Characteristics of brain vessels in normal conditions and in conditions of prenatal exposure to alcohol from week 10 to week 12 of intrauterine development (x ± sx).
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",isbn:"978-1-83969-057-0",printIsbn:"978-1-83969-056-3",pdfIsbn:"978-1-83969-058-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"5f388543a066b617d2c52bd4c027c272",bookSignature:"Prof. Christophe Hano and Dr. Jen-Tsung Chen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10539.jpg",keywords:"Plant Description, Botany, Phylogeny, Genome, Phytochemical Analysis, Extraction, Phytochemical Diversity, Phytochemical Analysis, Extraction, Phytochemical Diversity, Biotechnological Production, Traditional Medicinal Uses",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 8th 2020",dateEndSecondStepPublish:"November 23rd 2020",dateEndThirdStepPublish:"January 22nd 2021",dateEndFourthStepPublish:"April 12th 2021",dateEndFifthStepPublish:"June 11th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Assistant Professor at the University of Orleans at Research INRAE Lab LBLGC USC1328 and a member of the Cosm'ACTIFS Research Group (CNRS GDR3711). 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He has written more than 100 scientific papers, reviews and book chapters in internationally renowned journals and edited one book as well as a variety of journal topical issues on plant secondary metabolism, including polyphenols. He is Academic, Assistant Editor and/or Editorial Board Member of several renowned Q1 Journals in Plant Biochemistry and Biotechnology (including Plos ONE, Biomolecules, Plant Cell Tissue and Organ Culture, Frontiers in Plant Science, Cosmetics). He was reviewers for more than 500 papers for ca 35 International Journals, and recognized scientific expert for several national and international Institutions. Currently, he is developing research projects aimed at studying plant secondary metabolism to lead to the development of natural products with interests in pharmacology or cosmetics. His research focuses on the green extraction and analytical methods applied to plant polyphenols, elucidation of biosynthetic mechanisms of plant natural products and their exploitation by metabolic engineering approaches. He was a leader (project manager) in 6 scientific projects and major investigator in several more. In this context he conducts research projects in cooperation with industrial companies and he coordinates in the European Le Studium® Consortium Action on the bioproduction of bioactive extracts for cosmetic applications through plant cell in vitro cultures. In this context, he explores the potential of the Loire Valley Flora Area for cosmetic applications. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"59131",title:"Molecular-Cellular Targets of the Pathogenetic Action of Ethanol in the Human Brain in Ontogenesis and the Possibility of Targeted Therapy Aimed at Correcting the Effect of Pathogenic Factors",doi:"10.5772/intechopen.73333",slug:"molecular-cellular-targets-of-the-pathogenetic-action-of-ethanol-in-the-human-brain-in-ontogenesis-a",body:'Prenatal alcohol exposure at moderate and higher levels increases the odds of child behavior problems with the dose, pattern and timing of exposure affecting the type of behavior problems expressed [1, 2]. Disruption in the neural activation of the prefrontal cortex (PFC) and neurobehavioral disorders were detected in children with severe prenatal exposure to alcohol (PAE) [3, 4, 5, 6]. The developing brain is extremely sensitive to the effects of ethanol [6, 7]. The use of significant doses of ethanol during pregnancy can result in a combination of profound morphological and neurological changes called fetal alcohol syndrome (FAS) [8, 9].
The use of moderate doses of ethanol can cause abnormalities that are not associated with multiple morphological and neurological damage associated with FAS, but are associated with the development of cognitive deficits and more serious consequences in the offspring, which can be particularly pronounced in puberty [10, 11]. This formed the basis for an expanded diagnostic classification of fetal defects and a new category—neurodevelopmental disorders caused by alcohol. There is a complex relationship between the dose, nature and timing of prenatal exposure to alcohol and problems of child behavior in the future. Fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE) are preventable forms of mental retardation and developmental disability caused by heavy prenatal alcohol exposure.
The human brain is arguably one of the most complicated organism living systems. This elaborate structure originates from a simple neural tube, followed by a series of differentiation processes. The possible contributions of PAE to nervous system malformations must be considered in the context of developmental timing. Neural tube defects typically occur during weeks 3–4 of human gestation [12]. Morphometric characterization of the brain at each stage not only aids in understanding this highly ordered developmental process but also provides clues to detecting abnormalities caused by genetic or environmental factors. Some observations have shown that the development of brain abnormalities: brain microencephaly, neural tube defects, hydrocephalus with various etiology and severity and cerebral vascular lesions, is not associated with complications at birth or as a result of prematurity [12].
Alcoholism of the mother can lead to the development of the FAS or FAE, which is apparent as a complex of disorders in the somatic and mental domains, reflecting impaired nervous system development [13, 14]. A number of authors have shown that the development of this syndrome is mainly due to impaired fetal brain development [15, 16, 17], starting from the earliest stages of neurogenesis and brain formation structures, which leads to a delay in migration and differentiation of neurons and some disorders of angiogenesis and synaptogenesis [15, 18, 19, 20, 21]. The function of the blood-brain barrier (BBB) in the embryonic brain is mediated by cellular elements—endotheliocytes, developing glial cells and pericytes, and also by the noncellular structures of capillary basal membranes. Elements of BBB are under the direct influence of alcohol, with prenatal exposure to it during pregnancy in conditions of mother’s alcohol abuse. In the early stages (5–6 weeks of intrauterine development), the neural tube does not have blood vessels. Neuroectodermal structures are fed from a protein-rich fluid into the neural tube. Due to their rapid growth and increase in mass, nutrients enter the newly formed blood vessels [22, 23].
At the molecular-cellular level, changes in the nervous system in the formation of alcohol dependence are associated with activation of the processes of synaptic plasticity. With the development of alcohol dependence, stimulation of neuroplasticity is considered one of the reasons for the rapid formation of a behavioral stereotype—addictive behavior. At the same time, long-term consumption of ethanol leads to a permanent disruption of synaptic plasticity, which can cause cognitive impairment, learning and memory problems, and the formation of alcoholic motivation and obsessive directed behavior in experimental animals and people with prolonged use of alcohol [24].
Neurogenesis is the basis for ensuring the plastic function of the brain and is regulated by many factors. Stimulation of neurogenesis is observed in a number of pathological conditions: brain ischemia, trauma, the development of neurodegenerative pathology, the influence of neurotoxic agents, including high doses of alcohol, prolonged use. Neurogenesis is the key adaptive function of the brain, represents one of the most important mechanisms of brain plasticity, which is expressed in an increase in the number of cells involved in the restructuring of neuronal networks. Exposure to ethanol limits early development by delaying or inhibiting the formation of postsynaptic neurons from progenitor neuronal cells (PNA) [19, 20, 21, 25].
The effects of ethanol in the early stages of development can disrupt the signaling mechanisms that regulate synaptogenesis. Negative effects of ethanol are associated also with its influences on the lipid component of neuron membranes. As lipotropic agent, ethanol is able to change the essential physico-chemical properties of cell membranes, which is reflected in the current fetal brain synaptogenesis [26, 27]. It has been shown that ethanol triggers apoptotic neurodegeneration [17] in the developing brain, when administered to infant rodents during the period of synaptogenesis, also known as the brain growth spurt period [19, 20]. Prenatal alcohol exposure inhibits neurogenesis [24, 28] and dendritic growth of newborn neurons [18].
The effects of ethanol cause neuronal death, impairment of differentiation, migration of neuronal elements and changes in neuronal plasticity, acting through various receptors and their signaling pathways [29]. Rapidly developing neural networks form synapses, mediate the communication and functioning of a multitude of synapses, through neuromediation part of them associated with a neurotransmitter gamma-aminobutyric acid (GABA), which operates via chloride-permeable GABA type A receptor channels. At an early stage of development, neurons have a high concentration of intracellular chloride, which leads to an outflow of chloride and exciting actions of GABA in immature neurons. Transmission of GABA signals is also established prior to the formation of glutamatergic transmission. Thus, GABA is the main excitatory transmitter in the early stages of development and modulates the cell cycle, the formation of cells and their migration [30, 31, 32, 33].
The currently accepted position is that the adverse effects of ethanol are also linked with interactions with specific proteins, ion channels and receptors, leading to changes in their functions [17, 34, 35]. The ability of ethanol to interact with receptor proteins was demonstrated, which contributed to a change in neuronal excitability. GABAergic neurotransmission plays an important role in the mechanisms of action of ethanol. GABA receptors fulfill the inhibitory role in the CNS. GABAAR is an oligomeric protein complex, which contains various allosteric binding sites that modulate receptor activity, and these allosteric binding sites are the targets for various agents, including benzodiazepines (BzD) and ethanol. Benzodiazepines, which bind to the specific sites—benzodiazepine receptors (BzDR) on the GABA receptor complex, change its conformation and affinity [35, 36, 37]. Sedative and anxiolytic effects of alcohol and benzodiazepines are based on the potentiation of inhibitory effects of GABA by the inactivation of GABAA receptors. In the experiment, it was shown that the acute effect of ethanol enhances the gain of GABAergic transmission, but chronic alcoholization increases the binding of inverse BzDR agonists and reduces GABAergic function [38, 39]. Recent data point to the existence of a relationship between the actions of ethanol and the functioning of the GABA-BzD-receptor complex.
One of the theories of alcoholism involves a shift in the general excitability of the brain as a result of reduced inhibition processes. GABAAR are modulated by the main inhibitory neurotransmitter in the central nervous system—GABA, are potential targets for alcohol and mediate the effects of ethanol [40, 41, 42, 43, 44]. Alcohol can activate GABAAR, possesses anxiolytic properties, and in connection with its use of this ability is a form of self-medication by patients. Decrease of GABAergic functioning was found in patients with alcoholism and persons with a high risk of alcohol addiction development [44, 45]. The sedative and anxiolytic effects of alcohol and BzD are associated with potentiating of the inhibitory effect of GABA [41, 43]. At current time has not been revealed endogenous ligands for BzDR, as for opiate receptors and others, but their role is very significant in neuropharmacology of inhibitory processes in the CNS. There are cross-reactions (tolerance and dependence) between alcohol and BzD, which confirm the interaction of ethanol with BzDR [38].
In addition to BzDR “central” type (CBR) that associated with GABAAR and having synaptic localization, known BzDR “peripheral” type (PBR), not associated with GABAAR and localized in the mitochondrial membrane, more of them are located in the glial cells of the brain.
These receptors make very important function—transfer of cholesterol into the mitochondria; this is limited step in the regulation of the neurosteroids biosynthesis. Neurosteroids are endogenous modulators of the GABAA/BzDR in the CNS [46]. BzD, anxiolytics, anesthetics and alcohol are implementing some of its effects through the PBR and regulating production of neurosteroids and their active metabolites, which are very significant for normal brain functioning [46, 47].
Understanding of the basic signaling mechanisms that regulate the excitability and inhibition of brain processes involved in the formation of alcohol addictive behavioral, the determination of the target of alcohol effects can contribute to the creation of new pharmaceutical preparations to influence these targets and to develop a potentially effective therapies to prevent the consequences of alcohol abuse and withdrawal.
In this regard, it is impossible to overestimate the importance of further studying the processes associated with angiogenesis and synaptogenesis and the formation of receptor systems in the developing human brain, in particular, the GABA-benzodiazepine receptor system under conditions of chronic effects of ethanol, their role in the development of alcohol dependence, which may contribute to further clarification of the etiopathogenesis of the disease and the search for new medications necessary for pharmacotherapeutic correction, and prevention of harmful effects of ethanol.
The study of the effect of mother’s alcoholism on the developing fetal brain (prenatal exposure to alcohol) was carried out in the brain tissue of embryos and human fetuses at the 7–15 week of pregnancy in accordance with the requirements of the Ethics Committee and with the consent of patients during abortion procedures under strict medical indications. About 33 embryos and fetuses were obtained from female, suffering from alcoholism and constituted the main study group. The age of women who suffered from alcoholism was 26–39 years old, and the duration of the disease was from 3 to 13 years. In all cases, according to ICD-10 criteria, alcoholism of grade II was diagnosed (ICD-10 F10.201, F10.202). The diagnosis of alcoholism was established in the Department of Addictive Conditions, the Institute of Mental Health, Tomsk National Scientific Medical Center Russian Academy of Science (RASci). The control group included samples of the brain tissue of embryos and fetuses obtained from healthy women who do not have a history of neurological or mental diseases comparable in age. Exclusion criteria were cases of adverse effects on brain development of embryos, namely exposure to radiation, chemicals, certain pharmacological agents and maternal diseases during pregnancy: influenza, rubella, toxoplasmosis and others.
Ultrastructure of synaptic contacts and vessels of the brain tissue from embryonic and fetal brain were examined under JEM-100B and JEM-100CX electron microscopes. Electron microscopy studies addressed the intermediate layer of the wall of the forebrain, which is an accumulation of neuroblast and glioblast (including microglial cells), between which blood vessels start to grow. Morphometric analysis was performed using photographic prints from 6 to 9 cm negatives obtained from the electron microscopes. Some negatives were digitized with the scanner without intermediate paper prints. Scion Image for Windows, developed at the National Institutes of Health by Scion Corporation, was used to assess the areas of presynaptic terminals, their perimeters and the lengths of postsynaptic densities. Quantitative assessments by computerized morphometric analysis were performed by subdividing electron micrographs of embryo brain synapses into four groups, according to the period of embryo development: 7–8, 9–10, 10–11 and 11–12 weeks. This was performed in both the study group and the control group. Analyses involved five cases for each age period in the control and study groups.
The rapidly growing neuronal structures of the developing brain of the embryo and fetus are powered by a protein-rich fluid in the lumen of the neural tube. Subsequently, this mechanism becomes inadequate when their mass increases, and the task of delivering nutrients and removing metabolic products falls on blood vessels. It is extremely important to assess the degree of alcohol exposure to vasculogenesis of the developing brain fetus under the influence of prenatal alcohol exposure associated with maternal alcoholism [48].
As our studies showed, the vessels in the developing brain of embryos and fetuses for 8–9 weeks of development under normal conditions and in the presence of prenatal exposure to alcohol consisted only of capillaries with thin walls. Endotheliocytes and pericytes are presented on microphotographs, and the lumen of the vessels was open and contained formed blood elements. On the vessels, a basal membrane, consisting of a loose fibrillar material, was visible. Morphological differences in the development of vessels between the embryos of the control and main groups during the 8–9 weeks of pregnancy were not observed. In samples of the brain tissue of the fetuses from the main experimental group, the developmental period of 10 weeks of pregnancy identified erythrocyte stasis in some forming vessels (Figures 1 and 2). Our data show that vessels in the human brain start to differentiate into arteries and veins from 10 weeks of gestation (Figures 3 and 4). Brain vessels are differentiated into arterioles, capillaries and venules. Capillary basal membranes in the main experimental and control group were already clearly visible at 12 weeks of development (Figures 5 and 6). In both groups, we found that the apical surfaces of endotheliocytes remained smooth, with only occasional microvillus and no significant protrusions of these cells into lumens, which remained open. We studied quantitative computer morphometric and established a series of characteristics of brain tissues samples in experimental group in comparison with control group (Table 1). Mean vessel cross-sectional areas and vessel perimeters in the main experimental group were significantly reduced by 11 weeks as compared with controls. The tendency for these measures to decrease in the experimental group compared with controls persisted at 12 weeks of development. Relative vessel cross-sectional area in samples of brain tissue from the main experimental group was greater than in control group. This measure was significantly greater in this group at 11 and 12 weeks of development. The number of vessels per unit area was significantly increased in the main experimental group at weeks 11 and 12 of fetal brain gestation as compared with control group.
Capillaries of the intermediate layer embryonic brain. Control group, embryo 10 weeks of development. Coloring methylene blue. 740×.
Stasis of erythrocytes in the vessel between the exact layers. Main group, embryo 10 weeks of development. Coloring methylene blue. 740×.
In the center of the picture, the forming venule with the shaped elements of blood in the lumen of the vessel. Control group, embryo 10 weeks of development. Coloring methylene blue, 740×.
Two arterioles are visible in the field of vision. Control group, embryo 10 weeks of development. Coloring methylene blue, 740×.
Ultrastructure of the basal membrane and capillary endothelium. The erythrocyte is visible in the lumen of the vessel. Main group, fetus 11–12 weeks of development, 10,000×.
Basal membrane of the capillary without damage to the structure and a fragment of the cytoplasm of the endothelial cell. Main group, fetus 12 weeks of development, 45,000×.
Measure | Control group | Experimental group | ||||
---|---|---|---|---|---|---|
Week 10 | Week 11 | Week 12 | Week 10 | Week 11 | Week 12 | |
Mean cross-sectional area of vessels, μm2 | 45.61 ± 0.81** | 65.73 ± 2.77 | 59.25 ± 5.38 | 49.08 ± 2.61 | 51.82 ± 3.07* | 48.26 ± 1.67 |
Relative cross-sectional area of vessels in brain tissue, % | 0.79 ± 0.11 | 1.26 ± 0.11 | 1.38 ± 0.2 | 1.02 ± 0.34 | 5.96 ± 1003* | 7.59 ± 1.44* |
Number of vessels per 1 μm2 cross-sectional area of sections | 0.00017 ± 0.000023 | 0.000189 ± 0.000013 | 0.00023 ± 0.000025 | 0.000214 ± 0.000078 | 0.001137 ± 0.000189* | 0.000624 ± 0.000314* |
Vessel perimeter, μm | 349.44 ± 18.24 | 492.71 ± 34.28 | 269.83 ± 26.0 | 340.58 ± 35.87 | 292.20 ± 16.87* | 244.69 ± 16.41 |
Characteristics of brain vessels in normal conditions and in conditions of prenatal exposure to alcohol from week 10 to week 12 of intrauterine development (x ± sx).
Significant difference with control, p < 0.05.
Significant difference compared with fetuses at 11 and 12 weeks of development, p < 0.01.
The first blood vessels in the human endbrain are seen at the start of week 7 of embryogenesis in the area of the ganglionic tubercle (the rudiment of the corpus striatum) and rather later in the rudiment of the neocortex (lateral wall of the lateral ventricle). The formation of blood vessels in the neocortical rudiment directly precedes the large scale migration of neuroblasts from the ventricular zone to the area of the cortical plate [22]. At 6–9 weeks of prenatal ontogenesis, developing intracerebral structures are not differentiated into arteries and veins, but have the structure of capillaries, which is consistent with our data. Endotheliocytes of intracerebral vessels are not fenestrated and contain small numbers of transport vesicles. At 8–9 weeks of gestation, vessels acquire basal membranes, which consist of a very loose fibrillar material with low electron density; there are also locations at which the endothelium makes direct contact with the intercellular space. At areas of contact between endotheliocytes and pericytes, interaction of the plasmalemmas of these cell types is seen in the form of mutual invagination [22].
We have shown that the differentiation of vessels into capillaries, venules and arterioles in the developing brain of a person begins in 10–11 weeks of pregnancy. Computer morphometric analysis showed that the main effect of alcohol on the blood vessels in the brain of the fetuses was found during the development of 11 weeks of pregnancy. An increase in the number of vessels per unit cross-sectional area of the fetal brain was observed, while the average cross-sectional area and perimeter of the vessels were reduced. Under conditions of prenatal alcohol influence, brain tissue undergoes hypoxia. Increase in the number of cerebral vessels per unit cross-sectional area is a compensatory adaptive mechanism in the development of this state.
Thus, the influence of alcohol during pregnancy can significantly affect the dynamics of the cerebral circulation in the embryo and fetus, which is manifested by altering the vascularization of the developing human brain.
As a lipotropic agent, ethanol, is able to change the basic physicochemical properties of cell membranes, which are reflected in the current synaptogenesis of the embryonic brain in order to establish the nature of this effect, we conducted the following studies.
In human embryonic brain in the early period—7–8th week of gestation, the desmosome-like contacts were represented as we observed. Contacting membranes are in their middle part of thickening, which both sides approach to each other, forming a fissure. In these places of the thickening, the membrane can be connected. Electron-dense material is in the field of adhesion. Contacts of this type are found between dendritic processes and neuronal cells. During the development of 9–10 weeks of pregnancy, these types of contacts are less frequent. Contacts with the presence of vesicular elements have been revealed. Synaptic vesicles were rounded and had a bright center, and the diameter of these vesicles was approximately 40 nm. The width of the synaptic space of immature synapses was approximately 20 nm. The length of the area of the sealing membrane reached 0.1–0.15 microns (Figure 7). In the transitional stage from synapse-like contacts to their true synaptic form, single synaptic vesicles were visualized near the presynaptic membrane. Such synapses are located mainly at the lower boundary of the intermediate layer of the cerebral cortex (Figures 8 and 9). They can already be considered functionally competent.
Contact with uniformly thickened membranes. Main group, the fetus of 10–11 weeks. Magnification 160,000.
The emerging synapses in the cerebral cortex the intermediate layer brain. Main group, 12-week fetus. Magnification 40,000.
Completely formed functionally competent synapse. Main group, the fetus of 11–12 weeks. Magnification 70,000.
At the stage of fetal development 10–12 weeks, the number of synapses with relatively mature structures increased. They are located in the border of the ventricular and intermediate layers and in the intermediate layer of the cortical plate and nerve cells. In synaptic contacts, all the necessary components were found; from the mature synapses, their difference was the smaller number of synaptic vesicles. Synaptic contacts on neuroblasts and glioblasts have fewer synaptic vesicles compared to the synapses of the mature brain. All of the above features were inherent in both the control group and the main group of embryos and fetuses (Figures 10 and 11).
Single synaptic vesicles in the formation of contact, the main group is a fetus of 12 weeks of development, magnified 60,000.
Single synaptic vesicles in the formation of contact, the main group is a fetus of 12 weeks of development, magnified 144,000.
In the brain tissue of embryos and fetuses obtained from women suffering from alcoholism, a slowdown in the formation of synaptic structures was observed. Non-synaptic contacts in the samples of the main study group did not differ from those of control in the frequency of occurrence in the brain tissue and in its structure. The fully formed structure of the synaptic contacts is associated with the appearance of synaptic vesicles comparable with structure control; however, the area of the synapse was smaller [49].
The strong evidence we have obtained suggests that the developing brain is vulnerable to the pathogenic effects of ethanol. In the cells of the brain of embryos and fetuses from the main group of the study group, a slowing down of the process of synaptogenesis in comparison with the norm was revealed, which can be critical for neurotransmitter processes in the developing human brain.
Morphometric analysis of synaptic characteristics was performed in the study and control groups, using as a criterion the stage of development of embryos and fetuses.
In the main study group, a significant decrease in all parameters of synaptic structures was revealed in comparison with the control. More detailed analysis of synapse parameters was then performed, taking cognizance of embryo and fetus developmental period (Figures 12–14, Table 2).
Morphometric values for presynaptic terminal perimeters in the control and study groups at different weeks of development.
Morphometric values for presynaptic terminal areas in the control and study groups at different weeks of development.
Morphometric values for postsynaptic density lengths in the control and study groups at different weeks of development.
Stage of development | 7–8 Weeks | 9 Weeks | 10 Weeks | 11 Weeks | ||||
---|---|---|---|---|---|---|---|---|
Measure | C M ± SE N = 90 | S M ± SE N = 90 | C M ± SE N = 210 | S M ± SE N = 210 | C M ± SE N = 210 | S M ± SE N = 210 | C M ± SE N = 210 | S M ± SE N = 210 |
Length of postsynaptic density | 25.21 ± 3.0 | 23.56 ± 2.4 | 36.21 ± 1.56 | 32.45 ± 1.23* | 42.37 ± 1.70 | 35.80 ± 2.37* | 63.33 ± 2.51 | 51.90 ± 2.88* |
Area of postsynaptic terminals | – | – | 54.521 ± 2673 | 48.861 ± 6773* | 66.964 ± 3833 | 63.178 ± 3168* | 75.742 ± 3207 | 66.750 ± 4436* |
Perimeter of postsynaptic terminals | – | – | 896.28 ± 63.7 | 798.90 ± 40.09* | 948.19 ± 58.2 | 941.56 ± 64.44 | 1276.02 ± 73.08 | 1129 ± 86.87* |
Morphometric parameters of synapses in the human brain at different stages of embryonic development.
Significant differences between study and control groups (p < 0.01).
Notes: C, control group; S, study group (materials from alcoholic mothers).
We found that the length of postsynaptic density was lower in the main group compared to the control group already at the 7–8th week of gestation. At the 9th week of pregnancy, we identified synaptic contacts, especially at the upper margin of the middle layer. At this period of brain development, all synaptic parameters studied were significantly smaller in the main group with respect to the control. At week 10, we also noted a decrease in all parameters of the study at the synapses; however, the presynaptic perimeters did not differ.
At 11–12 weeks of development, there was a more pronounced change in the parameters of synaptic contacts in the main group relative to the control group. Most synapses in the brain of the fetuses of 11–12 weeks of gestation are axodendritic positively bent synapses with some insignificant amount of synaptic vesicles and single mitochondria in the presynaptic terminals of the synapses.
The fully formed structure of synaptic connections with the appearance of synaptic vesicles compared to the control, but synapse core area considerably less resulting computer-morphometric analysis, we identified a delay of synapses and their structural immaturity which is probably due to a direct effect of alcohol on nerve cells, primarily due to its membranotropic action. Our morphometric studies have revealed that the prenatal influence of alcohol has a pronounced effect on the structural organization of synaptic contacts and their parametric characteristics. Our data confirm the data of other researchers obtained in studies in the culture of hippocampal tissues under the influence of a solution of ethanol [50, 51].
Thus, as a result of computer-morphometric analysis, we found a delay of synapses and their structural immaturity, which is probably linked to the direct effect of alcohol on nerve cells in the first place due to its membranotropic action.
To study the formation of benzodiazepine receptors of the synaptic structures of the brain of the developing fetus in normal and prenatal influences of alcohol, BzDR were investigated by radio-receptor binding with [3H]-flunitrazepam using synaptosomal fraction obtained from the brain of fetuses and human embryos. Radioanalysis was performed in a Rack-beta scintillation β-counter. The dissociation constant (Kd) and number of specific binding sites (Bmax) were determined by analysis of saturation curves in Scatchard coordinates. Linear Scatchard blots were analyzed in all cases which confirm the presence of only a specific population of binding sites. Distributions of parameters did not deviate from the normal, so statistical analysis of the data was performed by parametric variational statistics (Student’s test) on Statistika 10.0; differences were regarded as significant at p < 0.05. Correlational relationships were assessed by Spearman analysis. Experimental work was carried out in the Department of Clinical Neuroimmunology and Neurobiology of Mental Health Research Institute, Tomsk National Research Medical Center RASci (Tomsk) and in the Laboratory of Clinical Neuromorphology and Laboratory of Clinical Biochemistry of Mental Health Research Center RASci (Moscow). All the studies were approved by the Ethics Committee of the Mental Health Research Institute.
Studies of the properties of human brain BzDR at 8–9 weeks of development showed that specific [3H]-flunitrazepam binding site density (Bmax) was greater in the study group than the control group (Figure 15, Table 3). There was a decrease in receptor affinity for the [3H]-flunitrazepam, in the main study group, related to the increase in the value of Kd (Figure 16, Table 3). The dissociation constant—Kd is inversely proportional to the receptor affinity for their ligand, that is affinity corresponds—1/Kd. The observed increases in Kd indicate a decrease in the affinity of the receptors. The data obtained indicate an increase in the expression of receptors with a decrease in their affinity for the ligand in human embryo brains under the prenatal alcohol exposure.
Statistical analysis of [3H]-flunitrazepam binding parameters [Bmax (fmol/mg of protein) – density of binding sites] with synaptosomal membranes of human embryonic and fetuses brain in the control (a) and study (b) groups in dynamics.
Developmental period, weeks | Control group | Study group | ||||
---|---|---|---|---|---|---|
Bmax fmol/mg protein | Kd nM | n | Bmax fmol/mg protein | Kd nM | n | |
8–9 | 984.22 ± 11.64 | 1500 ± 0.024 | 9 | 1210.00 ± 32.79* r = 0.47 p = 0.0001 | 1591 ± 0.023* r = 0.22 p = 0.014 | 9 |
10–11 | 1156.00 ± 15.22 | 1700 ± 0.019 | 8 | 1367.40 ± 30.38* r = 0.50 p = 0.0001 | 1792 ± 0.019* r = 0.49 p = 0.04 | 10 |
12–13 | 1456.29 ± 24.17 | 1900 ± 0.023 | 7 | 1824.13 ± 33.51* r = 0.23 p = 0.0001 | 1982 ± 0.018* r = 0.19 p = 0.014 | 8 |
14–15 | 1712.00 ± 35.24 | 2120 ± 0.031 | 5 | 1938.17 ± 47.28* r = 0.73 p = 0.005 | 2450 ± 0.068* r = 0.56 p = 0.0027 | 6 |
[3H]-flunitrazepam binding properties with synaptosomal membranes from human embryo and fetus brains (8–15 weeks of development).
Notes: Bmax, [3H]-flunitrazepam binding density with synaptosomal BzDR; Kd, ligand-receptor complex dissociation constant ([3H]-flunitrazepam with synaptosomal BzDR). *Statistically significant differences between study and control groups, p < 0.01.
Statistical analysis of [3H]-flunitrazepam binding parameters [Kd (nM) – constant of dissociation ligand-receptor complex] with synaptosomal membranes of human embryonic and fetuses brain in the control (a) and basic groups (b) in dynamics.
At 10 weeks of gestation, there were not expressive changes in [3H]-flunitrazepam-binding parameters (Kd and Bmax) in compared groups. However, it should be noted that the dynamics of changes in receptor density is discrete, nonlinear. At this period, slight changes in the binding parameters in the control and experimental groups were noted. Density of receptors increases slightly between the 9th and 10th weeks of fetal development. There is some inhibition of growth in receptor density (Figure 16, Table 3), especially in the main group. This correlated with morphometric evaluation of synapses: decreases in presynaptic terminal area and postsynaptic density length in the main experimental group relative to the control group (Table 4).
Developmental period. weeks | Control group (M ± SE) | Study group (M ± SE) | ||||||
---|---|---|---|---|---|---|---|---|
Bmax | P | S | L | Bmax | P | S | L | |
8–9 | 984.22 ± 11.64 | 896.28 ± 63.7 r = 0.80 p = 0.0006 * | 54.521 ± 2673 r = 0.79 p = 0.0003 ** | 36.21 ± 1.56 r = 0.89 p = 0.0004 *** | 1210.00 ± 32.79 | 798.90 ± 40.09 r = 0.78 p = 0.0004 * | 48.861 ± 6773 r = 0.64 p = 0.0002 ** | 32.45 ± 1.23 r = 0.85 p = 0.0007 *** |
10–11 | 1156.00 ± 15.22 | 948.19 ± 58.2 r = 0.77 p = 0.0004 * | 66.964 ± 3833 r = 0.62 p = 0.0002 ** | 42.37 ± 1.70 r = 0.87 p = 0.0008 *** | 1367.40 ± 30.38 | 941.56 ± 64.44 r = 0.82 p = 0.0006 * | 63.178 ± 3168 r = 0.71 p = 0.0001 ** | 35.80 ± 2.37 r = 0.88 p = 0.0005 *** |
12–13 | 1456.29 ± 24.17 | 1276.02 ± 73.1 r = 0.83 p = 0.0008 * | 75.742 ± 3207 r = 0.76 p = 0.0001 ** | 63.33 ± 2.51 r = 0.91 p = 0.0003 *** | 1824.13 ± 47.28 | 1129 ± 86.87 r = 0.79 p = 0.0004 * | 66.750 ± 4436 r = 0.70 p = 0.0003 ** | 51.90 ± 2.88 r = 0.83 p = 0.0008 *** |
Correlation analysis of morphometric parameters of synapses (presynaptic terminal area perimeter and area, postsynaptic density length) and [3H]-flunitrazepam specific binding site density (BzDR) at different developmental stages.
Notes: L, postsynaptic density length; S, presynaptic terminal area; P, presynaptic terminal perimeter; r, correlation between control and study groups between Bmax and P (*), Bmax and S (**) and Bmax and L (***); p, level of significance of correlational relationships.
Alcohol in the early stages of pregnancy, according to the data, negatively affects the formation of synaptic contacts and benzodiazepine receptors in the human brain, reducing the functional activity of the brain and its development. We found that from the 12–13 weeks of pregnancy, a significant increase in receptor expression (Bmax) was observed, and this trend of increasing prescription density continued during the gestation period of 14–15 weeks (Figures 15 and 16, Table 3). However, in the experimental group, with prenatal exposure to alcohol, the affinity of the receptors decreased at all stages of the human brain development, and the increase in expression and density of receptors can be considered as compensatory adaptive brain reaction with decreasing affinity of receptors. The change in receptor affinity is attributed to neuroplastic changes in the tissue of the developing brain due to the chronic effects of alcohol.
In ontogenesis, in the early stages of gestation, the benzodiazepine receptor system of the human brain is normally formed, starting with the 7th week of development. According to the data obtained, the density of BzDR during pregnancy 8–9 – 14-15 weeks increases by almost 200%. During prenatal influence of alcohol, associated with maternal alcoholism, we found that expression of BzDR was higher in comparison with control, at different developmental stages. The data of receptor analysis showed that the density of synaptic BzDR (Bmax) correlates with the morphometric characteristics of the synapses (Table 4). We have shown that the affinity of receptors for the ligand during the development of the brain is somewhat reduced, which indicates the greatest sensitivity of receptors at the earliest stages of development—8–10 weeks of gestation. The prenatal influence of alcohol significantly reduced the affinity of the receptors in the experimental group, which confirms the greatest sensitivity of the BzDR to alcohol at the earliest stage of the formation of the human brain. The results of our study of the human embryonic brain in normal and under the influence of alcohol, which is associated with mother’s alcoholism, indicate significant neuroplastic changes in the human brain during the early stages of its growth and development [52, 53].
Neuroplastic changes in blood vessels, synapses associated with GABAergic activity and BzDR receptors, in the developing brain under the influence of maternal alcoholism, are aimed at adapting the nervous system of the embryo and fetus to the phenomena of hypoxia, as well as functional failure of GABAergic neurotransmission. However, these adaptive changes in the human embryonic brain differ significantly from the processes of formation of angiogenesis and synaptogenesis and GABAAR neurotransmitter system of the normal human brain, which leads to various somatic disruptions and mental disorders, including the development of FAS and PAE.
Benzodiazepine receptors in different human mature brain of the alcoholics were performed using autopsy material (postmortem) obtained as a result of an urgent autopsy. Samples of autopsy material of the human brain were obtained during urgent autopsy (no later than 6 hours after the onset of death). Samples of the tissue of the prefrontal cerebral cortex, the cerebellar cortex and the head of the caudate nucleus of the brain in persons who were chronically subjected to alcoholization (based on anamnesis) and control subjects were postmortem. Samples of the brain were frozen and stored in thermoses with liquid nitrogen. A total of 126 samples from different areas of the human brain were obtained for the study of radio-receptor binding, including the basic group and the reference control group. In addition to the data of the anamnesis, the objective biological criteria for chronic alcoholization of man (fatty liver, cirrhosis, etc.) were used to form the main group. The control group included patients who did not have neurological and mental illnesses. Autopsy material was obtained only from males, and the age range was 33–54 years. Alcoholic patients were under the supervision by psychiatrists of Mental Health Research Institute and had a diagnosis according to ICD-10: F10.232; F10.302. Patients with other psychiatric disorders were not included in this study. The study included only patients whose lethal outcome occurred as a result of acute heart failure and not subjected to resuscitation measures.
The separation of tissue from human brain samples into membrane fractions (synaptosomal and mitochondrial) was carried out by preparative ultracentrifugation. The resulting membrane fractions were frozen and stored at t = −80° C. Investigation of the properties of BzDR “central” type (CBR) and BzDRs “peripheral” type (PBR) was performed by the radioreceptor assay of binding synaptosomal and mitochondrial membranes with selective ligands. We used the parametric method (t test) using Statistika 10.0.
The experimental part of the research was carried out by us in the Laboratory of Neurobiology Mental Health Research Institute (Tomsk) and Laboratory of Clinical Biochemistry Research Center for Mental Health Sciences (Moscow). All ongoing studies were approved by the Ethics Committee.
A study of the binding characteristics of the selective ligand [3H]-flunitrazepam with synaptosomal fractions of membranes obtained from various regions of the human brain (postmortem) has shown that the properties of synaptosomal BzDR differ in the structures of the brain studied. The highest affinity of CBR was detected in the caudate nucleus and the lower affinity receptors have been identified in the cerebral cortex (the region of the prefrontal cortex) and in the cerebellar cortex (Figure 17, Table 5).
The density of the receptors in the brain structures studied was also different: the maximum receptor density (Bmax) was detected in the caudate nucleus, in the cerebral cortex (the region of the prefrontal cortex) and in the cerebellar cortex (Figure 18, Table 5). Thus, the results obtained by us testify to the heterogeneity of the CBR in various areas of the human brain in the control group. A comparative analysis of the kinetic characteristics of the binding of [3H]-flunitrazepam showed a significant increase in the Kd values in the studied brain structures in the patients of the main group as compared to the patients in the control group, which indicates a decrease in receptor affinity. The largest changes in Kd were found in the cerebral cortex, the caudate nucleus and, to a lesser extent, in the cerebellar cortex (Figures 17 and 18, Table 5). Thus, the changes revealed by us indicate a decrease in the affinity of CBP in the brains of patients under the exposure of chronic alcoholization and an increase in their density in relation to the control group, which can be compensatory adaptive in nature [54].
A comparative analysis of the PBR properties in the study of the binding of [3H]PK-11195 to the mitochondrial fraction of membranes isolated from various regions of the human brain showed that the degree of manifestation of changes in the PBR properties is not the same in the studied brain structures of patients who had alcoholism according to anamnesis. The greatest changes of PBR in comparison with the control were detected in the caudate nucleus and the cerebellar cortex (Figures 19 and 20, Table 5). The obtained results indicate a heterogeneous change in the properties of BzDR of selective ligands in the human brain under the influence of chronic alcoholization, which confirms the hypothesis of adaptive receptor neuroplasticity and the heterogeneity of the physiological response in various brain regions to the effect of chronic alcohol exposure [54].
Statistical analysis of [3H]-flunitrazepam binding parameters [Kd (nM) – constant of dissociation ligand-receptor complex] with synaptosomal membranes in different areas of the human brain in control group (a) and study group (b) (alcoholic patients).
Area of the brain | [3H]-flunitrazepam binding to synaptosomal membranes | [3H]-PK-11195 binding to mitochondrial membranes | ||||||
---|---|---|---|---|---|---|---|---|
Control group (n = 21) | Study group (n = 21) | Control group (n = 21) | Study group (n = 21) | |||||
Kd1 (nM) | Bmax1 (fmol/mg protein) | Kd1 (nM) | Bmax1 (fmol/mg protein) | Kd2 (nM) | Bmax2 (fmol/mg protein) | Kd2 (nM) | Bmax2 (fmol/mg protein) | |
Prefrontal cortex {М ± SE} | 1.82 ± 0.07 | 1772 ± 79 | 2.12 ± 0.09* | 3165 ± 565* | 2.45 ± 0.17 | 1824 ± 11 | 3.12 ± 0.13** | 2245 ± 168** |
N.caudatus {М ± SE} | 1.68 ± 0.05 | 948 ± 112 | 1.97 ± 0.09* | 2817 ± 386* | 1.12 ± 0.09 | 724 ± 36 | 2.31 ± 0.16** | 1895 ± 77** |
Cerebellar cortex {М ± SE} | 1.98 ± 0.1 | 1048 ± 67 | 2.24 ± 0.21* | 1845 ± 217* | 2.61 ± 0.21 | 1209 ± 98 | 3.32 ± 0.19** | 2479 ± 123** |
Properties of [3H]-flunitrazepam and [3H]PK-11195 binding to the synaptosomal and mitochondrial membranes from different areas of the human brain in alcoholic patients and control.
Notes: Bmax1, density of binding sites [3H]-flunitrazepam with synaptosomal membranes; Kd1, constant of dissociation ligand-receptor complex [3H]-flunitrazepam with CBR; Bmax2, density of binding sites [3H]PK-11195 with mitochondrial membranes; Kd2, constant of dissociation ligand-receptor complex [3H]PK-11195 with PBR; n, the number of cases studied. *Statistically significant difference indicators binding [3H]-flunitrazepam and **[3H]PK-11195 between study and control groups, p < 0.05.
Statistical analysis of [3H]-flunitrazepam binding parameters [Bmax (fmol/mg of protein) – density of binding sites] with synaptosomal membranes in different areas of the human brain in control group (a) and study group (b) (alcoholic patients).
Statistical analysis of [3H]PK-11195 binding parameters [Kd (nM) – constant of dissociation ligand-receptor complex] with mitochondrial membranes in different areas of the human brain in control group (a) and study group (b) (alcoholic patients).
Statistical analysis of [3H]PK-11195 binding parameters [Bmax (fmol/mg of protein) – density of binding sites] with mitochondrial membranes in different areas of the human brain in control group (a) and study group (b) (alcoholic patients).
The results we obtained are consistent with data from other studies showing a decrease in the function of GABAA/BzDR in the cerebral cortex in patients with alcohol dependence [36, 55]. These data confirm that the low affinity of BzDR can be a neuronal marker of the development of anxiety and conditions associated with chronic alcohol use and AAS. The study of BzDR carried out by us in various areas of the human brain (on postmortal material) showed that the properties of synaptosomal and mitochondrial receptors differ in the brain structures studied: the prefrontal cortex, the caudate nucleus and the cerebellar cortex. CBR are the sites of specific binding of ligands of benzodiazepine series, neurosteroids and alcohol to the GABA receptor, modulating its function allosteric and regulating the processes of inhibition in brain structures that affect the activity of various neurotransmitter systems, including the activity in the structures of the brain associated with the process of natural reinforcement. The higher affinity and density of CBR in the caudate nucleus and the prefrontal cortex are related to their functional activity in the regulation of emotions and motivated human behavior.
The effect of ethanol causes a change in PBR not associated with GABAAR, localized in the mitochondrial membrane, predominantly in glial cells of the brain, and providing cholesterol transfer into the mitochondria [46], thus affecting the regulation of the synthesis of neurosteroids, which are endogenous modulators of GABAA/BzDR in the CNS [42]. Alcohol carries out some of their effects through PBR, regulating the production of neurosteroids and their metabolites, which are critical components of normal brain function [46]. Thus, PBR indirectly affects GABAergic function in the brain, mainly reacting to neurotoxic effects and various brain damage [36, 55, 56].
The data obtained by us confirm the existence of regulatory mechanisms mediating the relationship between the properties of GABAA/BzDR caused by receptor neuroplasticity and alcohol addiction.
An important factor that can influence addiction liability is exposure of alcohol and other psychoactive substances during the early life period. Exposure to ethanol, early in life, can have long-lasting implications on brain function and drugs of abuse response later in life.
One of the mechanisms of action of alcohol is the ability to induce vascular spasm, which leads to hypoxia of the developing embryo and affects the retardation of development and growth of the fetus with prenatal effects of alcohol. These changes can lead to the development of fetal alcohol syndrome. Compensatory mechanism in the conditions of this pathology, leading to a decrease in the perimeter of the vessel and the area of the vessel in the cross section, is an increase in the number of vessels in the brain [57]. Alcoholization of the mother, leading to prenatal effects of alcohol on the developing fetus, affects the dynamics of embryonic development of the circulatory system in the human brain, which manifests itself in a change in the vascularization of the growing human brain [23].
The effects of ethanol in the early stages of development can disrupt the signaling mechanisms that regulate synaptogenesis. The result was “dilution” of the structure of elementary membranes and damaged membranes are less able to establish strong contact with each other, which is probably due also to a reduced ability of cells that are in constant contact with ethanol, synthesized mediators filling synaptic vesicles. This significantly violated the formation of neuronal mechanisms underlying the susceptibility and processing of information, which in turn could adversely affect a person’s mental activity.
The data obtained by us showed a structured picture of synaptogenesis as one of the most significant periods in the formation and development of the brain, providing its functions and determining the adaptive potential in prenatal alcohol influences. The influence of prenatal ethanol on the development of synaptic structures was expressed in reduction of morphometric parameters, namely slowing the formation of synaptic contacts and reducing their formation in the brain of the embryo and fetus in the early stages of development, in contrast to the normally developing brain, which affects synaptogenesis in the developing brain of a person and can underlie fetal death or serious disorders the child in the future [23, 49, 52, 53, 54].
On the background of the decrease in the formation of synaptic structures seen here in the fetal brain during gestation under the influence of maternal alcoholism and the simultaneous decrease in the affinity of synaptosomal BzDR, the tendency to an increase in receptor density can be evaluated as neuroplastic features and compensatory reaction directed to adapting the embryo and fetus nervous system to conditions of functional insufficiency of GABAergic neurotransmission. These new data can broaden the understanding of the molecular basis of predisposition not only to alcoholism but also to various disorders associated with PAE. Children and adolescents who were under the influence of alcohol during the period of prenatal development noted functional disorders of neurocognition, self-regulation and adaptive functioning and various neurobehavioral disorders associated with PAE [58]. Plasticity of ion channels and receptors linked to ion channels regulated by neurotransmitters is significant for the realization of adaptive processes in the brain, providing synaptic plasticity for the formation and development of neural network, physiological and pathophysiological processes. Prenatal alcohol exposure (PAE) can cause irreversible physical, neurological and psychiatric impairments that are present at birth and can have lifelong implications [14, 59]. The relationship between prenatal exposure to alcohol and the frequency of behavioral disorders in children and adolescents is established. [60]. The effect remained significant compared to other variables, including environment, maternal psychopathology and some others, and can cause a different mental dysfunction associated with a violation of brain metabolism in children and adolescents in the future [61].
Similar changes in the benzodiazepine receptor binding were identified by us in the brains of patients with alcoholism also. A decrease in the ability of receptors to bind agonist ligands impairs the ligand:receptor protein ratio, leading to decreased binding of the major neurotransmitter GABA and impairment to synaptic transmission. Our results are consistent with other studies that showed a reduction in the function of GABAA/BzDR in the prefrontal cortex in patients with alcohol dependence [36, 55]. Alcohol causes neuroplastic changes in BzDR associated with a decrease in the affinity of the receptors, a change in the conformational state of the GABAA/BzD rector complex, as a result of inhibition of the binding kinetics of BzDR by the polypeptide DBI (Diazepam Binding Inhibitor), as well as its metabolites. The endogenous peptide DBI possesses anxiogenic action and is the inverse agonist of BzDR [62]. Chronic alcohol exposure induces the expression of endogenous DBI interacting with receptors and suppresses binding affinity to [3H]-flunitrazepam.
Neuroplastic changes of GABAAR, caused by the influence of ethanol, are associated with a change in the composition of subunits of the receptor complex and change in the pharmacological sensitivity and receptor function associated with the development of tolerance to ethanol and alcohol dependence. High heterogeneity of different isoforms of subunits of the GABAA receptor (α1-α6; β2,β3) in various regions of the brain: nuclei of the basal ganglia, prefrontal cortex and limbic regions of the brain, underlies the functional differentiation of the GABAA receptor complex and provides a varying degree of modulation functions of GABAAR by ethanol in various brain structures [63]. Changes in the expression of neuronal elements induced by alcohol, leading to changes in neurotransmitter function adaptation systems in the brain associated with neuroplasticity [64].
Benzodiazepines, anxiolytics, anesthetics and alcohol are implementing some of its effects through the BzDR “central” and “peripheral” types regulating the synthesis of neurosteroids, which are critical for the provision of brain functions. Ethanol modulates GABAA/BzD receptor complex function by affecting synthesis neurosteroids de novo in the brain, stimulating the mitochondrial receptors of the “peripheral type”—PBR, providing the transfer of cholesterol to mitochondria and synthesizing neurosteroids, independent of the functions of the HPA axis. This mechanism can play a principal role in the central effects of alcohol. Thus, the functional activity of PBR has a modulating effect on GABAergic function in the structures of the brain, reacting to various neurotoxic effects and damage [65].
Alcohol does not have specific receptors in the brain; however, the receptor proteins are exposed to ethanol. The research of a number of authors is aimed at studying long-lasting adaptive changes (neuroplasticity), which contribute to the development of alcohol dependence. Our studies aimed at studying neuroadaptation under the influence of chronic alcohol effects on the benzodiazepine receptor system of the brain have revealed that a low affinity of BzDR can be a marker of disorders of synaptogenesis and regulatory mechanisms mediating the GABAA/BzDR bond that induces receptor neuroplasticity and alcohol addiction [41, 54, 65, 66].
BzDR “central” and “peripheral” types can be a key link to the discovery of new promising therapy for the treatment of compulsive craving for alcohol, alcohol abuse and dependence. The integration of current data and our data is necessary to define the role of GABAAR in modulating the rewarding and aversive effects of ethanol and may lead to the development of pharmacotherapy that targets GABAA/BzD receptors to treat alcoholism in human beings [65, 66, 67, 68].
The temporal bone is a dense complex bone that constitutes the lower lateral aspect of the skull and has complex anatomy because of the three-dimensional relationships between neurovascular structures. The petrous portion of the temporal bone has a role as the partition between the middle and posterior cranial fossae. It articulates with the occipital bone (occipitomastoid suture) posteriorly, the parietal bone (squamous suture) superiorly, the sphenoid bone (spheno-squamosal suture) and the zygomatic bone (arcus zygomaticus) anteriorly, and the mandible (temporomandibular joint) inferiorly [1, 2]. It contains multiple intrinsic channels, along with the internal carotid artery (ICA), cranial nerves, and sigmoid sinus (SS), all within intricate spatial architecture. Owing to a complex web of foramina and neurovascular structures of the temporal bone, the lateral skull base is a technically difficult region for surgeons. Because the middle and inner ear structures of hearing and equilibrium are preserved in the temporal bone, a surgical dissection of it requires thorough understanding of three-dimensional (3D) map of the topographic anatomy to avoid iatrogenic risks. The relationship between the surface landmarks and expected internal structures and the segmentation of the temporal structures by using key surgical lines and spaces allow a better understanding of its anatomic architecture. Each temporal bone consists of five distinct osseous segments including the squamous, tympanic, petrous, mastoid, and styloid portions [3, 4].
The anterosuperior part of the temporal bone is a large flattened scale-like plate that forms the lateral boundary of the middle cranial fossa. It has three borders and two surfaces [1].
Superiorly, it overlaps the sculpted squamous margin of the middle third of the parietal bone and constructs the squamosal suture. Posteriorly, it forms the occipitomastoid suture with the squamous part of the occipital bone. Also, there is an angle, parietal notch, between the squamous and mastoid portions of the temporal bone (Figure 1). Antero-inferiorly, its thick serrated margin takes part in pterion formation and articulates with the greater wing of the sphenoid bone to form the spheno-squamosal suture. Inferiorly, it fuses and forms the petro-squamous suture with the superior surface of the petrous portion by extending medially as tegmen tympany [5, 6].
The surface landmarks on the squamous portion: 1, temporal fossa; 2, supra-meatal crest; 3, temporal line; 4, external acoustic meatus; 5, supra-meatal triangle (Macewen’s triangle); 6, middle temporal artery; 7, squamo-mastoid suture; 8, mandibular fossa (glenoid fossa); 9, articular eminence; 10, zygomatic process; 11, petrotympanic fissure (Glaserian fissure); 12, mastoid foramen; 13, parietal notch; 14, mastoid process; 15, mastoid notch (digastric fossa); 16, occipital sulcus; 17, tympano-mastoid suture; 18, vaginal process; 19, styloid process.
External surface, the greater part of the temporal fossa, provides origin to the temporalis muscle and is limited below by the curved line, the temporal line, that lies from the supra-meatal crest to the mastoid cortex posteriorly. Below this line, just above and behind the external acoustic meatus (EAM), the supra-meatal triangle (Macewen’s triangle) contains the supra-meatal spine, spine of Henle and the cribriform area (Figure 1). Also, the squamo-mastoid suture is located approximately 1 cm below the temporal line [5, 6, 7]. On this smooth surface, there is a sulcus for the middle temporal artery, which is the medial branch of the superficial temporal artery (STA). Antero-inferiorly, the zygomatic process projects by two roots: the upper border of the posterior root forms the supra-meatal crest and the lower border forms a laterally based projection, known as post-glenoid tubercle or process (PGP). Inferiorly, the concavity along the surface of the anterior root is called the glenoid fossa (GF), which is bounded by the articular eminence (ArE) anteriorly and the PGP posteriorly [5, 6, 7].
Internal surface is rough and concave in shape, and the anterior and posterior divisions of middle meningeal artery (MMA) run in a groove on this surface that defines the boundary of middle cranial fossa with impressions for the gyri of the temporal lobe. Inferiorly, it forms the petro-squamosal suture with the anterior surface of the petrous part [5, 6].
The Macewen’s triangle, a surgical surface marking for the mastoid antrum (MA), is formed between the temporal line superiorly, the posterosuperior wall of the EAM antero-inferiorly, and the opening of the mastoid emissary vein or sinodural angle posteriorly (Figure 1). The temporal line corresponds to the tegmen tympani (TT), which is a bony plate below the middle cranial fossa dura and over the mastoid air cells. The mastoid cortex posterior to the spine of Henle is a guide to the lateral wall of the MA and located 15 mm deep to it in adults but in new born about 2 mm [5, 6, 8]. The cribriform area in Macewen’s triangle is perforated by numerous small holes that serve as a passage for the vessels of the mucosa of the antrum. The dissection along the margins of this triangle is safer because the vital neurovascular structures are absent. Peris-Celda et al. reported that the temporal line is supratentorial and infratentorial in 93% and 7% of the cases, respectively [9]. During retro-auricular mastoidectomy, the MA may be exposured by drilling the cribriform area and provides a safer surgical approach to the tympanic cavity. The tympanic portion and the styloid process may show variations depending on the shape and the position of the spine of Henle. The MA is located in the same line of the spine of Henle at about 10 years; then the MA is enlarged and placed 1 cm behind it [6, 9].
The MMA lies underneath the pterion which is a common junction between the temporal, parietal, frontal, and sphenoid bones. The fracture of this weakest bony part may result in an epidural bleeding. Between the temporal muscle and fascia, the STA and the superficial temporal vein (STV) courses in close proximity with the zygomaticotemporal (ZTN) and the auriculotemporal (ATN) nerves, branches of the trigeminal nerve (TN). Because of a vessel running superficial to the nerve (80% STA), the underlying nerve may be compressed and results in temporal migraine headache. Lee et al. reported that the intersection (compression) point among the ATN, STA, and STV was at an average of 40 mm superior and 10 mm anterior to the tragus, which is a significant surface landmark at the most anterosuperior point of the EAM. The applications of surgical decompression of the ATN in these compression points improve migraine headache [10].
The anterior articular part of the GF is formed by a gentle sloped area of the squamous portion, which facilitates the movement of the temporomandibular joint (TMJ) during wide mouth opening. At the lateral aspect of the ArE, a small bony ridge, articular tubercle (AT), serves as an attachment for the lateral collateral ligament. The PGP inhibits backward displacement of mandibular head and participates to the superior wall of the EAM [8]. The posterior nonarticular part of the GP is formed by the tympanic portion and the squamo-tympanic suture intervenes between them. The inferior edge of the TT (petrous part) divides this suture into two: a petro-squamosal fissure in front and a petrotympanic fissure (Glaserian fissure) behind (Figure 1). The chorda tympani nerve, a branch of the facial nerve, exits the temporal bone through the Glaserian fissure and joins the lingual nerve as the parasympathetic input to start the submandibular and sublingual gland secretions [2, 4, 5].
The articulation between the GF and the condyle of the mandible is called TMJ, which plays an essential role in speech, respiration, swallowing, and specially mastication. Because the TMJ is in close proximity with the MMA, some surgical landmarks around the TMJ and foramen spinosum (FS) play a critical role in surgical approaches. Miller et al. reported that researchers measured the distances from the zygomatic root (first projection of the zygomatic arch = PGP) to some surgical landmarks such as the arcuate eminence (AE), the head of the malleus (HM) under the TT, and the FS to identify the location of the internal auditory meatus (IAM) or the superior semicircular canal (SSC). Also, they described the superior petrosal triangle as a consistent triangle between the zygomatic root, the FR, and the HM to localize the bony tegmen over the tympanic cavity [11]. Baur et al. offered simply identifiable reference landmarks including the AE, the most lateral aspect of the Glaserian fissure and the FS and measured the distances between them to predict the location of the MMA [12]. According to these researchers, the internal landmarks including the HM and Bill’s bar (the vertical crest in the fundus of the internal auditory canal) are in a single plane with the zygomatic root [11].
After the ArE forming the anterior limit of the GF, the anterior root continues in front as a bony ridge that forms the posterior boundary of the infratemporal fossa, which is a small triangular area transmitting the neurovascular structures between the pterygopalatine fossa and temporal fossa. Then, a serrated anterior end of the zygomatic process passes straight forward and articulates with the temporal process of the zygomatic bone and completes the zygomatic arch. The temporal fascia inserts to this arch and the temporal line superiorly and also the masseter muscle origins from the arch inferiorly. The lateral temporomandibular ligament attaches to the AT, and the GF is covered with an articular disc to construct the synovial TMJ with the condyle of the mandible [5, 6, 7].
Anteriorly, the small part of squamous portion takes part in the infratemporal fossa formation with the zygomatic bone and the greater wing of the sphenoid bone. Below the zygomatic bone, the branches of the first and second mandibular parts of the MA with veins and the pterygoid plexus of veins, the mandibular and lingual nerves pass through the infratemporal fossa. During the infratemporal fossa approaching for surgical removal of tumors localized in the orbit, the maxillary and sphenoid sinuses, the detailed anatomical knowledge of these neurovascular structures is needed. Depending on the position of the infratemporal fossa below the floor of the middle cranial fossa and posterior to the maxilla, it is in close proximity with the parapharyngeal and masticator spaces. The parapharyngeal carotid artery enters the carotid canal (CC) behind the FS and foramen ovale. During transpterygoid infratemporal fossa approach, the positions of these surgical landmarks can be used to prevent ICA injury [13].
Ossification of the squamous portion starts intramembranously from one center around the zygomatic process at the 2nd month. At birth it fuses with the other membranous bone, tympanic portion. Normally, at birth the temporal bone consists of three parts; the petrous, squamous, and the tympanic [1].
The mastoid portion forms the pneumatized thick posterior part of the temporal bone. It fuses with the squamous portion antero-superiorly and the tympanic portion anteriorly and the petrous portion anteromedially. It has three borders and two surfaces [5, 6].
Posteriorly, it articulates with the squamous part of the occipital bone between lateral angle and the jugular process and constructs the occipitomastoid suture. Inferiorly, the mastoid process extends as a rough and conical shaped projection and filled with mastoid cells variable in shape and size. Anteriorly, it associates with the tympanic portions of the temporal bone to form the tympano-mastoid suture, and the inferior auricular branch of the vagus nerve (Arnold’s nerve) exits through this suture [5, 14, 15].
Near the squamo-mastoid suture, the occipital belly of occipito-frontalis and auricularis posterior muscles attach on the external surface that is perforated by numerous small foramina. At the posterior border of the mastoid portion or the occipitomastoid suture, the largest one, mastoid foramen is located and transmits an emissary vein connecting the SS with the posterior auricular vein and a branch of occipital artery to the dura mater (Figure 1). The mastoid process serves for the attachment of the sternocleidomastoid, splenius capitis, and longissimus capitis muscles and shows variations in shape and size with respect to sex. The posterior belly of the digastric muscle is originated from the mastoid notch (digastric fossa), which is a depression on the inferomedial margin of the mastoid process (Figure 1). More medial to the notch lies a sulcus, the occipital sulcus, forming a groove for the occipital artery [4, 6].
The internal surface includes a well-defined and curved sigmoid sulcus lying along its junction with the posterior surface of petrous part and lodges the SS, partially the transverse sinus, which are separated from mastoid air cells by a thin plate of bone. The mastoid foramen transmitting the mastoid emissary vein may be open to this sulcus. The SS begins as the continuation of the transverse sinus and lies downward in a S-shaped groove and opens into the superior jugular bulb. There is a sinodural angle between the dura plates of the SS and middle and posterior cranial fossae [2, 5, 9, 16].
The mastoid process shows tree types of pneumatization patterns including pneumatic (full air cell), sclerotic (solid mass of bone), and mixed (air cells and bone marrow) types. Especially, in the anterosuperior part of the mastoid process, there is an irregular cavity that is larger than other mastoid cells and called MA, which corresponds to the cribriform area. It is covered with the mucous membrane of the tympanic cavity and communicates anteriorly with the epitympanic recess of the middle ear via the aditus ad antrum. The tegmen antri, a roof of the MA, separates it from the middle cranial fossa. During embryonic period, the squamous and petrous portions fused each other and forms the petro-squamous suture. In adults, it forms a thin bony septum, the Körner’s septum, by extending into the mastoid process [1, 4, 6, 9, 17]. Körner’s septum divides the mastoid air cells in the mastoid process into a deep petrous part medially and a superficial squamous part laterally. The petro-squamosal sinus or the mastoid emissary vein may infrequently be observed along this septum. During mastoidectomy or transmastoid approaches, awareness of this crucial landmark and its variations is essential to avoid iatrogenic complications. The squamous part starts to develop at 8th week, whereas the petrous part develops later at 6th months during embryogenesis, and each part opens into the MA separately [1]. Also, the mastoid cells are separated by bony plates from the adjacent structures such as the posterior wall of the EAM anteriorly, tegmen plate superiorly, SS posteriorly, digastric ridge inferiorly, and the lateral semicircular canal (LSC) or solid triangle medially. The solid triangle is a compact bony angle between three SCs. During the mastoidectomy, all the air cells around this septum and adjacent bony structures should be removed without damaging the bony plates. To avoid iatrogenic injury to the adjacent structures, the MA must be open superiorly toward TT. The tympano-mastoid suture at the posterior wall of the MA is surface marking of the course of the vertical portion of the facial nerve (FN) [9, 16, 18]. Peris-Celda et al. reported that the parietal notch corresponds to the posterior petrosal point and the SS (the transverse-SS junction) in 66 and 34% of the cases, respectively [9].
Ossification of the mastoid portion is endochondral which is identical to the petrous and styloid portions. At birth, the mastoid process is absent, and the MA is invisible and covered by a thin bony plate that is extension of the squamous portion. At the first year, the mastoid process becomes prominent and the petro-squamous suture arises. The antrum can be seen obviously at about the fifth year. During puberty, the thickness of the process increases, and it becomes pneumatic that is lined by mucous membrane. In adults, the mastoid process may not contain air cells in 20% cases [1, 2, 17].
An annular shaped part of the temporal bone forms the tympano-mastoid suture posteriorly and the squamo-tympanic suture superiorly (Figure 1). Medially, it fuses with the petrous portion, whereas a free lateral part of it constructs the major part of the EAM and also serves an attachment for the cartilaginous part of the external auditory canal (EAC). Its inferior margin is free, and it has two parts on the lateral surface; posterosuperior part forms the EAM, and anteroinferior part limits the mandibular fossa posteriorly [5, 19].
Medially, just above the GF, this suture is subdivided by a thin tegmen part of the petrous portion into two: the petrotympanic fissure posteriorly and the petro-squamosal fissure anteriorly. Lateral part of this upper margin fuses with the back of the PGP to form the nonarticular part of the GF. Inferiorly, the lateral part of the margin gives an attachment for the deep part of the parotid fascia and forms the vaginal process, which wraps the root of the styloid process laterally [2, 4].
Laterally, external surface is bounded by the cartilaginous part of the EAC which extends from the auricle to the tympanic membrane. The EAC is an S-shaped tube, about 2.5 cm in long, that is composed of the lateral third cartilaginous part and the medial two-thirds osseous part [14, 15, 18]. The tympanic part constructs the anterior wall and floor and the lower part of posterior wall of the EAM, whereas the squamous part forms the superior and upper part of the posterior wall of it (Figure 1). The tympanic part grows from the tympanic ring, which is open U-shaped possessing two edge anterior and posterior. The anterior edge forms the tympano-squamous fissure within the anterosuperior part of the EAM and the petrotympanic fissure within the middle ear, whereas the posterior edge forms the tympano-mastoid fissure within the posteroinferior part of the EAM near the stylomastoid foramen (SMF) [2, 4, 19].
The internal surface fuses with the petrous portion and forms the tympanic sulcus for the lodgement of the tympanic membrane, which forms an angle about 55° with the floor of the EAM and separates the external and middle ear (ME). At the upper part, the tympanic sulcus does not fuse each other by forming the greater and lesser tympanic spines and a notch called Rivinus between them. This notch is closed by the pars flaccida of the tympanic membrane. The notch of Rivinus corresponds to the junction between the squamous and tympanic portions [1, 4, 14, 20].
Ossification starts from the four centers around the tympanic ring at the end of the embryonic period (8th week) via intramembranous ossification of the EAM. The tympanic ring at first is nearly straight and then turns into horseshoe shape (annular) and then, the open arms extending upwards terminate in a notch for the location of the tympanic membrane between them. After birth, the upper segment of the tympanic bone grows rapidly but because of the gradual development of the lower segment, a deep notch (tympanic foramen) is left in the anterior part of the bony EAM. Normally, the tympanic ring fuses until the age of 5 year but a dehiscence may persist (range 4.6−22.7%) at the anteroinferior aspect of the EAM, called foramen of Huschke (foramen tympanicum). This fusion defect is not a true foramen, but it may cause a connection between the EAM and the posteromedial part of the TMJ and results in TMJ herniation and the secretion of the parotid gland and also the dissemination of tumor and infections into the EAM [1, 14, 19, 20]. Anteriorly, the EAM may communicate with the retromandibular part of the parotid gland via the fissures of Santorini within the anterior cartilage. Peris-Celda et al. reported that the SSC dehiscence can be observed approximately 1.5 cm posterior to the middle point of the EAM in 86% of the cases [9]. In newborn, the tympanic membrane is infiltrated with air and the tympanic ring forms a bony plate, which may cause the development of a cleft, the auricular fissure, posteriorly and a cleft, the tympano-squamous fissure, anteriorly [19, 20].
The petrous portion is a dense pyramid-shaped bone and composed of the labyrinth of the internal ear, the tympanic cavity of the middle ear and a bony part of the auditory Eustachian tube (ET), and canals for the passage of the ICA and the FN. It is ossified from the otic capsule by forming a 45° angle with the horizontal axis. It has a base, an apex, and three surfaces and three borders [3, 4, 21].
Superiorly, the petrous ridge is the longest border and a boundary between the posterior part of the middle cranial fossa (the anterior surface of the petrous part) and the anterior part of the posterior cranial fossa (the posterior surface of the petrous part). It contains a groove that lodges the superior petrosal sinus (SPS) and the lateral margin of tentorium cerebelli attaches to this margin (Figure 2). Posteriorly, the medial part of the posterior margin articulates with the basilar part of occipital bone along the petro-clival fissure and forms a groove that lodges the inferior petrosal sinus (IPS) that extends from the posteroinferior part of the cavernous sinus to the internal jugular vein (IJV). The lateral part of the posterior margin is free and limits the jugular foramen (JF) supero-laterally and has a triangular notch for the lodgement of the inferior ganglion of the glossopharyngeal nerve (Jacobson’s nerve = GPN). Anterolateral border is formed by the ET extending from the anteroinferior wall of the tympanic cavity to the nasopharynx [3, 4, 9].
The surface landmarks on the anterior surface of the petrous portion: a, petrous ridge (sulcus of the superior petrosal sinus); b, arcuate eminence; c, tegmen tympani; d, sulcus of the lesser petrosal nerve; e, sulcus of the greater petrosal nerve; f, trigeminal impression; g, petrous apex; ıocc, internal opening of carotid canal.
The base is integrated with the inner surface of the squamous and mastoid portions, whereas the apex forms the posterolateral margin of the foramen lacerum (FL) and faces the Meckel’s cave medially. There is a fibrocartilage connection between the apex and the clivus. The internal opening of the carotid canal (IOCC) is observed at the apex for the intracranial entry of the ICA. At the anterolateral part of the FL, the petro-sphenoid ligament connects the tip of the apex to the dorsum sellae of the sphenoid and the abducent nerve lies below this ligament and enters the cavernous sinus adjoining the ICA [1, 7, 16].
Anterior surface describes a triangular area, between the linear lines as follows: a horizontal line that starts from the preauricular burrhole in front of the tragus to petrous apex at the FL and passes through the FS anteriorly, the petrous ridge posteriorly and the petro-squamous suture, which lies along the junction of the petrous pyramid with the vertical part of the squamous portion laterally [3, 16, 22]. It consists of some marking landmarks (Figure 2).
The anteromedial two-third of the musculotubal canal is cartilaginous, whereas the posterolateral third is bony. The bony part consists of two small canals that are separated by a thin bony septum at the lateral part the petrous portion. The tensor tympani muscle passes through the superior semicanal, whereas the inferior semicanal forms the bony portion of the ET. The tensor tympani muscle originates from the greater wing of the sphenoid and inserts into the upper part of the medial surface of the handle of malleus after making a bend around the processus cochleariformis in the tympanic cavity [4, 6]. The ET lies between the tympanic orifice and the isthmus, which has the smallest diameter at the intersection point of the petrous and squamous parts of the temporal bone just behind the sphenoid spine. Brown et al. reported that the ET is subdivided by genu within the membranocartilaginous part into two portions; posterior horizontal ET between the genu and the anterior attachment of the tympanic membrane ridge, whereas the anterior vertical ET lies from the genu to the nasopharyngeal orifice and opens into the nasopharynx. During endoscopic eustachian tube obliteration, the ET is cannulated to treat refractory CSF rhinorrhea by identifying three anatomic parameters: the ET length, isthmus diameter, and genu location. According to a new surgical classification, the cartilaginous portion of the ET is divided into the petrous, lacerum, pterygoid, and nasopharyngeal parts. The bony part attaches to the ET sulcus or sulcus tuba, which is contiguous to the FL medially. The FL is located in the incomplete confluence of the union of the body and the lingular process of the greater sphenoid wing anteriorly, the clivus of the occipital bone medially and the petrous apex posteriorly and covered with the fibrocartilaginous tissue that separates the ET from the ICA [23].
The internal opening of the CC is located near the FL for the passage of the ICA, which is freed at the petrous apex into the cavernous sinus (Figure 2). It is localized medial to the ET, below the greater superficial petrosal nerve (GSPN), a branch of the FN and the trigeminal ganglion [1, 3, 4]. The petrous segment of the ICA within the CC has four anatomic parts, called vertical, posterior genu, horizontal, and anterior genu. During endoscopic endonasal surgery, the junctional part of the ET at the sphenoid spine and FS is crucial landmark to identify and protect the petrous segment of the ICA [13]. The anatomical and surgical relationships between the ET and the petrous segment of the ICA are as follows:
The first curve, posterior genu is located at the level of the bulging basal turn of the cochlea within the bend of the CC. Laterally, the bony part of the ET and the tendon of the tensor tympani muscle; posterolaterally, the promontory and posterosuperiorly, geniculate ganglion are paramount landmarks for the posterior genu of the ICA. The V3 lying anteromedially to the FS and the parapharyngeal segment of the ICA, which passes posteroinferiorly to the sphenoid spine, are critical landmarks. Posterolaterally, the petroclival fissure cartilage is an important landmark to separate the pharyngobasilar fascia from the anterior genu of ICA.
The second turn of the ICA, anterior genu, above the fibrous tissue of the FL is in close proximity to the lacerum segment of the cartilaginous ET laterally and continues as the paraclival ICA in the carotid groove. During the endoscopic approach, the Vidian artery and nerve (VN) are critical landmarks for the second curve of the ICA.
For safe manipulation of the horizontal part of the ICA, the GSPN can be used as surgical landmark. Above the anterolateral margin of the FL the union of the GSPN and the deep petrosal branch of the carotid neural plexus forms the VN which is located anteroinferiorly and lateral to the second turn of the ICA. Malignancies that involve the petrous apex or the carotid artery require the extended endoscopic endonasl approach (EEA). During this procedure, the medial and lateral optico–carotid recesses in the cavernous sinus and the vidian canal (VC) are vital surgical landmarks, which allow to identify the position of the ICA for safe surgical resection near the ICA [13].
At the apex above the CC, a shallow fossa called trigeminal impression (Figure 2) is located for the lodgement of the sensory ganglion of the TN (semilunar ganglion or Gasser’s ganglion) that is covered by a pouch-shaped dura mater called Meckel’s cave [3]. Vascular compression and arachnoid adherence of the TN branches result in trigeminal neuralgia. During endoscopic vascular decompression and Meckel’s cave approaches, the VC, the bone between V2 and the VC and the pneumatization of the sphenoid sinus form a safe route to access and to decompress Gasser’s ganglion with branches, the cranial nerves (III, IV, VI), and the petrous ICA [13, 23].
Behind the trigeminal impression, the roof of the IAM is indicated as a shallow fossa, then it continues with the AE, which is a surgical landmark for the middle fossa approach and located at the junction of the posterior third and the anterior two-thirds of the petrous portion (Figure 2). It is a valuable guide to signify the SSC and the roof of the vestibule up to 93% of the temporal bones [19, 22].
The TT is a thin bony layer covering all of the anterior surface (Figure 2). It forms the roof of the mucosal line including from behind to forward the MA, tympanic cavity and ET which are lined with mucosa. Also, its lateral edge turns downward to subdivide the squamo-tympanic fissure into two parts [1, 3].
On the TT, a bony roof of the geniculate ganglion, there are two foramina, which continue as a small groove adjoining anteromedially; the medial one starts from the hiatus of the facial canal and lodges the GSPN, a branch of the FN and the petrosal branch of the MMA, whereas the lateral one lodges the lesser superficial petrosal nerve, a branch of GPN (Figure 2) [3, 9, 16, 22].
Kaen et al. described the “VELPPHA” area indicating the posterior limit of the transpterygoid EEA. It is composed of the VC (V), the ET (E), the FL (L), the petroclival fissure (P), the pharyngobasilar fascia (PHA), and multiple cartilaginous fibers between them. The posterior opening of the VC, the posterior limit of surgical corridor in the transpterygoid approach, is located above the ET and below the petrous ICA. Behind the posterior margin of the medial pterygoid process, the superomedial border of the ET attaches to the cartilaginous fibers of the FL. The petroclival fissure is situated between the lateral border of the clivus (occipital bone) and the petrous part of the temporal bone and lodges the IPS. The horizontal segment of the petrous ICA turns upward at the medial border of the petrous apex to form the anterior genu of the ICA, and then it continues as the lacerum segment, second vertical segment of the ICA. So, the VC-ET junction is a safe and critical landmark for efficient localization of the lacerum segment of the ICA, as part of the transpterygoid extension of EEA [24].
Tayebi Meybodi et al. described the pterygoclival ligament as a thickened extension of the pharyngobasilar fascia from the pterygoid process to the anteromedial aspect of the lacerum segment of the ICA and reported that the course of the pterygoclival ligament consistently refers to the anteromedial aspect of the lacerum ICA. So, they suggested that the pterygoclival ligament can be used as a safe landmark in case of tumor invasion of the VN, and drilling along the medial aspect of this ligament is more reliable way compared with the VN to avoid the ICA injury during extended EEA. Also, they remarked that this ligament may localize in a venous compartment, which is in contact with the cavernous sinus superiorly and the pterygoid venous plexus posteroinferiorly [25].
The posterior surface, anterior wall of the posterior cranial fossa, is encircled by a venous triangle that is formed by the grooves for SS posteriorly and SPS at the petrous ridge and IPS at the junction of the pars lateralis of the occipital bone and the temporal bone anteroinferiorly. The SS drains into the bulb of the IJV, which exists from the JF together with the cranial nerves (IX-XI) [1, 6, 9].
The IAM is a short canal, about 1 cm long, and has a large orifice, which allows passage of the vestibulocochlear nerve below the FN, the superficial petrosal artery (a branch of the MMA) and the labyrinthine artery (branch of the basilar artery). The bottom (fundus) of the IAM is subdivided into unequal superior and inferior portions by a transverse falciform crest, and into the anterior and posterior portions by a vertical segment, Bill’s bar, respectively (Figure 3) [2, 15]. The localization of the nerves within the IAM is determined by a triangular shaped Bill’s bar as follows; posteriorly the superior and inferior vestibular nerves, anteroinferiorly the cochlear nerve, anterosuperiorly the FN and nervus intermedius pass through the foramina of the fundus (Figure 3) Mortazavi [1, 4, 6].
The aqueductus vestibuli is a bony canal which contains the saccus and ductus endolymphaticus. Its opening is an oblique slit behind the IAM (Figure 3). The endolymphatic sac is located at the lateral part of the posterior surface medial to the posterior SSC [2, 18].
The subarcuate fossa is an indistinct depression (large in new born) located behind the IAM (Figure 3) and transmits a small vein and the subarcuate artery, which is a branch of the meatal segment of the anterior inferior cerebellar artery [4, 5, 9, 14].
The surface landmarks on the posterior surface of the petrous portion: a, petrous ridge; b, arcuate eminence; h, internal acoustic meatus; ı, subarcuate fossa; j, aqueductus vestibuli; k, sigmoid sinus sulcus; m, sulcus of the middle meningeal artery; 12, mastoid foramen.
The inferior surface articulates with the basilar part of occipital bone medially, and the greater wing of the sphenoid bone anteriorly and forms an irregular external surface of the base of the skull. Below the apex, there is a quadrilateral area that serves as an attachment for the levator veli palatini muscle. The lateral part of this area merges with the posterior margin of the greater wing of sphenoid to form the sulcus tuba in front of the cartilaginous portion of the auditory tube [4, 5, 21]. It presents some anatomical landmarks as follows:
The external opening of the CC, which shows an inverted L-shape course, forms the entrance for the ICA, which is surrounded by a plexus of sympathetic nerves (Figure 4). The anterior margin of the horizontal segment of the CC is separated from the musculotubal canal by a thin layer of bone laterally [1, 5, 18].
The jugular fossa is a deep dome-shaped depression at the lateral wall of the JF and located behind the CC and below the floor of the tympanic cavity. It houses the superior bulb of the IJV and the mastoid canaliculus (Figure 4) for the entry of the Arnold’s nerve, which provides sensory innervation of the EAC and auricle [9, 15]. The jugular spine in the jugular notch of the occipital bone divides the JF into the pars nervosa (anterior) and pars venosa (posterior) [4, 5, 9]. Normally, the jugular bulb is located between the IJV and the horizontal course of the SS. Abnormalities of it (80% below the FN in the mastoid cavity) result in dehiscence of the adjacent structures such as: the mediolateral enlargement of the JB results in the vestibular aqueduct, PSC, and IAC dehiscence, whereas the anteroposterior enlargement of the JB may cause the FN dehiscence. Abnormal high riding JB shows both mediolateral and anteroposterior enlargement and results in dehiscence of the FN [26].
Between the jugular fossa and the CC, the inferior ganglion of the GPN is localized in a triangular depression, whereas the inferior tympanic canaliculus penetrates into wedge-shaped bony ridge and transmits the tympanic branch of the GPN and inferior tympanic artery. At the apex of this triangular depression, there is an external opening of the cochlear aqueduct (Figure 4), which connects the perilymphatic space to the subarachnoid space and transmits the cochlear vein [1, 5, 14].
Behind the CC the vaginal process which is the extension of the sharp lower border of the tympanic plate wraps the root of the styloid process (Figure 4). The lower border of that extension serves an attachment for the deep layer of parotid fascia [1, 3, 5, 6].
The surface landmarks on the inferior surface of the petrous portion: FM, fossa mandibularis; FS, foramen stylomastoideum; FJ, fossa jugularis; ET, eustachian tube; eocc, external opening of carotid canal; ıocc, internal opening of carotid canal; star: inferior tympanic canaliculus; arrowhead: cochlear aqueduct.
Internal structures in the petrous portion contain the ME and inner ear. The ME contains an air-filled tympanic cavity and the ossicular chain which is composed of the malleus, incus, and stapes [14]. The walls of the ME:
Lateral wall contains the tympanic membrane and the scutum pointed infero-medially from the squamous portion. The tympanic membrane has two parts; pars flaccida is located in a fibrocartilaginous ring called the tympanic sulcus and susceptible to perforations and pars tensa is situated in the notch of Rivinus above the lateral process of the malleus. At the medial surface of the membrane a depression called umbo is formed by attachment of the manubrium of the malleus.
Medial wall consists of the cochlear promontory, the FC, the oval and round windows. It is divided into three part by the bony ridges: the ponticulus superiorly and the subiculum inferiorly. The oval window (vestibular window) is located above the ponticulus whereas the round window (cochlear window) is below the subiculum, and the tympanic sinus between them is located medial to the FC. The vestibular window is closed by the base of the stapes. The facial recess lies below the lateral SSC and superolateral to the oval window.
Superior wall, the TT, which forms the roof of the ME.
Inferior wall is a bony roof of the IJV.
Anterior wall includes the anterior epitympanic recess superiorly, below it the tensor tympani muscle lies posteriorly and attaches to the neck of the malleus after turning laterally. The orifice of the ET and below it the CC is located inferiorly.
Posterior wall consists of the pyramidal eminence, epitympanum, and facial recess. The stapedius muscle passes through the pyramidal eminence and inserts to the head of the stapes [2, 5, 7, 14, 18].
The tympanic cavity is lined with the mucous membrane that extending into the MA posteriorly and the ET anteriorly. This cavity consists of three parts changing according to the level of the tympanic membrane; the epitympanum (superior to the level of the tympanic membrane), mesotympanum (at the level of the tympanic membrane), and hypotympanum (inferior to the level of the tympanic membrane). The hypotympanum has the orifice of the ET. At the lateral part of the epitympanum below the lateral malleal ligament there is the Prussak space which is bounded by the neck of the malleus medially and the pars flaccida and scutum laterally [2, 3, 5, 14].
Inner ear is comprised of the otic capsule (osseous labyrinth), which surrounds the membranous labyrinth and is divided into three parts from anterior to posterior including the cochlea, vestibule, and three SCs [14]. Cochlea is the spiral shaped bony labyrinth of the inner ear that looks like a snail shell making 2¾ turns about the modiolus and consists of the vestibular and the tympanic and the cochlear ducts, which are formed by an inner membranous partition. The vestibular duct (scala vestibuli) locates at the superior part of the cochlear canal and contains perilymph (rich in sodium ions) and is limited by the oval window, and is separated from the cochlear duct by Reissner’s membrane. The cochlear duct (scala media) locates at the middle part of the cochlear canal and contains endolymph (rich in potassium ions) and is separated from the tympanic duct by the basilar membrane, which has the Organ of Corti including the sensory hair cells. The stereocilia of these cells perceives the potential difference between the perilymph and the endolymph and converts that motion to electrical signals and finally hearing occurs. The tympanic duct (scala tympani) locates at the inferior part of the cochlear canal and contains perilymph as the vestibular duct and is limited by the round window [3, 5, 14, 15]. Vestibule contains the utricle and saccule. SSCs containing three semicircular ducts organized like three flower leafs that join the vestibule. They are located perpendicular to each other; the superior corresponds to the AE, the posterior is parallel to the posterior surface of the pyramid, and the lateral is perpendicular the mucosal plane and angled at 30°from the transverse plane [3, 15].
The FN passes through the anterosuperior part of the IAM and enters the fallopian canal (FC). It contains motor, sensory, and parasympathetic fibers and has six segments as follows:
Cisternal segment lies from the brain stem to the IAM. This part runs together with the cisternal part of vestibulocochlear nerve in same pia mater coverage.
Meatal segment is the smallest part of the FC and contains Bill’s bar as an important landmark.
Petrous (labyrinthine) segment forms first genu (geniculate ganglion) above the cochlea at the lateral wall of the ME and gives a branch named as GSPN. Then, it enters the tympanic cavity and forms an angle ranging from 19 to 107° with tympanic segment of the FC [7, 20]. Because of this segment is the narrowest part and lack of arterial anastomoses, it is susceptible to embolic attacks and vascular compression.
Tympanic segment (first part) starts from first genu and turns backwards to lie in a thin-walled bony canal that runs evenly between the lateral SSC superiorly and the oval window inferiorly and medial to the incus. A dehiscence of the bony canal is more common at this segment in average 41–75%.
Pyramidal segment (second part of the tympanic segment) forms second genu at the posterior wall of the ME above the pyramidal process. It forms an angle ranging from 95 to 125° with mastoid segment of the FC [7, 20].
In the mastoid or vertical segment, the FN gives the acoustic branch for the stapedius muscle, the chorda tympani, and sensitive branch for the auricular region. This segment is located 5.50 mm anteromedially to the SS and extends from the level of the LSC to the digastric ridge (~3.8 mm). Then it exits the temporal bone at the SMF and enters the parotid gland [14, 27].
According to the classical description, the FC has four segments: labyrinthine, tympanic, pyramidal, and mastoid, but the meatal segment is important from an anatomical and surgical perspective. The stylomastoid artery, a branch of the posterior auricular or the occipital arteries, supplies the inferior parts of the FC up to the second genu and anastomoses directly with the petrosal branch of the MMA, which supplies the geniculate ganglion. The FC pathologies are composed of agenesis, aplasia, narrowing, and osteopetrosis of the canal, which result in complete or incomplete facial paralysis. Bell’s palsy depending on the activation of a dormant herpes virus, is responsible for 50% of peripheral FN palsies. The FC dehiscence can be congenital or secondary to the surgical intervention or pathology of adjacent structures and results in cerebrospinal fluid (CSF) otorrhea. Several surgical approaches, including the translabyrinthine, transcochlear and retrosigmoid, are used to treat the FC pathologies [27].
Ossification of the petrous portion begins from the 14 centers that fuse to form otic capsule and is completed at birth. The petrous portion develops from the cartilaginous differentiation of the mesenchyme by endochondral ossification at the 16th week of gestation. The cementum layer in teeth roots and petrous portion of the temporal bone contain the optimal endogenous DNA substrate which can provide information to specify the geographic location for genomic analyses [28]. Damgaard et al. reported that the prevalence of the endogenous DNA contents in nonpetrous bones and teeth is ranged from 0.3 to 20.7%, while the levels for petrous bones ranges between 37.4 and 85.4% [29]. Due to the high density and resistance to harsher climatic conditions of the petrous bone, the otic capsule of the petrous bone preserves DNA substrate extremely well and has much higher endogenous DNA level than the teeth by 5.2-fold on average. So, it is currently acknowledged as the optimal substrates for ancient genomic research [28, 29].
Kawase’s triangle: Borghei-Razavi et al. evaluated the safety of this posteromedial middle fossa triangle for removal of the tumors locating or spreading into the cerebellopontine angle and petroclival area. Kawase’s triangle was identified between the GSPN laterally, the geniculate ganglion at the AE posteriorly, and ganglion gasserian at the trigeminal impression anteriorly. During anterior petrosectomy for accessing the posterior cranial fossa via middle fossa, the GSPN forms the lateral border of the surgical approach (Figure 5) [30].
The surgical triangles on the anterior surface: Kawase’s triangle: Post-med (posteromedial triangle) and Glasscock’s triangle: post-lat (posterolateral triangle). FS, foramen spinosum; GG, geniculate ganglion; TI, trigeminal impression.
Glasscock’s triangle, or the posterolateral middle fossa triangle, is identified between the TN (V3), the geniculate ganglion at the AE and FS (Figure 5). The margins of this triangle are formed by a line between where the GSPN crosses under V3 and the FS medially, a line between the FS and geniculate ganglion laterally, and GSPN describing the base [3, 5, 16].
Rhomboid area (Kawase triangle+postmeatal area) is situated between the GPN, petrous ridge, AE, and the posterior border of the V3. A large tumor located in the midline skull base or spreading into the infratemporal and petroclival region even the cavernous sinus can be removed by extended EEA through V2-V3 corridor to avoid complications including ICA injury, IPS bleeding, TN injury and CSF leak [31].
Trautmann’s triangle is bounded by the SPS superiorly, SS posteriorly, and solid angle which is formed by three SCs anteriorly (Figure 6). In this triangle, the retro-labyrinthine tract from the MA, the endolymphatic sac, and the vestibular aqueduct are located [5, 9].
The surgical triangles on the posterior surface: Trautmann’s triangle margins are formed between the superior petrosal sinus superiorly, the sigmoid sinus posteriorly, and the semicircular canals antero-inferiorly. Star: Citelli’s angle (sinodural angle) is formed between the dural plates of the middle fossa superiorly, the posterior fossa anteriorly and the sigmoid sinus posteriorly.
Donaldson’s line is a surgical line that is parallel to the LSC whereas it is vertical to the posterior SSC and divide it into superior and inferior portions. Below this line medial to the labyrinth the endolymphatic sac is situated. Citelli’s angle (sinodural angle); is bounded by the middle fossa dura plate (SPS) superiorly, posterior fossa dura plate (bony plate covering the MA) anteriorly and the SS posteriorly (Figure 6). During mastoidectomy the air cells in this triangle should be removed [1, 5, 6].
In clinical applications, for fully understanding of the tridimensional architecture of the petrous portion, a reference lines and angles can be defined on the anterior and posterior surfaces from a superior view.
Peris-Celda et al. reported that the EAM and the IAM are located in the same coronal plane on the anterior surface forming surgical triangle [9]. Tawfik-Helika et al. separated the pyramid into four compartments and described two segmentation method to provide better understanding of the distributions of these compartments. They identified four compartments based on their connections: mucosal, cutaneous, neural, and vascular [3, 21].
The mucosal compartment consists of an air filled and mucosa lined cavities from anterior to posterior: the ET, ME, and the MA (Figure 7). The mucosal line in an oblique anteromedial direction extends along these structures and is used for segmental description of this pyramid, and all major anatomical landmarks can be identified relative to this axis for surgical approaches [3, 9, 21].
(A) The margins of the anterior surface of the left petrous portion from a superior view are shown posteriorly by a (thick black) line along the PR, petrous ridge; anteriorly by a (dashed black) line lying from the preauricular burrhole to PA, petrous apex and passing through the FS, foramen spinosum; and laterally by a (dashed white) line along the petro-squamous suture. OC, optic canal; ACP, anterior clinoid process; FL, foramen lacerum; SOF, superior orbital fissure; FR, foramen rotundum; FO, foramen ovale; MMA, middle meningeal artery; IOCC, internal opening of carotid canal; GSPN, greater petrosal nerve; AE, arcuate eminence; TT, tegmen tympani; JF, jugular foramen; IAM, internal acoustic meatus; SSS, sulcus sigmoid sinus. (B) The segmentation of the left petrous pyramid into four compartments including mucosal, cutaneous, neural, and vascular is shown on the left petrous portion.
Extending the mucosal line posteriorly, the MA is separated into medial and lateral parts, whereas anteriorly, the bony portion of the ET is localized at the junction of the petrous and squamous parts and the cartilaginous part opens into the pharynx anteriorly. Medially the line passing through the sulcus of the GSPN and laterally a straight line lying between the foramen ovale and FS are parallel to this line (Figure 7) [3, 9, 21].
The cutaneous compartment is composed of the EAM, which is covered by the skin and separated from the ME by the tympanic membrane medially.
The neural compartment is composed of the otic capsule, which is located medial to ME and the mucosal line. In this bony container, the cochlea, vestibule, and SCs are located from anterior to posterior around the fundus of the IAM (Figure 7).
The vascular compartment is composed of the ICA. The axis passing through the horizontal part of the CC is parallel and medial to the mucosal line (Figure 7) [3]. Moreover, Tawfik-Helika et al. described X and V segmentation methods to advance and enhance education of the compartments.
The X method divides the petrous pyramid into four spaces by using two reference lines intersecting with each other at the ME; the mucosal line and the EAM-IAM line form the X letter (Figures 8 and 9). These four spaces around the ME and the contents in it are as follows:
The anteromedial space—the cochlea and the petrous apex including the ICA
The anterolateral space—the roof of the TMJ
The posterolateral space—the lateral part of the MA
The posteromedial space—the posterior labyrinth and the medial part of the MA
Schematic representations of the segmentation of the left petrous portion by using X and V methods.
Schematic representation of the external and internal landmarks on the left petrous portion. V, trigeminal nerve and branches (V1, V2, V3); TI, trigeminal impression; IOCC, internal opening of carotid canal; ET, Eustachian tube; GG, geniculate ganglion; ME, middle ear; MA; mastoid antrum; EAM, external acoustic meatus; TMJ, temporomandibular joint; SCCs, semicircular canals; IAM, internal acoustic meatus; VII, facial nerve; VIII, vestibulocochlear nerve; IX, glossopharyngeal nerve; X, vagus nerve; XI, accessory nerve.
The V method arranges five segments around the mucosal line (Figures 8 and 9) These five segments and the contents in it are as follows:
The petrous apex segment—the ICA medial to the ET
The otic capsule segment—the IAM, cochlea, vestibule and SCs
The mastoid segment—the angle around the MA
The EAM segment—the lateral part of the ME
The TMJ segment—the roof of the TMJ lateral to the ET [3].
Detailed description of the temporal anatomy pointing to relationships between internal and external landmarks and a holistic approach including X an V segmentation methods that break down the petrous pyramid into spaces and compartments can provide an easy way to understand and to use surgical applications. The compartmental approach can be helpful in the fields of education and radiological applications as well as surgery.
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