperative seizure outcome in this population. Clinical data of 48 patients under 18 years of age with diagnosis of intractable rolandic epilepsy who underwent surgery from January 1996 to September 2009 were reviewed. Patients` mean age at surgery was 9.9 +/- 5.3 years; mean age at epilepsy onset was 3.9 years; mean seizure duration prior to surgery was 6 years; and mean follow-up was 5.1 years. The most frequent etiologies were cortical dysplasia, astrogliosis, tumors, tuberous sclerosis complex, and Sturge-Weber syndrome, which were observed in 20/48 (41.6%), 10/48 (20.8%), 10/48 (20.8%), 5/48 (10.4%), and 3/48 (6.2%) of the patients, respectively. After surgery, 20 patients (41.6%) showed neurological deficits, which in turn recovered within no longer than 6 months after surgery. Seizure outcome was classified as Engel class I in 29 (60.4%), Engel class II in 10 (20.8%), and Engel class III in 9 (18.8%) of the patients. The factors significantly related with seizure outcome were histological features (tumor versus non-tumor cases, p = 0.04) and lesion site (focal lesions versus non-focal lesions, p = 0.04). Tailored resection of rolandic cortex for intractable epilepsy can be safely performed in children. Accurate mapping of both functional cortex and epileptogenic areas may lead to improved seizure outcome. Tumor as well as focal lesions in hand and face motor areas are associated with good seizure outcome.

Interictal hyperemia correlates with epileptogenicity in polymicrogyric cortex

Objective: To investigate pathophysiological factors underlying the presence of interictal hyper-perfusion within the limits of the polymicrogyric (PMG) cortex in epileptic patients. Methods: Retrospective observational study on interictal perfusion by Single Photon Emission Computed Tomography (SPECT) in 16 patients with PMG and its correlations with a number of clinical and neurophysiological variables. Patients underwent video-EEG monitoring, neurological and psychiatric assessments, invasive EEG, and the interictal SPECT coregistered to Magnetic Resonance Imaging (MRI). Results: Patients with interictal hyperperfusion within the PMG cortex had a significantly higher spike rate on interictal EEG than patients with normal perfusion. Interictal hyperperfusion was not correlated to sex, age at epilepsy onset, age at evaluation, number of seizures per month, presence of initial precipitating insult (IPI), abnormal neurological examination, EEG findings, ictal serniology, and seizure outcome. The high interictal spike rate did not correlate to a high frequency of seizures per month. Conclusions: Our work provides further evidences for an intrinsic epileptogenesis of the PMG cortex during the interictal state, which accounts for the major rote of PMG tissue in seizure generation. These results might help to increase our understanding about epileptogenesis related to the PMG cortex, providing new toots for more tailored epilepsy surgery in PMG patients. (c) 2008 Elsevier B.V. All rights reserved.

Stimulation of 5-HT1A or 5-HT2A receptors in the ventrolateral periaqueductal gray causes anxiolytic-, but not panicolytic-like effect in rats

Evidences from studies using electrical or chemical stimulation of the midbrain periaqueductal gray (PAG) suggest that whereas the dorsal PAG is critical for the regulation of panic-related defensive behaviors, the ventrolateral PAG (vlPAG) modulates generalized anxiety-related responses. In the present study we evaluated whether the activation of 5-HT1A and 5-HT2A/2C receptors in the ventrolateral column of the periaqueductal gray (vlPAG) causes differential effects on an anxiety- and a panic-related defensive behavior, respectively, inhibitory avoidance and escape, in male Wistar rats submitted to the elevated T-maze. Our results showed that intra-vlPAG injection of the endogenous agonist serotonin, the 5-HT1A/7 agonist 8-OH-DPAT or 5-HT2A/2C agonist DOI impaired the acquisition of inhibitory avoidance, without interfering with escape performance. The same selective anxiolytic effect was also observed after local administration of the benzodiazepine receptor agonist midazolam. Moreover, as shown by the results of antagonism studies, 5-HT2A receptors are recruited for the anxiolysis caused by serotonin and DOI. while 5-HT1A receptors account for the effect of 8-OH-DPAT. In conclusion, our data show that the activation of 5-HT1A and 5-HT2A receptors in the vlPAG affects defensive responses related to generalized anxiety, but not panic disorder. (C) 2008 Elsevier B.V. All rights reserved.

Stimulation-Produced Analgesia From the Occipital or Retrosplenial Cortex of Rats Involves Serotonergic and Opioid Mechanisms in the Anterior Pretectal Nucleus

The electrical stimulation of the occipital (OC) or retrosplenial (RSC) cortex produces antinociception in the rat tail-flick test. These cortices send inputs to the anterior pretectal nucleus (APtN) which is implicated in antinociception and nociception. At least muscarinic cholinergic, opioid, and serotonergic mechanisms in the APtN are involved in stimulation-produced antinociception (SPA) from the nucleus. In this study, the injection of 2% lidocaine (.25 mu L) or methysergide (40 and 80 ng/.25 mu L) into the APtN reduced the duration but did not change the intensity of SPA from the OC, whereas both duration and intensity of SPA from the RSC were significantly reduced in rats treated with lidocaine or naloxone (10 and 50 ng/.25 mu L), injected into the ANN. Naloxone or methysegide injected into the APtN was ineffective against SPA from the OC or RSC, respectively. Atropine (100 ng/.25 mu L) injected into the ANN was ineffective against SPA from either the OC or RSC. We conclude that the APtN acts as an intermediary for separate descending pain inhibitory pathways activated from the OC and RSC, utilizing at least serotonin and endogenous opioid as mediators in the nucleus. Perspective: Stimulation-induced antinociception from the retrosplenial or occipital cortex in the rat tail-flick test depends on the activation of separate descending pain inhibitory pathways that utilize the APtN as a relay station. (C) 2011 by the American Pain Society

Cardiovascular responses to noradrenaline microinjection in the ventrolateral periaqueductal gray of unanesthetized rats

The periaqueductal gray area (PAG) is a mesencephalic area involved in cardiovascular modulation. Noradrenaline (NA), a neurotransmitter involved in central blood pressure control, is present in the rat PAG. We report here on the cardiovascular effects caused by NA microinjection into the ventrolateral PAG (vlPAG) of unanesthetized rats and the peripheral mechanism involved in their mediation. NA microinjection in the vlPAG of unanesthetized rats evoked dose-related pressor and bradycardiac responses. No significant cardiovascular responses were observed in urethane-anesthetized rats. The pressor response was potentiated by pretreatment with the ganglion blocker pentolinium (5 or 10 mg/kg, intravenously). Pretreatment with the vasopressin antagonist dTyr(CH(2))(5) (Me)AVP (50 mu g/kg, intravenously) blocked the pressor response evoked by the NA microinjection into the vlPAG. Additionally, circulating vasopressin content was found to be significantly increased after NA microinjection in the vlPAG. The results suggest that activation of noradrenergic synapses within the vlPAG modulates vasopressin release in unanesthetized rats. (c) 2007 Wiley-Liss, Inc.

The ventrolateral periaqueductal gray is involved in the cardiovascular response evoked by L-glutamate microinjection into the lateral hypothalamus of anesthetized rats

Microinjection Of L-glutamate (L-glu: 1, 3, 10 and 30nmol/100nL) into the lateral hypothalamus (LH) caused dose-related depressor and bradycardiac responses. The cardiovascular response to L-glu stimulation of the LH was blocked by pretreatment of the ventrolateral portion of the periaqueductal gray matter (vIPAG) with CoCl(2) (1 mM/100nL), indicating the existence of a synaptic relay of the hypotensive pathway in that area. Furthermore, the response to L-glu Was blocked by pretreatment of the vIPAG with 2 nmol/100 nL of the selective NMDA-receptor antagonist LY235959 and was not affected by pretreatment with 2 nmol/100 nL of the selective non-NMDA-receptor antagonist NBQX, suggesting a mediation of the hypotensive response by NMDA receptors in the APAG. In conclusion, our results indicate that the hypotensive pathway activated by microinjection Of L-glu into the LH involves a NMDA synaptic relay in the vIPAG. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

INTERMITTENT ACTIVATION OF PERIPHERAL CHEMORECEPTORS IN AWAKE RATS INDUCES Fos EXPRESSION IN ROSTRAL VENTROLATERAL MEDULLA-PROJECTING NEURONS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS

Despite the well-established sympathoexcitation evoked by chemoreflex activation, the specific sub-regions of the CNS underlying such sympathetic responses remain to be fully characterized. In the present study we examined the effects of intermittent chemoreflex activation in awake rats on Fos-immunoreactivity (Fos-ir) in various subnuclei of the paraventricular nucleus of the hypothalamus (PVN), as well as in identified neurosecretory preautonomic PVN neurons. In response to intermittent chemoreflex activation, a significant increase in the number of Fos-ir cells was found in autonomic-related PVN subnuclei, including the posterior parvocellular, ventromedial parvocellular and dorsal-cap, but not in the neurosecretory magnocellular-containing lateral magnocellular subnucleus. No changes in Fos-ir following chemoreflex activation were observed in the anterior PVN subnucleus. Experiments combining Fos immunohistochemistry and neuronal tract tracing techniques showed a significant increase in Fos-ir in rostral ventrolateral medulla (RVLM)-projecting (PVN-RVLM), but not in nucleus of solitarii tract (NTS)-projecting PVN neurons. In summary, our results support the involvement of the PVN in the central neuronal circuitry activated in response to chemoreflex activation, and indicate that PVN-RVLM neurons constitute a neuronal substrate contributing to the sympathoexcitatory component of the chemoreflex. Published by Elsevier Ltd on behalf of IBRO.

Modulation of respiratory responses to chemoreflex activation by L-glutamate and ATP in the rostral ventrolateral medulla of awake rats

Moraes DJA, Bonagamba LGH, Zoccal DB, Machado BH. Modulation of respiratory responses to chemoreflex activation by L-glutamate and ATP in the rostral ventrolateral medulla of awake rats. Am J Physiol Regul Integr Comp Physiol 300: R1476-R1486, 2011. First published March 16, 2011; doi:10.1152/ajpregu.00825.2010.-Presympathetic neurons in the different anteroposterior aspects of rostral ventrolateral medulla (RVLM) are colocalized with expiratory [Botzinger complex (BotC)] and inspiratory [pre-Botzinger complex (pre-BotC)] neurons of ventral respiratory column (VRC), suggesting that this region integrates the cardiovascular and respiratory chemoreflex responses. In the present study, we evaluated in different anteroposterior aspects of RVLM of awake rats the role of ionotropic glutamate and purinergic receptors on cardiorespiratory responses to chemoreflex activation. The bilateral ionotropic glutamate receptors antagonism with kynurenic acid (KYN) (8 nmol/50 nl) in the rostral aspect of RVLM (RVLM/BotC) enhanced the tachypneic (120 +/- 9 vs. 180 +/- 9 cpm; P < 0.01) and attenuated the pressor response (55 +/- 2 vs. 15 +/- 1 mmHg; P < 0.001) to chemoreflex activation (n = 7). On the other hand, bilateral microinjection of KYN into the caudal aspect of RVLM (RVLM/pre-BotC) caused a respiratory arrest in four awake rats used in the present study. Bilateral P2X receptors antagonism with PPADS (0.25 nmol/50 nl) in the RVLM/BotC reduced chemoreflex tachypneic response (127 +/- 6 vs. 70 +/- 5 cpm; P < 0.001; n = 6), but did not change the chemoreflex pressor response. In addition, PPADS into the RVLM/BtC attenuated the enhancement of the tachypneic response to chemoreflex activation elicited by previous microinjections of KYN into the same subregion (188 +/- 2 vs. 157 +/- 3 cpm; P < 0.05; n = 5). Our findings indicate that: 1) L-glutamate, but not ATP, in the RVLM/BtC is required for pressor response to peripheral chemoreflex and 2) both transmitters in the RVLM/BtC are required for the processing of the ventilatory response to peripheral chemoreflex activation in awake rats.

High CO(2)/H(+) dialysis in the caudal ventrolateral medulla (Loeschcke`s area) increases ventilation in wakefulness

Central chemoreception, the detection of CO(2)/H(+) within the brain and the resultant effect on ventilation, was initially localized at two areas on the ventrolateral medulla, one rostral (rVLM-Mitchell`s) the other caudal (cVLM-Loeschcke`s), by surface application of acidic solutions in anesthetized animals. Focal dialysis of a high CO(2)/H(+) artificial cerebrospinal fluid (aCSF) that produced a milder local pH change in unanesthetized rats (like that with a similar to 6.6 mm Hg increase in arterial P(CO2)) delineated putative chemoreceptor regions for the rVLM at the retrotrapezoid nucleus and the rostral medullary raphe that function predominantly in wakefulness and sleep, respectively. Here we ask if chemoreception in the cVLM can be detected by mild focal stimulation and if it functions in a state dependent manner. At responsive sites just beneath Loeschcke`s area, ventilation was increased by, on average, 17% (P < 0.01) only in wakefulness. These data support our hypothesis that central chemoreception is a distributed property with some sites functioning in a state dependent manner. (C) 2010 Elsevier B.V. All rights reserved.

Detection of Auditory Cortex Activity by fMRI Using a Dependent Component Analysis

Functional MRI (fMRI) data often have low signal-to-noise-ratio (SNR) and are contaminated by strong interference from other physiological sources. A promising tool for extracting signals, even under low SNR conditions, is blind source separation (BSS), or independent component analysis (ICA). BSS is based on the assumption that the detected signals are a mixture of a number of independent source signals that are linearly combined via an unknown mixing matrix. BSS seeks to determine the mixing matrix to recover the source signals based on principles of statistical independence. In most cases, extraction of all sources is unnecessary; instead, a priori information can be applied to extract only the signal of interest. Herein we propose an algorithm based on a variation of ICA, called Dependent Component Analysis (DCA), where the signal of interest is extracted using a time delay obtained from an autocorrelation analysis. We applied such method to inspect functional Magnetic Resonance Imaging (fMRI) data, aiming to find the hemodynamic response that follows neuronal activation from an auditory stimulation, in human subjects. The method localized a significant signal modulation in cortical regions corresponding to the primary auditory cortex. The results obtained by DCA were also compared to those of the General Linear Model (GLM), which is the most widely used method to analyze fMRI datasets.

Arthrodesis of the equine proximal interphalangeal joint: a biomechanical comparison of 3-Hole 4.5 mm locking compression plate and 3-hole 4.5 mm narrow dynamic compression plate, with two transarticular 5.5 mm cortex screws

Objectives To compare the biomechanical characteristics of 2 arthrodesis techniques for the equine proximal interphalangeal joint (PIP) using either a 3-hole 4.5 mm locking compression plate (LCP) or 3-hole 4.5 mm narrow dynamic compression plate (DCP), both with 2 transarticular 5.5 mm cortex screws. Study Design Experimental. Sample Population Cadaveric adult equine forelimbs (*n=6 pairs). Methods For each forelimb pair, 1 limb was randomly assigned to 1 of 2 treatment groups and the contralateral limb by default to the other treatment group. Construct stiffness, gap formation across the PIP joint, and rotation about the PIP joint were determined for each construct before cyclic axial loading and after each of four, 5000 cycle loading regimens. After the 20,000 cycle axial loading regimen, each construct was loaded to failure. Results There were no significant differences in construct stiffness, gap formation, or sagittal plane rotation between the LCP and DCP treatment groups at any of the measured time points. Conclusion Biomechanically, fixation of the equine PIP joint with a 3-hole 4.5 mm LCP is equivalent to fixation with a 3-hole 4.5 mm narrow DCP under the test conditions used.

Spontaneous and stimulus-evoked intrinsic optical signals in primary auditory cortex of the cat

Spontaneous and tone-evoked changes in light reflectance were recorded from primary auditory cortex (A1) of anesthetized cats (barbiturate induction, ketamine maintenance). Spontaneous 0.1-Hz oscillations of reflectance of 540- and 690-nm light were recorded in quiet. Stimulation with tone pips evoked localized reflectance decreases at 540 nm in 3/10 cats. The distribution of patches activated by tones of different frequencies reflected the known tonotopic organization of auditory cortex. Stimulus-evoked reflectance changes at 690 nm were observed in 9/10 cats but lacked stimulus-dependent topography. In two experiments, stimulus-evoked optical signals at 540 nm were compared with multiunit responses to the same stimuli recorded at multiple sites. A significant correlation (P < 0.05) between magnitude of reflectance decrease and multiunit response strength was evident in only one of five stimulus conditions in each experiment. There was no significant correlation when data were pooled across all stimulus conditions in either experiment. In one experiment, the spatial distribution of activated patches, evident in records of spontaneous activity at 540 nm, was similar to that of patches activated by tonal stimuli. These results suggest that local cerebral blood volume changes reflect the gross tonotopic organization of A1 but are not restricted to the sites of spiking neurons.