Rom J Leg Med [27] 95-102 [2019] DOI: 10.4323/rjlm.2019.95 © 2019 Romanian Society of Legal Medicine FUNDAMENTAL RESEARCH

Anatomic enigmas of the olfactory neuronal system structures in man. Implications in psychopathology

Gheorghe S.Drăgoi1,2,*, Elena Pătrașcu3, Ileana Marinescu4

______Abstract: The anatomic enigmas of the olfactory neuronal system have blocked the real denominations and their systemic integration for a long time. They were finally understood as a result of anatomic and physiological studies on the dynamics of their ontogenesis and phylogeny. In the present paper we aim at bringing to light the issues associated with the anatomic enigmas of the olfactory neuronal structures in man. The object of the present paper is to report an ample anatomic study on extracerebral olfactory neuronal structures in man. The anatomic evaluation was carried out on 18 human encephala free of acute or chronic lesions taken from 8 adults (between 40 and 62 years of age), 6 feti (aged between 3 and 7 months antepartum life), and 4 embryos (30 to 36 mm long from vertex to coccigis). Prelevation, conservation and processing of the encephala was carried out on the basis of protocols worked out by the authors. Three olfactory neuronal structures in man were anatomically analyzed: the , the olfactory peduncle and the . The morphogenesis of these structures was microanatomically evaluated on serial sections of embryo encephala, as well as macroanatomically on fetal samples. We encountered difficulties in denomination criteria, classification of topographic locations of chain stations and interconnective pathways. The elucidation of these issues opens up new integrative potentials of olfactory neuronal structures within the neuronal system of behavior and cognition with further implications in psychopathology. Key Words: olfactory neuronal structures, olfactory bulb, olfactory peduncle and olfactory tubercle.

INTRODUCTION issues connected to the macroscopic anatomy and the morphogenesis of these structures. Our main object is to The olfactory neuronal system structures achieve the anatomic analysis of the following structures: in man has generated a score of problems regarding the olfactory bulb as a first extracerebral synaptic chain denomination, anatomic evaluation and integration in station, the olfactory peduncle as an interconnective the neuronal system the process behavior and cognition. structure and the olfactory tubercle as a first synaptic Localization and characteristics of interconnection station of the cortical chain. require the mastering of encephalon dissection methods which enable the access paths to these structures situated MATERIALS AND METHOD at the border between neocortex and . Anatomically speaking, they are forms of relief that Materials can be grouped in: synaptic stations of extracerebral The anatomic study was carried out on 18 human chains; interconnective structures and synaptic stations encephala free of acute or chronic lesions taken from of cortical integration. The present paper raises current 8 adults (between 40 and 62 years of age), 6 feti (aged

1) University of Medicine and Pharmacy of Craiova, Doctoral School, Craiova, Romania 2) Romanian Academy of Medical Sciences, Bucharest, Romania * Corresponding author: E-mail: [email protected] 3) University of Medicine and Pharmacy of Craiova, Department of Anatomy, Craiova, Romania 4) University of Medicine and Pharmacy of Craiova, 5th Department, Craiova, Romania

95 Drăgoi G.S. et al. Anatomic enigmas of the olfactory neuronal system structures in man. Implications in psychopathology between 3 and 7 months antepartum life), and 4 embryos of the peduncle. It is oval in form, surrounded by the (30, 32, 34 and 36 mm long) from vertex to coccigis. arachnoid that forms a full sleeve. It lies on the above the cribriform plate. The longitudinal Methods antero-posterior axis is oblique regarding the olfactory Prelevation and preservation of encephala was peduncle which, in turn, makes an obtuse angle, laterally done in accordance with the protocols set up by the open, of about 165 degrees. The medial margin is convex, authors of the paper (Drăgoi et al., 2019). Variability while the lateral margin is a straight line. A circular of locations, relations, connexions and morphogenesis groove is seen at the borderline of the olfactory peduncle of olfactory neuronal structures in man required the (Fig. 1B). selection of adequate anatomic methods for the two The olfactory peduncle was visualized in the anatomic entities under study: two rostral olfactory olfactory sulcus, in direct continuation of the olfactory neuronal structures and a caudal olfactory neuronal bulb. Its form is a triangular prism. The inferior face has structure. a longitudinal groove that divides it into two tracts: the Rostral olfactory structures – the olfactory bulb olfactory medial tract and the olfactory lateral tract; they and the olfactory peduncle – that can be seen on the are more distanced in the lower third and become the inferior face of the were individualized by olfactory medial stria and the olfactory lateral stria that dissecting the subarachnoidian space after inflating it participate in the delimitation of the olfactory trigone with air through the chiasmatic cistern situated ventrally (Fig. 1B and Fig. 2B). The apex of this triangle is in the and rostrally as reported to the optic . A large terminal part of the olfactory peduncle, while the basis number of arachnoidian trabeculae were split open in lies against the anterior perforated substance. We followed order to individualize the structural characteristics of the the routes of the two olfactory striae. The lateral olfactory form. stria is continuous, from the lateral angle of the olfactory The caudal olfactory structure – the olfactory trigone to the posterior and the lateral parts, and reaches tubercle in the anterior perforated substance – was the anterior border of the temporal lobe. The olfactory identified as the Sylvius’ valley after cutting a frontal medial stria goes from the margin of the medial angle of plane in the anterior extremity of the temporal lobe and the olfactory trigone to the medial and disappears in the pulling the towards the posterior. Following antero-medial of the anterior perforated substance (Fig. the opening up of the chiasmatic cistern by sectioning the 1C and Fig. 2B). arachnoid, we identified the rostral components of the The anterior perforated substance was visualized internal carotid system: the anterior cerebral artery and the as a small rectangular space, its long axis parallel to the middle cerebral artery. The former, as the terminal branch that makes up its posterior part. The medial of the internal carotid artery, passes medially and rostrally part is formed, towards the inferior, by a blunt crease that between the optic and the anterior perforated is situated at the junction of medial and inferior faces of substance, further penetrating the longitudinal cerebral the frontal lobe. The lateral segment of the anterior face fissure where it comes into anastomoses with the collateral displays a prominent crease – the falciform crease – that homonymous artery through the anterior communicating separates the Sylvius’ valley from the lateral cerebral fossa artery (Fig.1A and 1B). The latter passes laterally and (Sylvius). The posterior face is made up of the optic tract rostrally between the temporal lobe and the frontal lobe which, from the optic chiasm, moves obliquely outwardly in the direction of the lateral cerebral fossae. We have also and to the posterior. identified the perforating branches of striate arteries that The anterior of the optic tract, the diagonal band enter the anterior perforated substance (Fig. 1A and 1C). (Broca) can easily be seen. The surface of the anterior perforated substance is smooth, grey in color and marked RESULTS by many orifices that make it look like a sieve because of the arterioles and venules of the corpus . These The evaluation of the olfactory neuronal orifices are co-linear and make up spaced regular rows. In structures in man is based on the macroscopic anatomic each of these rows the diameter of the orifices increases analysis and on the study regarding the formation from medial towards lateral. The orifices that are situated processes and their evolution in ontogenesis. on a tract parallel to the posterior border are oval in shape and their larger diameter is oriented transversally. A. Macroscopic anatomic analysis In the anterior part of the perforated space, but Three extracerebral olfactory neuronal structures posteriorly to the bifurcation of the olfactory peduncle, were macroscopically analyzed: the olfactory bulb, the we noticed a small oval prominence generated by olfactory peduncle and the olfactory tubercle in the the olfactory tubercle that had the larger diameter anterior perforated substance. transversally oriented. It is surrounded by a large number The olfactory bulb was identified on the inferior of orifices that correspond, in the deep structure, to the faces of the frontal lobe, looking like an anterior dilatation ventral striatum (Fig. 1C and Fig. 2B).

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Figure 1. Presentation of olfactory structures in pars basalis telencephali. 1. Olfactory sulcus. 2. Olfactory bulb. 3. Longitudinal cerebral fissure. 4. Olfactory peduncle. 5. Anterior cerebral artery - postcommunicating part. 6. Anterior cerebral artery - precommunicating part. 7. Internal carotid artery. 8. Fusiform gyrus. 9. Uncus, 10. Posterior communicating artery. 11. Rhinal sulcus. 12. Parahippocampal gyrus. 13. Posterior cerebral artery. 14. Basilar artery. 15. Longitudinal axis of an olfactory bulb. 16. Longitudinal axis of an olfactory peduncle. 17. Olfactory medial tract. 18. Olfactory lateral tract. 19. Middle cerebral artery. 20. Medial orbital gyrus. 21. Corpus callosum – rostrum. 22. Straight gyrus. 23. . 24. Olfactory fossa. 25. Diagonal band – horizontal limb. 26. Diagonal band – vertical limb. 27. Lamina terminalis. 28. Olfactory trigone. 29. Lateral olfactory stria. 30. Falciform crease. 31. Lateral cerebral fossa (Sylvius). 32. Anterior perforated substance. 33. a;b. Sylvius’ valley. 34. Olfactory trubercle. 35. Optic chiasm. 36. Optic tract.

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B. Anatomic analysis of morphogenesis disputes regarding denomination and visualization of The anatomic study of the genesis and evolution the following olfactory structures: the olfactory bulb, the of the neuronal system structures of olfaction was carried olfactory peduncle and the olfactory tubercle. out on human embryos 30 to 36 mm in length from The olfactory bulb, although easy to identify on vertex to the coccigis and on human feti of 3 to 7 months the anterior face of the frontal lobe, its denomination (1786 of antepartum life. Examining the serial sections in the – 1830) could not be correlated to the actual anatomic cephalic extremity of the embryo, in sagittal paramedian relationships. The denomination errors were generated planes, at the level of the rostral extremity of the ventral by the strange evaluation of the olfactory peduncle as wall of the telencephalic superventricle (the future , i.e.: olfactory nerve (Bartholin, 1611) lateral ventricle), we easily identified the presence of an [1], nervus odoratorios (Rolfinck 1656) [2], trunk of evagination of the olfactory neuroepithelium facing the the olfactory nerve (Scarpa 1785) [3]. Therefore quite a olfactory placode which is the basis of the primordial large number of mistaken denominations appeared for olfactory bulb. the olfactory bulb as well, because they were reported to The ventral part of this evagination will a fictitious olfactory nerve, i.e.: head of olfactory nerve contribute to the formation of the olfactory (Vicq d’Azyr,1786)[4]; bulb olfactory nerve (Soemmerring (syn. fila olfactoria), while its dorsal part, that unites 1798)[5]; ganglion of olfactory nerve (Gall & Spurtzheim the primordial olfactory bulb with the primordial of 1810)[6]; bulbous extremity of olfactory nerve (Swan, the cerebral hemisphere, will generate the olfactory 1830)[7]. peduncle. The caudal extremity of the ventral wall of the The current name of the olfactory bulb (Bulbus telencephalic superventricle contributes, through the olfactorius) was introduced in the Basel Nomina telencephalic epithelium, to the formation of the ventral Anatomica (BNA, 1895)[8] later; the French school striatum structures: the anterior perforated substance, of anatomy – Charpy (1899)[9] and Testut (1929)[10] the olfactory tubercle, innominate substance, nucleus accepted the new terminology at further date. accumbens, the ventral pallidum and the septum verum The olfactory peduncle is visible on the inferior (Fig.2B and Fig.3A). face of the frontal lobe and has been correctly termed The examination of the basal face of the eversince 1836 by Solly [11]. Confusions occurred later telencephalon in a 3-month old fetus enabled the when terms and/or structural components were changed. identification and evaluation of the anterior perforated The first confusion appeared in 1895 when BNA substance. In the Sylvius’ valley it is bordered by the [8] replaced the tract for the initial name. This name temporal pole laterally and the optic chiasm caudally. In changing proved to be incorrect because, in the olfactory the 6-7-month old feti the access to the Sylvius’ valley is peduncle there are neuronal structures that cross it and made difficult because of the increased volume towards were termed tracts (lateral olfactory tract, intermediate the rostral of the temporal lobe. We also identified the olfactory tract and medial olfactory tract). The term thridimensional increase of the olfactory bulb, olfactory tractus should not be used in the denomination of the peduncle and the olfactory lateral stria (Fig. 3B and 3C). olfactory peduncle. The term pedunculus (little foot In the fetal stage of ontogenesis, the extracerebral olfactory – serif) was chosen for the macroscopic anatomy and neuronal structures in man are visible and termed lateral defines a bridge-like structure between the olfactory olfactory gyrus and medial olfactory gyrus. The lateral bulb and the primary centers of olfaction through the is in straight line and is situated rostrally and laterally to olfactory tracts contained in its structure. the anterior perforated substance. The medial is poorly The second confusion was generated and developed in man and looks like a tiny gyrus lying between perpetuated by the French school of anatomy (Testut the olfactory trigone and the ventral extremity of the 1929)[10] by including the olfactory striae in the olfactory cingulated gyrus, as part of the carrfour olfactif de Broca. peduncle. The third confusion is still persisting since 1998 DISCUSSION in the International Anatomical Terminology (IAT,1998) [12] in which, most strangely, the olfactory peduncle and The present results made it possible for us to the olfactory tract were included in the structure of the identifiy the heterogeneity of the location, of the relations olfactory bulb (ITA, page 129, pos. 14,1,069.429)[12]. and of the morphogenesis of the olfactory neuronal Finally, and only in 2016, the structure was validated as structures in man. olfactory peduncle, as suggested by Solly (1836)[11] in the current Neuro Anatomical Terminology accepted A. On the anatomic enigmas regarding structure by the International Associations of Anatomists at the and denomination Götingen Congress (September 24, 2016). Neuronal structures of olfaction in man have The olfactory tubercle is a structure both always been difficult to understand as far as its anatomy ambiguous and strange (Nieuwenhuys, 2008)[14]. and functions are concerned. This fact is seen in the Through its trilaminary structure resembling the cortex

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Figure 2. Caudal paleopalleale structures in pars basalis telencephali. A. Frontal section through anterior commissure. B Prechiasmatic space that belongs to the anterior perforated substance. 1. Indusium griseum. 2. Trunk of corpus callosum. 3. Frontal horn of lateral ventricle. 4. Foramen interventriculare (Monro). 5. Septum pellucidum. 6. Choroid plexus of lateral ventricle. 7. Head of . 8. Thalamostriate vein. 9. Thalamus. 10. Column of fornix. 11. Anterior limb of . 12. . 13. . 14. . 15. Anterior commissure. 16. . 17. Anterior perforated substance. 18. Lamina terminalis. 19. Middle cerebral artery. 20. Medial olfactory tract. 21. Intermediate olfactory tract. 22. Lateral olfactory tract. 23. Medial olfactory stria. 24. Intermediate olfactory stria. 25. Lateral olfactory stria. 26. Optic chiasm. 27. Optic tract. 28. Sylvius’ valley. 29. Olfactory tubercle. 30. Falciform crease. 31. Fossa lateralis cerebri.

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Figure 3. Morphogenesis of olfactory neuronal structures of the human encephalon. A. Median sagittal sections in a 33mm embryo. B. The inferior of the encephalon in a 3-month old fetus. C. The inferior face of the encephalon in a 6-month fetus.1. Olfactory placode. 2. Olfactory bulb. 3. Cortical olfactory neuroepitelium. 4. Olfactory recess. 5. Basal telencephalic neuroepithelium. 6. Ventral striatum.7.Dorsal striatum. 8. Telencephalic superventricle (Future lateral ventricle). 9. Interventricular foramen (Monro). 10. Preoptic area. 11. Thalamus. 12. Subthalamus. 13. . 14. Optic recess. 15. Sphenoidal bone. 16. Sella turcica. 17. Basilar part of occipital bone. 18. Pytuitary gland. 19. Diencephalic superventricle (Future third ventricle). 20. Tectum of the midbrain. 21. Superior colliculus. 22. Mesencephalic superventricle (Future Aqueduct). 23. Inferior colliculus. 24. Cerebellum. 25. Pons of the brainstem. 26. Rhombencephalic superventricle (Future fourth ventricle). 27. Upper medulla. 28. Lower medulla. 29. Budding rhombencephalic choroid plexus. 30. Nasal cavity. 31. Nasal conchae. 32. Frontonasal processs. 33. Olfactory peduncle. 34. Olfactory lateral stria (Syn: lateral olfactory gyrus). 35. Anterior perforated substance. 36. Optic chiasma. T =

Telencephalon. D = Diencephalon. MS = Mesencephalon. MT= Metencephalon. MY = Myelencephalon.

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(cortex-like) the olfactory tubercle has more to do with system in which the structures of the limbic forebrain are the regions adjacent to the ventral striatum (Hartz – also constitutive parts; the structures of „Broca’s great Schütt, 1991)[15]. limbic lobe” are taken as interfaces between the greater Based on our results and in agreement with limbic system and the neocortex and, last but not least, the official Neuro Anatomic Terminology (TNA, 2016) the ventral striatum is an interface between the limbic [13], we have come to the following conclusions: 1. the system and the extra-pyramidal motor system. olfactory bulb (TNA Latin bulbus olfactorius), appeared as a rostral evagination of the telencephalon, is a chain C. Implications in psychopathology station containing the synapses between the neurons The structures of the olfactory neuronal system in the and the mitral cells in the included in the neuronal circuits proposed by Papez (1937) olfactory bulb. It is also known that in marsupials and [17], Nauta (1986) [19] and Nieuwenhuys et al. (2008)[14] insectivorous animals it contains a large olfactory enable the implication of the former in the processing of ventricle, while in mammals this cavity is small and fully olfactory information under normal conditions and/or obliterated in the adult stage; 2. the olfactory peduncle pathological ones. The olfactory tubercle is considered a (TNA Latin pedunculus olfactorius) is a true connective multisensorial processing center either through the retinal structure between the olfactory bulb and central olfactory projections (Mick 1993) [20]or the olfactory auditory structures through the olfactory tracts and the olfactory integration (Wessen and Wilson, 2010) [21]. Olfactory striae; 3. the olfactory tubercle (TNA Latin tuberculum sensitivity is low in the patients suffering from major olfactorium) belongs, topographically, to the anterior depressive disorders (Negoias et al., 2010) [22]. Decrease perforated substance, structurally to the ventral striatum of the olfactory sensitivity threshold was recorded in the and functionally to the . patients suffering from Alzheimer’s disease (Bacon et al., 1998) [23]. A certain deficit in olfactory discrimination is B. On the integration of olfactory structures in encountered in schizophrenia (Rupp et al., 2005) [24]. man The integration of the olfactory structures in CONCLUSIONS the neuronal systems occurred gradually, in time, as a consequence of the progress achieved in deciphering 1. The olfactory neuronal system in man their functional anatomy. Charpy (1899)[9] introduced contains enigmatic structures that could be understood the anatomic concept of „olfactory lobe”, to integrate the as a result of deep investigations of functional anatomy following structures: olfactory bulb, olfactory peduncle in its ontogenetic and phylogenetic dynamics. and olfactory tubercle. Broca (1879)[16] connects the 2. Applying the morphogenetic criterion, they cingulated gyrus to the parahypocampal gyrus around can be grouped into rostral structures derived from the the corpus callosum under the term „the great limbic olfactory placode and the caudal structures derived from lobe” which was involved in the olfactory input. Papez the ventral striatum. (1937)[17] connects the hypothalamus to „Broca’s great 3. Applying the anatomic and functional criteria, limbic lobe” and creates „the medial limbic circuit” they can be grouped into two classes, i.e. chain synaptic involved in the vegetative reactions triggered by olfactory structures and interconnective structures. impulses. MacLean (1958)[18] attaches to „Broca’s great 4. The integration of olfactory structures in the limbic lobe” the following subcortical structures that neuronal systems processing behavior and cognition in belong to the limbic forebrain: septum verum, , normal and/or pathological conditions has come a long the midline thalamus nuclei and the hypothalamus and way from the archaic to the current comes up with a new concept – „the limbic system”. greater limbic system. Nauta (1986)[19] expands the term limbic forebrain to „the limbic forebrain – midbrain circuit”. Nieuwenhuys et Conflict of interest. The authors declare that al. (2008)[14] suggests the concept of the greater limbic there is no conflict of interest.

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