Talk:Historic Embryology Papers

From Embryology

Marin-Padilla M. Structural organization of the human cerebral cortex prior to the appearance of the cortical plate. (1983) Anat Embryol (Berl). 168(1): 21-40.PMID 6650855

Anat Embryol (Berl). 1983;168(1):21-40. Structural organization of the human cerebral cortex prior to the appearance of the cortical plate. Marin-Padilla M. Abstract The early development and the structural organization of the human cerebral cortex, prior to the appearance of the cortical plate (Carnegie stage 22, ca. 54 days), was studied in two embryos: 43 (stage 18) and 50 day old (stage 20), respectively. It has been shown that the human cerebral cortex begins its ontogenetic development around the sixth rather than around the eighth week of gestation as it has been previously assumed. The human cerebral cortex starts to develop soon after the cerebral vesicles have been formed (stage 15) and a primitive internal capsule has been established (stage 17, ca. 41 days). By stage 18 of human development fibres from this primitive internal capsule have reached and probably have penetrated into the developing cerebral vesicle, through its more superficial zone. Fibres from this primitive internal capsule have been traced backward through the ventral thalamus to the mesencephalic tegmentum. The possible existence of primitive ascending fibres from the mid-brain which terminate in the superficial zone of the developing cerebral cortex (tegmento-thalamostriato-cortical tract) is suggested. The arrival of these primitive corticipetal fibres establishes in the outer zone of the cerebral cortex a primordial plexiform lamina or an external white matter. Horizontal-bipolar cells (embryonic Cajal-Retzius neurons) begin to differentiate by stage 18 of human development (43 days in our case). By stage 20 (50 days in our case), the primordial plexiform lamina is well established, extends throughout the entire surface of the developing cerebral cortex, and is considered to be functionally active. It is, by this age, a superficial, 40 micrometers thick, complex fibrillar neuronal organization composed of numerous horizontal corticipetal fibres (demonstrable with silver methods), horizontal-bipolar Cajal-Retzius neurons and a few other, less defined, cellular elements. This primordial plexiform lamina is considered to represent a primitive "premammalian" cortical organization. The next event in cortical ontogenesis is the appearance of the cortical plate or the mammalian neocortical grey at stage 22 (ca. 54 days). Migrating neuroblasts attracted toward the preexisting primordial plexiform lamina and guided by glial fibres start to accumulate within it.(ABSTRACT TRUNCATED AT 400 WORDS). PMID: 6650855 DOI: 10.1007/bf00305396

Osaka K. Matsumoto S. and Yasuda M. The development of cerebro-spinal fluid pathway in human embryos. (1977) (Article in Japanese) No Shinkei Geka. 5(10): 1047-1055. PMID 909616

No Shinkei Geka. 1977 Sep;5(10):1047-55. [The development of cerebro-spinal fluid pathway in human embryos (author's transl)]. [Article in Japanese] Osaka K, Matsumoto S, Yasuda M. Abstract The early development of the subarachnoid space, the choroid plexus, and the arachnoid villi was studied in 60 normal human embryos ranging from Carnegie stage 12 to 23. The embryos were fixed in Bouin's fluid, paraffin-embedded, serially sectioned and stained with hematoxylin-eosin and Azan. One abnormal human embryo with exencephaly and myeloschisis in the high cervical cord was added for the study. A primitive subarachnoid space (future subarachnoid space) is first distinguishable as cavity formation within the meninx primitiva in the areas ventral to the middle brain vesicle at stage 14. The development of the primitive subarachnoid space precedes the appearance of the choroid plexus. The primitive subarachnoid space appears earlier in the region ventral to the rhombencephalon than in the region posterior to the fourth ventricle. By stage 20, a primitive subarachnoid space almost completely surrounds the neural tube. A fairly-well developed primitive subarachnoid space was observed in the abnormal human embryo, in which the fourth ventricle was open to the amniotic cavity and the ventricular system was completely separated from the primitive subarachoid space. These findings imply that the extraventricular spread of fluid of choroid plexus origin is not an essential factors, and that probably it is not even an important factor, for the development of the subarachnoid space. The arachnoid villi dose not appear even at the end of the embryonal stage. Absorption of the cerebrospinal fluid in an embryo should be done by the way other than the arachnoid villi. PMID: 909616

Bandler SW. Uterine and tubal gestation. (1903) William Wood & Company, New York.

Uterine and tubal gestation. A study of the embedding and development of the human ovum, the early growth of the embryo, and the development of the syncytium and placental gland by Bandler, Samuel Wyllis, 1869-1932

Publication date 1903

Reference handbook of the medical sciences

Bresslau E. The mammary apparatus of the mammalia : in the light of ontogenesis and phylogenesis. (1920) London : Methuen & Co. IA

Thomson A. The maturation of the human ovum. (1919) J Anat. 53(2-3): 172-208. PMID 17103860

Thomson A. The ripe human Graafian follicle, together with some suggestions as to its mode of rupture. (1919) J Anat. 54(1): 1-40. PMID 17103878

Thomson A. The Ripe Human Graafian Follicle, together with some suggestions as to its mode of rupture. (1919) J Anat. 54(Pt 1): 1-40. PMID 17103878]

The Ripe Human Graafian Follicle, together with some suggestions as to its mode of rupture. Thomson A. J Anat. 1919 Oct;54(Pt 1):1-40. No abstract available. PMID: 17103878 Free PMC Article

Jenkinson JW. (1911). The Development of the Ear-Bones in the Mouse. J Anat Physiol , 45, 305-18. PMID: 17232891

Jenkinson JW. The development of the ear-bones in the mouse. (1911) J Anat Physiol. 45(4): 305–318. PMID 17232891

The Development of the Ear-Bones in the Mouse J. W. Jenkinson J Anat Physiol. 1911 Jul; 45(Pt 4): 305–318. PMCID: PMC1288837

Ivens F. (1911). Demonstration of a very young Tubal Ovum. Proc. R. Soc. Med. , 4, 313-22. PMID: 19975313

Ivens F. Demonstration of a very young tubal ovum. (1911). Proc. R. Soc. Med. 4: 313-22. PMID 19975313

Demonstration of a very young Tubal Ovum. Ivens F. Proc R Soc Med. 1911;4(Obstet Gynaecol Sect):313-22. No abstract available. PMID: 19975313

Bradley OC. (1903). On the Development and Homology of the Mammalian Cerebellar Fissures: Part I. J Anat Physiol , 37, 112-30. PMID: 17232548 On the Development and Homology of the Mammalian Cerebellar Fissures: Part I. Bradley OC. J Anat Physiol. 1903 Jan;37(Pt 2):112-30. No abstract available. PMID: 17232548

Robinson A. (1889). Observations on the Earlier Stages in the Development of the Lungs of Rats and Mice. J Anat Physiol , 23, 224-41. PMID: 17231783 Observations on the Earlier Stages in the Development of the Lungs of Rats and Mice. Robinson A. J Anat Physiol. 1889 Jan;23(Pt 2):224-41. No abstract available. PMID 17231783

Robinson A. (1896). Formation and Structure of the Optic Nerve, and its Relation to the Optic Stalk. J Anat Physiol , 30, 319-33. PMID: 17232192

Formation and Structure of the Optic Nerve, and its Relation to the Optic Stalk. Robinson A. J Anat Physiol. 1896 Apr;30(Pt 3):319-33. No abstract available. PMID: 17232192

Teratogenesis: An Inquiry into the Causes of Monstrosities. Ballantyne JW. Trans Edinb Obstet Soc. 1896;21:12-296. No abstract available. PMID: 29613167

The Early Stages of the Development of the Pericardium. Robinson A. J Anat Physiol. 1902 Oct;37(Pt 1):1-17. No abstract available. PMID: 17232538

The Sternum: Its Early Development and Ossification in Man and Mammals: Preliminary Communication. Paterson. J Anat Physiol. 1900 Oct;35(Pt 1):21-32.3. No abstract available. PMID: 17232454

Tait L. Lectures on ectopic pregnancy and pelvic haematocele. (1888) Birmingham, USA.

Tait L. Lectures on ectopic pregnancy and pelvic haematocele. (1888) Birmingham, USA.


Angle EJ. Development of the Wolffian Body in Sus Scrofa Domesticus.(1918) Trans. Amer. Micro. Soc. 37(4): 215-238.

Feli HB. The origin and developmental mechanics of the avian sternum. (1939) Phil. Trans. Roy. Soc. Lon. 229 pp.407-463.

The prenatal growth of the mouse. by e. c. macdowell, ezra allen, ~-n c. g. macdowell.

Schulte HVW. and Tilney F. The development of the neuraxis in the domestic cat to the stage of twenty-one somites. (1915) Ann. N. Y. Acad. Sc. 24: 319-346.

Volume 43, Issue 3

The first appearance in the anterior pituitary of the developing pig foetus of detectable amounts of the hormones stimulating ovarian maturity and general body growth Philip E. Smith Carl Dortzbach Pages: 277-297

Volume 43, Issue 2

Dodds GS. An abnormal human embryo 11 mm long. (1929) The Anat. Rec. 199-208.

An abnormal human embryo 11 mm. long G. S. Dodds Pages: 199-208

The growth in surface area of the human gastric mucosa Gordon H. Scott Pages: 131-144

Volume 43, Issue 1

Roentgenograms in embryology Walter E. Sullivan Pages: 107-108

Some embryonic anomalies, vascular and skeletal N. William Ingalls Grace Fairchild Pages: 33-45

Volume 42, Issue 3

Notes on the anomalies of the aortic arch and of its large branches Jacob Priman Pages: 335-353

Congenital skin, ear, and skull defects in a pig Julius E. Nordby Pages: 267-280 First Published: May 1929

Weinberg E. A note on the origin and histogenesis of the mesonephric duct in mammals. (1929) Anat. Rec.

A note on the origin and histogenesis of the mesonephric duct in mammals

Ernst Weinberg

Human Foetus

Romanes GJ. Cell columns in the spinal cord of a human foetus of fourteen weeks. (1941) J Anat. 75(2): 145-152. PMID 17104847

J Anat. 1941 Jan;75(Pt 2):145-152.1. Cell columns in the spinal cord of a human foetus of fourteen weeks. Romanes GJ1. Author information PMID: 17104847 PMCID: PMC1252654

Shanklin WM. Differentiation of pituicytes in the human foetus. (1940) J Anat. 74(4): 459-63. PMID 17104829

J Anat. 1940 Jul;74(Pt 4):459-63. Differentiation of pituicytes in the human foetus. Shanklin WM1. Author information PMID: 17104829 PMCID: PMC1252613

Keene MF. The connexions of the posterior commissure: a study of its development and myelination in the human foetus and young infant, of its phylogenetic development, and of degenerative changes resulting from certain experimental lesions. (1938) J Anat. 72(4): 488-501. PMID 17104719

Anat. 1938 Jul;72(Pt 4):488-501. The Connexions of the Posterior Commissure: A Study of its Development and Myelination in the Human Foetus and Young Infant, of its Phylogenetic Development, and of Degenerative Changes resulting from certain Experimental Lesions. Keene MF1. Author information PMID: 17104719 PMCID: PMC1252355

Covell WP. A quantitative study of the hypophysis of the human anencephalic fetus. (1927) Am J Pathol. 3(1) :17-28. PMID 19969726

Am J Pathol. 1927 Jan;3(1):17-28. A Quantitative Study of the Hypophysis of the Human Anencephalic Fetus. Covell WP. PMID: 19969726 PMCID: PMC1931763

Hewer EE. The development of muscle in the human foetus. (1927) J Anat. 62(1): 72-8. PMID 17104172

J Anat. 1927 Oct;62(Pt 1):72-8. The Development of Muscle in the Human Foetus. Hewer EE1. Author information London (Royal Free Hospital) School of Medicine for Women. PMID: 17104172 PMCID: PMC1250049

Emrys-Roberts E. The embedding of the embryo guinea-pig in the uterine wall and its nutrition at that stage of development. (1910) J Anat Physiol. 44(Pt 2): 192-203. PMID 17232840

J Anat Physiol. 1910 Jan;44(Pt 2):192-203. The Embedding of the Embryo Guinea-Pig in the Uterine Wall and its Nutrition at that Stage of Development. Emrys-Roberts E. Author information

PMID: 17232840 PMCID: PMC1289258

Macdowell EC. Allen E. and Macdowell CG. The prenatal growth of the mouse. (1927) J Gen Physiol. 11(1): 57-70. PMID 19872379

Macdowell EC. Allen E. and Macdowell CG. The prenatal growth of the mouse. (1927) J Gen Physiol. 11(1): 57-70.


On the idiosome, golgi apparatus, and acrosome in the male germ cells Bowen, Robert H. Anatomical Record, October 1922, Vol.24(3), pp.158-180

The phosphatase activity of human spermatozoa Macleod, J ; Summerson, W H The Journal of biological chemistry, October 1946, Vol.165(2), pp.533-9

DUPLICATION IN HUMAN SPERMATOZOA. Fawcett, E. The Lancet, 9 August 1919, Vol.194(5006), p.266

The relative viability of human spermatozoa Crooke, A. C ; Mandl, Anita M ; Irwin, J. O Journal of Hygiene, 1949, Vol.47(3), pp.297-302

Cytochemical reactions of human spermatozoa and seminal plasma Wislocki, George B. Anatomical Record, December 1950, Vol.108(4), pp.645-661

I.— Some Observations on the Various Forms of Human Spermatozoa Maddox, R. L. Journal of the Royal Microscopical Society, February 1891, Vol.11(1), pp.1-5

The duration of life of the spermatozoa in the human uterine tube Ohlin, Carl Axel Acta Obstetricia et Gynecologica Scandinavica, January 1935, Vol.15(1), pp.50-57

Comparison of Rates of Penetration of Unwashed and Washed Spermatozoa in Cervical Mucus. ∗ Pommerenke, W. T ; Viergiver, Ellenmae Proceedings of the Society for Experimental Biology and Medicine, 1947, Vol.66(1), pp.161-163

Biochemical Studies of Human Semen and the Mucin of the Cervix Uteri. I. Kurzrok, R ; Miller, E. G Proceedings of the Society for Experimental Biology and Medicine, 1927, Vol.24(7), pp.670-672

Biochemical Studies of Human Semen. III. Factors Affecting Migration of Sperm Through the Cervix. ∗ Miller, Edgar G ; Kurzrok, Raphael Proceedings of the Society for Experimental Biology and Medicine, 1931, Vol.28(8), pp.857-859

The survival of motility in mammalian spermatozoa 1 Wolf, Charles G. L The Journal of Agricultural Science, 1921, Vol.11(3), pp.310-322

Hart DB

1909 Testes Descent 1

Hart DB. The nature and cause of the physiological descent of the testes. (1909) J Anat Physiol. 43(3): 244-65. PMID 17232805

The Nature and Cause of the Physiological Descent of the Testes. Hart DB. Trans Edinb Obstet Soc. 1909;34:101-151. No abstract available. PMID: 29612220

Hart DB. The nature and cause of the physiological descent of the testes. (1909) J Anat Physiol. 44(1): 4-26. PMID 17232824

1909 Testes Descent 2

The Nature and Cause of the Physiological Descent of the Testes. Hart DB. J Anat Physiol. 1909 Apr;43(Pt 3):244-65. No abstract available. PMID: 17232805 Free PMC Article Similar articles Select item 29612220

Hart DB. The nature and cause of the physiological descent of the testes. (1909) Trans Edinb Obstet Soc. 1909;34:101-151. PMID 29612220

1909 Testes Descent 3

J Anat Physiol. 1909 Oct;44(Pt 1):4-26. The Nature and Cause of the Physiological Descent of the Testes. Hart DB1. Author information PMID: 17232824

Hart DB. The physiological descent of the ovaries in the human foetus. (1909) J Anat Physiol. 44(1): 27-34. PMID 17232822

1909 Ovaries Descent

The Physiological Descent of the Ovaries in the Human Foetus. Hart DB. J Anat Physiol. 1909 Oct;44(Pt 1):27-34. No abstract available. PMID: 17232822

On the Rôle of the Developing Epidermis in forming Sheaths and Lumina to Organs, illustrated specially in the Development of the Prepuce and Urethra. Hart DB. J Anat Physiol. 1907 Oct;42(Pt 1):50-6. No abstract available. PMID: 17232754

Preliminary Note on the Development of the Clitoris, Vagina, and Hymen. Hart DB. J Anat Physiol. 1896 Oct;31(Pt 1):18-28.11. No abstract available. PMID: 17232227

On the Atypical Male and Female Sex-Ensemble (So-Called Hermaphroditism and Pseudo-Hermaphroditism). Hart DB. Trans Edinb Obstet Soc. 1914;39:322-355. No abstract available. PMID: 29612446

1879 Development of the Ova

The Development of the Ova, and the Structure of the Ovary in Man and other Mammalia; with Special Reference to the Origin avd Development of the Follicular Epithelial Cells. Foulis J. J Anat Physiol. 1879 Apr;13(Pt 3):353-81. No abstract available. PMID: 17231267

1879 Koala male

The Male Generative Organs of the Koala (Phascolarctos cinereus). Young AH. J Anat Physiol. 1879 Apr;13(Pt 3):305-17. No abstract available. PMID: 17231260

1878 Organ of Corti

J Anat Physiol. 1878 Oct;13(Pt 1):99-103. The Development of the Organ of Corti. Pritchard U1. Author information PMID: 17231237

1881 Ovary Cystic Disease

The Ovary in Incipient Cystic Disease. Harris VD, Doran A. J Anat Physiol. 1881 Jul;15(Pt 4):i1-465. No abstract available. PMID: 17231408

1883 Membrana Tympani

On the Membrana Tympani. Crombie JM. J Anat Physiol. 1883 Jul;17(Pt 4):523-36. No abstract available. PMID: 17231499

Carey EJ. Studies in the dynamics of histogenesis - I. Tension of differential growth as a stimulus to myogenesis. (1920) J Gen Physiol. 20;2(4):357-72. PMID 19871818

Carey EJ. Studies in the dynamics of histogenesis: II. Tension of differential growth as a stimulus to myogenesis in the esophagus. (1920) J Gen Physiol. 20;3(1): 61-83. PMID: 19871849


Bloxam W. On the structure of the human placenta, and its connexion with the uterus. Med Chir Trans. 1840;23:224-438.9. PMID 20895708


Glasgow Medical Journal New (7th) Series January, 1943 Vol. XXI. No. 1.

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By Str JOSEPH BARCROFT, C.B.E., M.A., M.D., D.Sc., E.R.S., Fellow of King’s College, Cambridge.

HowEVER much the scientist may extol the merits of abstract science, I cannot think that any physiologist, however academic his outlook, can feel other than complimented when he receives an invitation from a Society such as yours to address it on the subject on which his sole right to speak consists of the trifle of knowledge which he himself accumulated. I can only interpret such an invitation as a hope on your part to glean from the plot which I have cultivated some grains useful to you in your great objective of understanding and relieving human suffering. On asking one of your number to tell me in a little more detail what you had in mind in giving me this invitation, he said, “ A general account of what you have been doing.” I think I can perhaps best approach the subject by trying to describe the foetus at certain phases of its growth. You may say that such a description is to be found in any book on embryology, but the description which I shall attempt will be in terms of physiological function and not in the current ones of structural morphology. I will try therefore to discuss the foetus at the following stages of its life -—

1. The trigeminal foetus.

2. The pontine foetus.

3. The mid-brain foetus.

4. The just pre-natal foetus.

Most of my information comes from the sheep which has a period of gestation of about 147 days or 21 weeks.

The foetus first becomes physiologically interesting at about the thirty-fourth day of gestation. Up to that time, while the

  • A Finlayson Memorial Lecture delivered at the Royal Faculty of

Physicians and Surgeons, Glasgow, 11th November, 1942.

VOL. XXXVIII. NO. I. 1 A Sir Joseph Barcroft

morphologist has said most of what he has to say about it, physiologically it is a lump of protoplasm, apart from the heart beat, though differentiated in various ways. On the 84th day it makes its first intrinsic movements, and of these the very first can be elicited by tapping it just under the eye. If you ask what virtue this particular spot possesses, the answer is “Look and see,” for, under the skin in that locality you will find the precise position to which the maxillary branch of the trigeminal nerve has grown; and the movement which is elicited is a jerk of the head involving certain neck muscles. Thus then starts the functional history of the most wonderful of all mechanisms, the central nervous system which .grows into that great font of movement and reservoir of personality which we know as ourselves. Within the next few days the sensitive area spreads as the trigeminal nerve develops; movement may be elicited on the 37th day from the nose or from the eyebrow, or indeed from the face as a whole. MHere is an example of a general principle applicable to many concrete instances, namely, the greater the area involved in the stimulation, the less the liminal strength of stimulus. As Sir Charles Sherrington pointed out years ago, you can without discomfort put a small area of skin into water which would be intoleraby hot were your whole body plunged into it; so here, by the 37th day a drop of salt solution falling on the eye suffices to evoke quite a marked motile response on the part of the foetus, whereas a sharp tap with a glass rod was necessary on the 34th day.

As day follows day not only does the area increase in size, but also, if any one spot be stimulated, the number of muscles involved in the motile response increases also, so that, in a very few days, if the nose be stimulated, you will get not merely a twitch of the neck, but a movement involving a great proportion of all the muscles in the body, in short, something which we may call a spasm, albeit a very tiny and feeble one. And then in a few more days, the response is not merely a spasm, but a succession of such spasms, perhaps as many as twenty forming a rhythm. Up to perhaps the 40th day or even later the 5th nerve has the field to itself and the whole foetus is its realm, receiving orders from no other seat of sensation, and therefore, as there are no other


. Phases in Foetal Life

-avenues to what will one day be common paths leading to -effector tracts, the impulse started at the nose spreads as a motor response over the body generally.

At the 44th day responses can be elicited from areas in the fore-limb, and the trigeminal therefore ceases to have undisputed sway, and as the sensory areas in the body

-assert themselves one by one, the spread of stimuli from the 5th nerve becomes more restricted. The limbs drop out of

the response, and later the head, so that stimulation of the

trigeminal produces only rhythmic spasms of the trunk,

including the diaphragm. At the risk of anticipating what I shall say later, I might point out that here we have the

fundamental basis of respiratory movement. I point it out

now because to the end of foetal life, or: should I say “at the end,” if difficulty arises about eliciting respiration at birth, it may be worth remembering that the trigeminal nerve never completely loses its ascendency.

Leaving the point about respiration and going back to the more general one, the history of the trigeminal foreshadows

‘the history of responses elicited by stimulation of other nerves,

though of course none of these starts with the field to itself. Each sensory nerve when first stimulated causes only a localised response. This response spreads as the days go by, but later, as yet other sensory nerves develop the response, it becomes localised again, though in every case the area of response

depends to some extent on the strength of the stimulation.

The Pontine Foetus. If you pick up almost any textbook

of Physiology you will see that the central nervous system

is considered in an ascending anatomical sequence starting with the spinal animal, proceeding to the medullary animal, from thence to the mid-brain animal, and so upwards. One

‘cannot adopt such a sequence with the fcetus, at anyrate

with the sheep foetus, nor could one adopt the opposite one, from above downwards. for the simple reason that the development of function in it starts at the trigeminal nucleus, and proceeds in each direction, which immediately ‘demands a consideration of the medulla before that of the spinal cord; indeed, we shall not consider a spinal foetus at

all because at no stage is there such a thing. The picture

between the thirty-fifth and fortieth days is that of the 3 Sir Joseph Barcroft

maxillary branch of the trigeminal entering the central nervous system at the level of the pons, of its fibres passing back to the reticular formation in the medulla, and relaying there around cells of the reticulo-spinal tract. These fibres form the efferent path of effector impulses to the periphery. What I have called “the trigeminal foetus” - is, therefore, so far as its cells are concerned, a medullary foetus. Nevertheless, if the medulla were severed from the pons the one reflex arc which exists before the fortieth day would be broken, because the descending fibres of ‘the trige- minal nerve would be cut.

If only the anatomy of the trigeminal nerve were a little less tortuous, if its fibres, stimulation of which leads to move- ments of the body, were like those in the sensory roots of the spinal cord: which enter the C.N.S. at the level of the first synapse on the receptor-effector path, then the trigeminal, or at least the parts concerned, would enter at, the level of the medulla. Then-all the sensory impulses, apart from those of special sense, would enter below a section separating the medulla from the pons, whilst the optic, the olfactory and the. auditory nerves entered above it. We would then have a preparation of which we could say, as a first approximation, that development below the section affected the complication of the response but not the essential nature of the movement, whilst development of the brain above the section affected the type of movement rather than the number of muscles. moved. '

Before there is.any evidence of sensory impulses from any other path than the trigeminal being operative, a change takes place in the nature of the movements. This commences. gradually about the forty-first day; indeed up to the forty- fourth day it can scarcely be called more than a tendency. By the forty-fifth day it becomes more marked and by the: forty-eighth day it is fully established. This change is one from a jerky movement to a sustained movement, and appears to be due to some influence exerted by the vestibular branch of the eighth nerve. In proof of this can be adduced the fact that if, at a later stage, say 55 days, when sensory nerves. entering from below the pons can afford a source of stimulation, the brain be cut behind or just behind the entrance of the

4 Phases in Foetal Life

eighth nerve, the movements all revert to the jerky type, and become mere twitches, whereas if the section be made above the eighth nerve the movements are of the “sustained” type, and that even though the higher parts of the brain have been removed.

Do I hear you say, “Is transection of the central nervous system a possible or practical thing in a foetus in utero?” The answer is, “ yes.”. I suppose that Dr. Barron and I, in a partnership in which I may say Dr. Barron, not I, supplied the surgical skill, would have never attempted it but for the encouragement of two persons whose names you no less than I respect, namely, Dr. Harvey Cushing and Dr. Ross Harrison. Actually, at any stage between about the fiftieth and eightieth days, that is, from the time the foetus has become sufficiently “tough” to stand the operation until the time when the skull becomes unduly resistant, the operation of transecting or otherwise cutting the central nervous system may be carried out without even affecting the _ subsequent rate of growth of the foetus. It has been our usual practice to examine such foetuses about a week or ten days after making the section. By that time Wallerian degeneration will be complete, and therefore the effects of trauma of the cut ends of nerve fibre can be disregarded, but we have, perhaps rather for curiosity than otherwise, allowed some of our animals to go the whole period of gestation, with the result that they grew normally and presumably could have lived had the sections not been so low down as to interfere with the respiratory centre.

Up till the fiftieth day the foetus remains approximately pontine, and we may briefly review its possible activities. By this time the central nervous system is capable of receiving impulses from areas other than those paREaed by the trigeminal nerve.

Stimulation then of almost any part of the body will produce movement in the foetus. The movement is still of rather a generalised type ; nevertheless, it is not the simple spasm of the trigeminal foetus, but a rather complicated movement. If the embryo be struck with a glass rod on the nose or the tail, it will first give a characteristic writhe, followed by a series of spasms involving the respiratory muscles; it therefore presents the

5 B Sir Joseph Barcroft

appearance of an animal which has made an effort, and is unduly out of breath as the result. If the foetus is on its side, the writhe consists in an effort to turn the head with the crown upwards, to put the foreleg which is uppermost forward, while the other leg is flexed at the knee or perhaps at the hip. The hind legs are put in a similar position.

Let us pause a moment to consider the nature of this writhe. It has a definite relation to gravity. The head, as I said, is turned crown upwards, but this orientation is not due to the influence of the semicircular canals ; it will take place if these are removed, It is apparently due to the unequal pressure on the two sides of the body caused by the weight of the foetus being borne by one. If a piece of cardboard be pressed on the other, that is on the side which is uppermost, the writhe will not involve the turning of the head. The movements of the limbs are secondary to those of the head, depending on the asymmetrical tension of the neck muscles, and may be stimu- lated by simply twisting the head.

Within these ten days, therefore, the spasm has broken up into a somatic portion, the writhe, and a respiratory portion, the subsequent rhythm, and these are getting more and more divorced from one another, but perhaps the most characteristic feature of the foetal movements at this stage is the extreme ease with which they can be elicited. It is almost impossible to hold a foetus so still that the rhythms of the respiratory type do not appear on the heel of some slight shift in the position of -a limb or what not.

In what I have been saying it will be understood that the foetus is either still in the amniotic sac or, if the membrane bad been broken, the circulation is efficient and the foetus in good condition.

The Mid-Brain Fetws.—Somewhere between the fiftieth and sixtieth day a new feature is appearing. I have just emphasised the extreme motility of the foetus at fifty days, but from this time onward that motility is commencing to disappear, and the fcetus gives only occasional movements, is almost as markedly static, one might almost say dormant, on the sixtieth day as it is active on the fiftieth. Indeed, one might suspect the normal foetus on the sixtieth day as being moribund, but for the fact that it can be wakened into activity. The

6 Phases in Foetal Life

-most ready ways of accomplishing this transformation are firstly, simple exposure, secondly, asphyxia due to pinching the umbilical cord, and thirdly, intra-uterine section of the brain between the mid-brain and the pons.

From the last of these we may draw the conclusion that whatever influence causes this inhibition of the foetus, for it is inhibition, is situated not lower than the mid-brain. If on the other hand, between sixty and seventy days, the section be made between the anterior and posterior corpora quadrigemina, the inhibition is not abolished, and therefore at this date it has its seat in the lower part of the mid-brain.

Here at the risk of breaking away a little from the main stream of argument, I should like to emphasise a point which I have just mentioned, namely, that at about 60 days asphyxia, for the first time, has an apparently stimulating effect upon the foetus. It converts a dormant foetus into an active one, and I wish to impress upon-you that the movements which it elicits are those of respiration. It obviously does so by removal of mid-brain inhibition... There seems to be no evidence at 60 days of inhibition emanating from tle upper part of the mid-brain, and so we pass to:—

Pre-Natal Fetus. To finish the story of the forward development of the brain, it remains to say that at a later stage, after the eightieth day, there does appear to be evidence of an inhibitory centre in the upper part of the fore-brain which indeed seems to take on the burden that had been earlier ‘borne at the level of the posterior corpora quadrigemina, though the precise relation of the two is not very clear.

Having stated the big fact that the main course of physiological development in the brain, unlike its anatomical development, is from below upwards, let me point out a limitation of this statement, namely, that before development at a lower level is complete, it commences at a higher one. Let me give two examples. Firstly; I said that sustained movement was due to the influence -of the pons upon the centres lower down, but the precise nature of this influence alters after the onset of inhibition by the mid-brain. Under cover of this inhibition something is taking place at the level of the pons which alters the type of writhe, and turns it from a gravitational. response, in which the head is twisted

7 Sir Joseph Barcroft

and the legs are placed in opposite directions, into a spasm which bears the general appearance of decerebrate rigidity.

By the sixtieth day, if steps be taken to release the animal from its inhibition and if it then be stimulated, the head is thrown back, the back is curved concavely and the legs are thrust out parallel to one another and in the rigid extended condition, the forelegs being thrust forward and the hind legs backwards.

I must here mention my indebtedness to Dr. Ivy McKenzie for acquainting me with the results of an investigation on a baby which was born at five months and was filmed by cinematograph two weeks later and at weekly intervals afterwards. Dr. McKenzie says (which is quite obvious from the film) “ The picture in the @arly stages............0+ resembles that of decerebrate rigidity. ' The head was strongly extended, the mouth firmly closed except during periods when sucking was automatic. The arms were fixed in flexion at the elbows with some extension at the shoulders. The spinal axis was extended; it differed however from the pathological rigidity in that the legs were not paralysed; they moved vigorously although it was obvious that the movements were on a background of rigidity.” Superficially, it would seem that this foetus was at about the same stage of develop- ment as corresponded to seventy to eighty days in the sheep. One cannot but institute a comparison between the movements made by this human baby at five months from conception, and those of the sheep’s foetus at about seventy to eighty days. The question which needs a little further investigation is the cause of the rigidity in each case. Dr. McKenzie draws attention to the fact that the baby did not show paralysis at the hips; indeed to me a very interesting feature of Dr. McKenzie’s films is the obvious breaking up of the decerebrate rigidity in the 7th month by what appears to be the develop- ment of the inhibitory impulses responsible for reciprocal action of the two legs, so that rigid extension is transformed into a stepping movement; in Dr. McKenzie’s words, “developed in the background of rigidity.”

Another instance of a centre or group of centres developing after the main regional development has taken place is furnished by the vascular reflexes. Of these we as yet* know little, and that little is chiefly confined to the centre for

vagus-inhibition of the heart. 8 Phases in Foetal Life

In the rabbit the whole development of this centre takes place after birth. In the sheep, however, which, is born in a much more mature condition, the vasomotor reflexes, or at all events - some of them, are established before birth. The first date at which stimulation of the distal end of the cut vagus has produced slowing of the heart in the experiments of Bauer has been the eighty-eighth day, and then the response was so slight as to make it probable that the mechanism between the electrodes and the heart had only just commenced to function. This mechanism consists of the preganglionic nerve ending, the postganglionic neurons and the myoneural junction up to the actual muscle. If on the other hand the proximal end of the vagus is stimulated, no response has been evoked in the _ pulse before the hundred and first day, so that the central machinery in the medulla is not established until some date between the eighty-eighth and the hundred and first days, that is, long after-the essential points of the whole somatic mechanism have been laid down. ‘ Even so, there is no proof at present that the heart is under any sort of vagus control at this date. Bauer in the rabbit made what has always been to me the remarkable discovery that both-the machinery for the depressor reflex and the carotid sinus were perfected before the blood pressure in the young rabbit was high enough to bring either into action, and that they were there waiting for the day when it became so. So with the pulse of the sheep foetus, any time from the hundredth day until the hundred and thirty-second day, that is about a fortnight before birth, you will find the heart beating at a rate of twenty pulsations in five seconds, uninfluenced by any nervous control. From the hundred and thirty-second day ‘onwards the pulse begins to slow and the disparity between the actual pulse rate and the rate at which the heart would be beating if it were freed from vagus influences increases. Towards the end of foetal life in the sheep both the depressor and the carotid sinus mechanisms appear to have been elaborated. It is less certain whether both are being used and, if only one, which is it?

I used the phrase, “the rate at which the heart would be beat- ing if it were freed from vagus influences,” and you may ask what method of so freeing it was in my mind. Experimentally,

9 Sir Joseph Barcroft

the cleanest method of doing this is to cool the vagus by putting a strip of copper underneath it; the other end of the strip is in ice. The merit of this method is that the strip can be taken away and the vagus allowed’to return to its natural temperature, in which case the slowing of the heart should be restored; and the reason why it is necessary to observe so strict an experimental procedure, instead of the simple method of cutting the vagus, is that alas! there is another method of freeing the heart from the trammels of the vagus which is the nightmare of all experiments of this type. I allude to the simple deterioration of the nervous system of the foetus through exposure to adverse conditions, anoxemia, exposure, and the like. When this takes place, the heart reverts to its basal pulse rate of about twenty in five seconds from which it is very difficult to shift it, except in the sense that further deterioration pointing to ultimate death will gradually slow it. The condition to which I have alluded is the nearest experimental one to that to which the term ‘foetal shock’ seems currently to be applied in the practice of midwifery’ You can always make a fair guess as to whether the sheep’s “foetus at the end of pregnancy is in a state of shock by counting the pulse. ‘Normally the pulse is about twelve in five seconds, and the nearer it approaches to twenty - the worse the condition of the foetus, unless indeed the foetus has gone so far down the hill that the heart is beginning to fail. ;

While on the subject of vaso-motor reflexes there is one special case which may be considered. I do not wish to put the position so strongly ag positively to affirm that it is a reflex, though the evidenee is trending more and more in that direction. I allude to the closure of the Ductus Arteriosus at birth, a subject which has appreciated in interest on account of the growing possibilities that are opening up to the surgeon in connection with its ligation.

Until quite recently, knowledge on the subject was quite

vague, and authorities could be found who taught everything

from the doctrine that it closed gradually over a period of weeks

after birth, cicatrising by degrees, to the doctrine that it closed

immediately on birth by some mechanism quite unknown.

Recent research by X-ray cinematograph methods seems to have 10 Phases in Foetal Life

established the latter position as being physiologically the correct one. If, for instance, an injection of radio-opaque material such as thorotrast be injected into the superior vena cava, it makes its way immediately through the right side of the heart and appears in the ductus arteriosus, in the descending aorta and in the pulmonary artery. Incidentally, it is rather surprising how broad is the shadow appearing in the ductus. A comparison of the ductus with the arch of the aorta indeed shows the former to be the wider vessel of the two. In a few minutes after birth, however, the picture is changed; a similar injection pursuing the same course through the heart appears in the pulmonary artery, but there is no trace of shadow in the ductus or the descending aorta, except perhaps a slight stump just where the ductus leaves the pulmonary trunk. It is clear therefore that the ductus, instead of being the main vessel by which the blood flows to the hinder part of the body, and before the cord is tied to the placenta, now becomes physiologically obliterated. I am not going to split hairs with my anatomical brethren as to whether the ductus is patent or not in the sense that you could or could not push a fine bristle through it. As a physiologist I am not interested in that question. The interesting point to me is not whether a bristle will go through it, but whether an appreciable amount of blood will do so, and the answer is that it will not; the mechanism of the closure is a very efficient one. The ductus not only narrows down in bore, but shortens in length, so that the lumen, as well as being constricted, is also kinked. This is achieved by a particular muscle in the wall of the ductus, and of the immediately adjacent part of the aorta. The histology of the vessels here is quite different from that of the neighbouring parts of the aorta and the pulmonary vessels. These are of course primarily elastic in type, but the wall of the ductus consists almost entirely of strands of unstriped muscle disposed in spiral, these spirals being both right-handed and left-handed. The result is that when the whole muscle contracts, the outside circumferance of the ductus does not greatly alter, but, as we have said, the lumen is constricted and the whole vessel being shortened, the lumen becomes tortuous. That the closure of the ductus is due to the action of a sphincter there can be no doubt, and its time relations are of the same order as 11 Sir Joseph Barcroft

those of the pylorus, or any of the sphincters of the alimentary canal. That the sphincter is dominated by the nervous system is at the present a less proven proposition. That there are nerve endings in the ductus has been proved histologically by Professor Dixon Boyd, and these are both sensory and motor, though the great majority are sensory. There is there- fore all the machinery present for a neuro-muscular action, and that being so there seems to be'a prima facie case for such a mechanism. On the other hand it has been contended that the closure is due to purely mechanical reasons of the same general nature as the closure of the umbilical vessels when:they are pinched. Such “mechanical reasons” could only be furnished by the act of respiration in some way tugging on the musculature of the ductus. The mechanism of closure would then be a purely local affair and should take place whether or not the nerves to the region were severed. On this point there is very little experimental information as yet, but in two experiments in which I cut the vagi shortly before ligating the cord, and allowed the new-born lamb to live for twenty minutes, the breathing was of the laboured type normal to section of the vagi, and the ductus was found in each case to be open.

You may ask what difference it makes to the foetus whether the ductus closes at birth or not. The question is answered in part at all events by the following table, which shows the length of time taken for blood to traverse the lung from the pulmonary artery to the pulmonary vein before and after closure of the ductus.

Time from ligation Condition of Pulmonary circulation of Cord. ductus, . time. minutes. seconds,

9 open 2°3 20 partly closed 17 32 closed 1:6 4] closed 1-0 55 ? slightly closed 13 80 open 23

It appears then that closure of the ductus has the effect of halving the circulation time through the lung, and therefore presumably greatly increasing the quantity of blood which traverses that organ per minute. What effect that has on the

12 Phases in Foetal Life

minute-volume round the body would depend on whether the foramen ovale were shut or not. If it were shut, failure of the ductus to close would mean a slowing of the circulation in the body corresponding to the slowing in the lung. On the other hand, if the foramen ovale were open, doubtless a larger quantity of blood could find its way to the left side of the heart and so to the body, but it would be rather venous blood.

I have wandered far from the development of the central nervous system; let me return. I was saying that under cover of an inhibition which obscured the patterns of muscular movements new developments took place in the brain and I instanced two, namely, those responsible for decerebrate rigidity and for cardio-inhibition respectively. Let me con- clude by reviewing quickly. the foetus as we see it before birth.

In the trigeminal foetus we saw that somatic and respira- tory movements did not exist as distinguishable. Movement consisted simply in a series of spasms. The motile unit was the spasm; a series of spasms following one another started as a rhythm as the result of a stimulus and died away.

In the pontine fcetus respiratory and somatic movements were in process of separating out from one another, the former losing its rhythmicality and tending to become sustained, postural, and gravitational.

In the mid-brain foetus inhibition becomes well marked, but intensified as the upper part of the fore-brain is formed.

Under the cloak of inhibition, decerebrate rigidity is elaborated, and later the machinery for breaking this up into reciprocated movements such as “ stepping.”

The essence of birth as seen from our angle consists on the one hand of a removal of inhibition sufficient to uncover respiration, sustained movement, posture, response to gravity, and ordered response to external stimuli. On the other hand, birth exposes the mechanism uncovered to a flood of stimuli.

The removal of inhibition is effected by some “degree of asphyxia. The flood of stimuli is incident on the projection of the foetus from a world which, so far as stimuli were concerned, was almost a vacuum, into one which imposed stimuli on every sensory nerve, not the least our old friend, THE


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