ICA is a frequent, self-limiting semiological feature of focal epilepsy, often starting before surface EEG onset, and may be the only clinical manifestation of focal seizures. However, prolonged ICA (≥60 s) is associated with severe hypoxemia and may be a potential SUDEP biomarker. ICA is more frequently seen in temporal than extratemporal seizures, and in typical temporal seizure semiologies. ICA rarely persists after seizure end. ICA agnosia is typical, and thus it may remain unrecognized without polygraphic measurements that include breathing parameters.

Summary Objective Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs). Methods Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔVE/ΔETCO2) for each subject was determined by linear regression. During the video–electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2, and capillary oxygen saturation (SPO2). Results Sixty‐eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from −0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2. Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope. Significance Measurement of the HCVR is well tolerated and can be performed rapidly and safely at the bedside in the EMU. A subset of individuals has a very low sensitivity to CO2, and this group is more likely to have a prolonged increase in postictal CO2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study.

Abstract-Because inhibition of neuronal nitric oxide synthase in the nucleus tractus solitarii blocks cardiovascular responses to activation of local glutamate receptors, and because glutamate is a neurotransmitter of baroreceptor afferent nerves, we sought to test the hypothesis that neuronal nitric oxide synthase inhibition would block baroreflex transmission and cause hypertension. We determined reflex heart rate responses to intravenous phenylephrine and sodium nitroprusside in 5 anesthetized rats before and after bilateral microinjection (100 nL) of the neuronal nitric oxide synthase inhibitor AR-R 17477 (7.5 nmol) into the nucleus tractus solitarii. The inhibitor significantly increased mean arterial pressure without affecting heart rate, and it significantly reduced the gain of the baroreflex. After administration of the inhibitor, reflex responses of heart rate to changes in mean arterial pressure were always less than those responses to the same, or less, change in mean arterial pressure in the same animal without administration of the inhibitor. Microinjection of saline (100 nL) bilaterally into the nucleus tractus solitarii did not lead to hypertension or change baroreflex responses. These data support the hypothesis and suggest that neuronal nitric oxide synthase is critical to transmission of baroreflex signals through the nucleus tractus solitarii. Key Words: baroreceptor reflex Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ rat A s the primary site of termination of baroreceptor and other cardiovascular and visceral afferent nerve fibers, 1-3 the nucleus tractus solitarii (NTS) plays a critical role in regulation of arterial pressure (AP) and peripheral blood flow. Stimulation of NTS leads to marked changes in AP and regional blood flow, 4 and lesions lead to acute hypertension in humans 5 and experimental animals. 6 Changes in AP regulation may be persistent with chronic perturbations of transmission in NTS. 7 There is broad support for the hypothesis that glutamate (Glu) is a transmitter released from baroreceptor afferent nerve terminals in NTS, 8,9 but Glu likely also participates in processing other cardiovascular signals such as those from chemoreceptor afferents. 10 Changes in responsiveness to Glu injected into NTS in hypertensive rats 11 suggest that alterations in Glu transmission may play a role in the genesis of some forms of hypertension. Thus, improved understanding of glutamatergic neurotransmission in the NTS in normotensive rats could shed new light not only on basic mechanisms of AP control but also on mechanisms that could contribute to hypertension.Recent studies indicate that nitric oxide (NO⅐) may participate in generating responses elicited by Glu. For example, NO⅐ may exert presynaptic and postsynaptic effects and may play a role in cardiovascular regulation at the level of NTS. 12 Furthermore, responses to injection of NO⅐ donors into NTS of anesthetized and awake animals mimic those elicited by injection of Glu agonists in anesthetized rats. [13][14][15] However, it is not clea...

Parasympathetic nerves from the pterygopalatine ganglia provide nitroxidergic innervation to forebrain cerebral blood vessels. Disruption of that innervation attenuates cerebral vasodilatation seen during acute hypertension as does systemic administration of a non-selective nitric oxide synthase (NOS) inhibitor. Although such studies suggest that nitric oxide (NO) released from parasympathetic nerves participates in vasodilatation of cerebral vessels during hypertension that hypothesis has not been tested with selective local inhibition of neuronal NOS (nNOS). We tested that hypothesis through these studies performed in anesthetized rats instrumented for continuous measurement of blood pressure, heart rate and pial arterial diameter through a cranial window. We sought to determine if the nNOS inhibitor propyl-L-arginine delivered directly to the outer surface of a pial artery would 1) attenuate changes in pial arterial diameter during acute hypertension and 2) block nNOS mediated dilator effects of N-methyl-D-Aspartate (NMDA) delivered into the window but 3) not block vasodilatation elicited by acetylcholine (ACh) and mediated by endothelial NOS dilator. Without the nNOS inhibitor arterial diameter abruptly increased 70 ± 15% when mean arterial pressure (MAP) reached 183 ± 3 mmHg while with nNOS inhibition diameter increased only 13 ± 10% (p<0.05) even when MAP reached 191 ± 4 (p>0.05). The nNOS inhibitor significantly attenuated vasodilatation induced by NMDA but not ACh delivered into the window. Thus, local nNOS inhibition attenuates breakthrough from autoregulation during hypertension as does complete interruption of the parasympathetic innervation of cerebral vessels. These findings further support the hypothesis that NO released from parasympathetic fibers contributes to cerebral vasodilatation during acute hypertension. Section: Regulatory Systems

Glutamate (GLU) receptor activation, which is important in cardiovascular reflex transmission through the nucleus tractus solitarii (NTS), leads to release of nitric oxide (NO·) from central nitroxidergic neurons. Therefore, we hypothesized that GLU and NO· are linked in cardiovascular control by NTS. We first sought to determine if NO· released into NTS led to cardiovascular changes like those produced by GLU and found that the nitrosothiol S‐nitrosocysteine, but not NO· itself or other NO· donors, elicited such responses in anesthetized rats. The responses were dependent on activation of soluble guanylate cyclase but, not being affected by a scavenger of NO·, likely did not depend on release of NO· into the extracellular space. Responses to ionotropic GLU agonists in NTS, like those to S‐nitrosocysteine, were inhibited by inhibition of soluble guanylate cyclase. Inhibition of neuronal NO· synthase (nNOS) also inhibited responses to ionotropic GLU agonists. The apparent physiologic link between GLU and NO· mechanisms in NTS was further supported by anatomical studies that demonstrated frequent association between GLU‐containing nerve terminals and neurons containing nNOS. Furthermore, GLU receptors were often found on NTS neurons that were immunoreactive for nNOS. The anatomical relationships between GLU and nNOS and GLU receptors and nNOS were more pronounced in some subnuclei of NTS than in others. While seen in subnuclei that are known to receive cardiovascular afferents, the association was even more prominent in subnuclei that receive gastrointestinal afferents. These studies support a role for nitroxidergic neurons in mediating cardiovascular and other visceral reflex responses that result from release of GLU into the NTS.

Forebrain arteries receive nitroxidergic input from parasympathetic ganglionic fibers that arise from the pterygopalatine ganglia. Previous studies have shown that ganglionic stimulation in some species led to cerebral vasodilatation while interruption of those fibers interfered with vasodilatation seen during acute hypertension. Because the ganglionic fibers are quite delicate and are easily damaged when the ganglia are approached with published techniques we sought to develop a method that allowed clear exposure of the ganglia and permitted demonstration of cerebral vasodilatation with electrical stimulation of the ganglia in the rat. We had found that an orbital approach during which the eye was retracted for visualization of the ganglion precluded eliciting vasodilatation with ganglionic stimulation. In the current study approaching the ganglion through an incision over the zygomatic arch provided clear exposure of the ganglion and stimulation of the ganglion with that approach led to vasodilatation.

Cerebral blood flow (CBF) is autoregulated at mean arterial pressures (MAP) ranging from approximately 50 to 150 mmHg. When MAP exceeds the upper limit, autoregulation breaks through, vasodilatation occurs, and CBF increases rapidly. Earlier studies have shown that the arterial baroreflex does not influence autoregulation. However, CBF may rise to a lesser degree during abrupt hypertension immediately after interruption of the baroreceptor reflex than it would at comparable levels of blood pressure in intact animals. Generally this shift of the breakthrough point has been attributed to an increase in sympathetic nerve activity immediately after sinoaortic denervation. We hypothesized that denervation of arterial baroreceptors would blunt vasodilatation during slow controlled increases of arterial pressure, and we sought to determine whether sympathetic nerves contributed to regulation of CBF during hypertension in baroreceptor-denervated animals. Thirty-eight rats were studied to determine whether sinoaortic denervation affected autoregulation or breakthrough during acute hypertension. In five intact rats, when arterial pressure was raised by phenylephrine to 155 +/- 4 mmHg, cerebrovascular resistance fell by 60% and CBF increased by 434%. After interruption of the baroreflex in six rats, such dramatic increases in CBF with breakthrough did not occur despite greater increases in MAP (to 185 +/- 2 mmHg). Similar results were obtained when arterial pressure was raised by infusion of arginine vasopressin in four intact and three denervated rats. The effects of baroreceptor reflex interruption were not significantly affected by bilateral removal of the superior cervical ganglia. Rates of rise of MAP and increases of pulse pressure were equivalent between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Lesions that remove neurons expressing neurokinin-1 (NK1) receptors from the nucleus tractus solitarii (NTS) without removing catecholaminergic neurons lead to loss of baroreflexes, labile arterial pressure, myocardial lesions and sudden death. Because destruction of NTS catecholaminergic neurons expressing tyrosine hydroxylase (TH) may also cause lability of arterial pressure and loss of baroreflexes, we sought to test the hypothesis that cardiac lesions associated with lability are not dependent on damage to neurons with NK1 receptors but would also occur when TH neurons in NTS are targeted. To rid the NTS of TH neurons we microinjected anti-dopamine β-hydroxylase conjugated to saporin (anti-DBH-SAP, 42ng/200nl) into the NTS. After injection of the toxin unilaterally, immunofluorescent staining confirmed that anti-DBH-SAP decreased the number of neurons and fibers that contain TH and DBH in the injected side of the NTS while sparing neuronal elements expressing NK1 receptors. Bilateral injections in 8 rats led to significant lability of arterial pressure. For example, on day 8 standard deviation of mean arterial pressure was 16.8 ± 2.5 mmHg when compared with a standard deviation of 7.83 ± 0.33 mmHg in 6 rats in which phosphate buffered saline (PBS) had been injected bilaterally. Two rats died suddenly at 5 and 8 days after anti-DBH-SAP injection. Seven treated animals demonstrated microscopic myocardial necrosis as reported in animals with lesions of NTS neurons expressing NK1 receptors. Thus, cardiac and cardiovascular effects of lesions directed toward catecholamine neurons of the NTS are similar to those following damage directed toward NK1 receptor containing neurons.