Michael George Zaki Ghali

Motoneuron firing patterns underlying fast oscillations in phrenic nerve discharge in the rat

Fast oscillations are ubiquitous throughout the mammalian central nervous system and are especially prominent in respiratory motor outputs, including the phrenic nerves (PhNs). Some investigators have argued for an epiphenomenological basis for PhN high-frequency oscillations because phrenic motoneurons (PhMNs) firing at these same frequencies have never been recorded, although their existence has never been tested systematically. Experiments were performed on 18 paralyzed, unanesthetized, decerebrate adult rats in which whole PhN and individual PhMN activity were recorded. A novel method for evaluating unit-nerve time-frequency coherence was applied to PhMN and PhN recordings. PhMNs were classified according to their maximal firing rate as high, medium, and low frequency, corresponding to the analogous bands in PhN spectra. For the first time, we report the existence of PhMNs firing at rates corresponding to high-frequency oscillations during eupneic motor output. The majority of PhMNs fired only during inspiration, but a small subpopulation possessed tonic activity throughout all phases of respiration. Significant time-varying PhMN-PhN coherence was observed for all PhMN classes. High-frequency, early-recruited units had significantly more consistent onset times than low-frequency, early/middle-recruited and medium-frequency, middle/late-recruited PhMNs. High- and medium-frequency PhMNs had significantly more consistent offset times than low-frequency units. This suggests that startup and termination of PhMNs with higher firing rates are more precisely controlled, which may contribute to the greater PhMN-PhN coherence at the beginning and end of inspiration. Our findings provide evidence that near-synchronous discharge of PhMNs firing at high rates may underlie fast oscillations in PhN discharge.

The role of spinal GABAergic circuits in the control of phrenic nerve motor output

While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexeds laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed.

Dynamic changes in phrenic motor output following high cervical hemisection in the decerebrate rat

Hemisection of the spinal cord at C2 eliminates ipsilateral descending drive to the phrenic nucleus and causes hemidiaphragmatic paralysis in rats. Phrenic nerve (PhN) or diaphragmatic activity ipsilateral to hemisection can occasionally be induced acutely following hemisection by respiratory stressors (i.e., hypercapnia, asphyxia, contralateral phrenicotomy) and becomes spontaneously active days-to-weeks later. These investigations, however, are potentially confounded by the use of anesthesia, which may suppress spontaneously-active crossed phrenic pathways. Experiments were performed on vecuronium-paralyzed, unanesthetized, decerebrate adult male rats and whole PhN activity recorded continuously before, during, and after high cervical hemisection at the C1 spinal level. Crossed phrenic activity recovered spontaneously over minutes-to-hours with maximal recovery of 11.8 ± 3.1% (m ± SE) in the PhN ipsilateral to hemisection. Additionally, there was a significant increase in PhN activity contralateral to hemisection of 221.0 ± 4 0.4% (m ± SE); since animals were artificially-ventilated, these changes likely represent an increase in central respiratory drive. These results underscore the state-dependence of crossed bulbophrenic projections and suggest that unanesthetized models may be more sensitive in detecting acute recovery of respiratory output following spinal cord injury (SCI). Additionally, our results may suggest an important role for a group of C1-C2 neurons exhibiting respiratory-related activity, spared by the higher level of hemisection. These units may function as relays of polysynaptic bulbophrenic pathways and/or provide excitatory drive to phrenic motoneurons. Our findings provide a new model for investigating acute respiratory recovery following cervical SCI, the high C1-hemisected unanesthetized decerebrate rat and suggest a centrally-mediated increase in central respiratory drive in response to high cervical SCI.

Vagal modulation of pre-inspiratory activity in hypoglossal discharge in the decerebrate rat

Respiration consists of three phases--inspiration (I), post-inspiration (post-I), and late expiration (E2). Pre-I is a subphase occurring at the end of E2. Hypoglossal (XII) discharge contains I and occasionally pre-I activity. Functionally, XII pre-I underlies tongue muscle contraction and expansion of the upper airway, causing a decrease in airway resistance in anticipation of the succeeding inspiratory effort. It has been shown that vagotomy causes an increase in pre-I activity in XII in anesthetized animals. Also, in anesthetized artificially-ventilated animals, XII onset is synchronized with that of inspiratory phrenic nerve (PhN) activity. Therefore, we sought to systematically test the hypothesis that XII pre-I is present in vagus-intact unanesthetized decerebrate animals and vagal afferents negatively modulate XII pre-I discharge in decerebrate rats, in the absence of confounding anesthesia. Experiments were performed on seven Sprague-Dawley unanesthetized decerebrate adult male rats and bilateral PhN and XII recordings performed. In three animals, vagotomy was performed during PhN recordings and one animal was vagotomized during initial surgical preparation prior to recordings. In vagus-intact animals, XII pre-I duration averaged 12.4 ms. Vagotomy was associated with greater XII pre-I duration, expressed in absolute time (89.5 vs. 12.4 ms; p<0.01) as well as relative to the XII bursting period (18.9 vs. 3.4%; p<0.01). Vagal deafferentation was also associated with a larger relative amplitude of the pre-I XII activity relative to total XII discharge (12.4 vs. 2.1%; p<0.01). We conclude that pre-I discharge is present in vagus-intact artificially-ventilated unanesthetized decerebrate animals and is negatively modulated by vagal afferents.

Intracavernous internal carotid artery mycotic aneurysms: Comprehensive review and evaluation of the role of endovascular treatment

Mycotic aneurysms may arise in the setting of many local or systemic infections. Those of the intracranial circulation are especially worrisome due to their potential to compress vital neural structures and their propensity for rupture with consequent hemorrhage. Mycotic aneurysms of the intracavernous internal carotid artery (ICA) represent an exceedingly rare clinical entity, described in less than fifty published cases. Typically presenting as a cavernous sinus syndrome with signs and symptoms of the underlying infection, they are often missed initially, with diagnosis and treatment commencing for the triggering infection or confused with cavernous sinus thrombophlebitis, which may be additionally coexistent, confounding timely diagnosis of the aneurysmal disease. Compared to non-mycotic aneurysms of the intracavernous ICA, which typically have a benign course, the infectious etiology of the mycotic variety increases their tendency to rupture, precludes surgical clipping as a viable treatment option, and requires institution of prolonged antibiotic therapy prior to definitive intervention. Their critical location, friability, and propensity to occur bilaterally result in an unpredictable risk of rapid neurological decline and death, making the timing and specific nature of treatment a unique dilemma facing the treating physician. This review seeks to discuss the natural history of and management strategies for mycotic aneurysms of the intracavernous ICA with special emphasis on the role, safety, and efficacy of endovascular therapies.

Cone-beam CT angiography (Dyna CT) for intraoperative localization of cerebral arteriovenous malformations.

Background Arteriovenous malformations (AVMs) of the brain are commonly treated in multimodality fashion, with endovascular embolization followed by surgical extirpation being one of the most effective strategies. Modern endovascular suites enable rotational angiography, also known as cone-beam CT angiography (CBCT-A), using the full capability of modern C-arm digital angiography systems. This imaging modality offers a superior image quality to current options such as digital subtraction angiography, MRI, or CT angiography. Preoperative planning can be greatly aided by the resolution of angioarchitecture seen in CBCT-A images. Furthermore, these images can be used for intraoperative neuronavigation when integrated with widely used frameless stereotactic systems. The utility and outcome of the use of CBCT-A for preoperative planning and intraoperative localization of AVMs was evaluated. Methods A retrospective review was performed of 16 patients in which CBCT-A was performed, including radiological review and all clinical data. Results CBCT-A was successfully employed in all cases including those with (n=9) and without (n=7) rupture. Complete resection confirmed by postoperative angiography was achieved in all cases. Conclusions We present a novel application of CBCT-A in the treatment of AVMs, both for preoperative surgical planning and an intraoperative reference during neuronavigation.

Effects of vagotomy on hypoglossal and phrenic responses to hypercapnia in the decerebrate rat.

Hypercapnia characterizes a variety of physiological and pathological states and must be compensated effectively by the respiratory, cardiovascular, renal, and intra- and extracellular pH buffering systems to maintain homeostasis. Several studies have examined the respiratory response to hypercapnia, but contemporaneous changes in respiratory frequency and tidal volume prevent investigating the pure influence on respiratory amplitude. Therefore, we sought to test the effect of hypercapnia on hypoglossal (XII) and phrenic nerve (PN) inspiratory (Insp) and XII pre-inspiratory (pre-I) activities in vagus-intact and vagus-denervated animals. Experiments were performed on six artificially-ventilated unanesthetized pre-collicular decerebrate Sprague-Dawley adult male rats. Vagotomy under normocapnic conditions effected the consistent appearance of significant XII pre-I and a greater increase in XII than PN Insp amplitude. In the vagus-intact state, administration of a hypercapnic (5% CO2, 95% O2) gas mixture resulted in a greater increase in XII than PN Insp activity. In the vagotomized state, hypercapnia caused a drastic increase in XII pre-I and significant non-differential increases in both XII and PN Insp activity. The increase in XII pre-I was significantly greater than hypercapnia-induced increases in XII and PN Insp discharges. Following vagotomy, duration and amplitude of XII pre-I are potently modulated by CO2 tension. Based on our results, we conclude that vagal afferents exert differential inhibition of PN Insp and XII pre-I/Insp motor outputs. The role of vagal control in orchestration and optimization of respiratory response to hypercapnia is discussed.

Craniosynostosis surgery: the legacy of Paul Tessier

Paul Louis Tessier is recognized as the father of craniofacial surgery. While his story and pivotal contributions to the development of the multidisciplinary practice of craniofacial surgery are much highlighted in plastic surgery literature, they are seldom directly discussed in the context of neurosurgeons. His life and legacy to craniosynostosis and neurosurgery are explored in the present paper.

Flow diversion for the treatment of posterior inferior cerebellar artery aneurysms: a novel classification and strategies

Background The pipeline embolization device (PED) is frequently used in the treatment of anterior circulation aneurysms, especially around the carotid siphon, with generally excellent results. However, treatment of posterior inferior cerebellar artery (PICA) aneurysms with flow diversion (FD) has not been specifically described or discussed. While there are reports of treating PICA aneurysms using placement of FD stents in the vertebral artery, there are no reports of treating these lesions by placement of flow diverting stents in the PICA vessel itself. Due to the unique anatomy and morphology of these aneurysms, it requires special attention. We assessed our multi-institutional experience treating these lesions, including the first reported cases of the PED placed within the PICA. Methods Institutional databases of neuroendovascular procedures were reviewed for cases of intracranial aneurysms treated with the PED. Patient and aneurysm data as well as angiographic imaging were reviewed for all cases of PICA aneurysms treated with the PED. PICA aneurysms were defined as aneurysms that involved the PICA. Vertebral aneurysms without disease in the PICA were excluded from the study. Results 10 PICA aneurysms were treated during the study period. These were classified based on their morphology and location into two main types and five total subtypes for consideration of treatment with flow diversion. All aneurysms were successfully treated, with 8/10 completely obliterated and 2 with a partial reduction in size. Three patients had the PED placed entirely in the PICA and no patient suffered from a medullary or cerebellar stroke. All PEDs were patent and all patients were independent at the last follow-up. Conclusions The PED may be used successfully to treat select aneurysms of the PICA. We present the first described cases of successful PED treatment of PICA aneurysms with direct placement of the PED in the PICA vessel itself. The proposed classification system aids in that selection.

The bulbospinal network controlling the phrenic motor system: Laterality and course of descending projections

The respiratory rhythm is generated by the parafacial respiratory group, Bötzinger complex, and pre-Bötzinger complex and relayed to pre-motor neurons, which in turn project to and control respiratory motor outputs in the brainstem and spinal cord. The phrenic nucleus is one such target, containing phrenic motoneurons (PhMNs), which supply the diaphragm, the primary inspiratory muscle in mammals. While some investigators have demonstrated both ipsi- and contralateral bulbophrenic projections, there exists controversy regarding the relative physiological contribution of each to phasic and tonic drive to PhMNs and at which levels decussations occur. Following C1- or C2 spinal cord hemisection-induced silencing of the ipsilateral phrenic/diaphragm activity, respiratory stressor-induced, as well as spontaneous, recovery of crossed phrenic activity is observed, suggesting an important contribution of pathways crossing below the level of injury in driving phrenic motor output. The precise mechanisms underlying this recovery are debated. In this review, we seek to present a comprehensive discussion of the organization of the bulbospinal network controlling PhMNs, a thorough appreciation of which is necessary for understanding neural respiratory control, accurate interpretation of studies investigating respiratory recovery following spinal cord injury, and targeted development of therapies for respiratory neurorehabilitation in patients sustaining high cervical cord injury.