The NEURONS and NEURAL SYSTEM: a 21st CENTURY PARADIGM

This material is excerpted from the full β-version of the text. The final printed version will be more concise due to further editing and economical constraints. A Table of Contents and an index are located at the end of this paper.

A few citations have yet to be defined and are indicated by “xxx.”

James T. Fulton Neural Concepts 1 (949) 759-0630 [email protected]

October 21, 2014 Copyright 2011 James T. Fulton

[xxx table of contents numbering still screwed up ] [xxx Broca & wernicke are minor foci in long signaling chains, see Lieberman, Eve Spoke page 100 ] [xxx consolidate 10.2 and 10.8 ]

10 The Morphology of the Neural system 1

Form follows function, and the available real estate

10.1 Introduction

Anatomy has played a major role in the past development of the neurological system. However, as science has advanced to the histological and cytological level, the ability to describe operations from a morphological perspective, particularly an intuitive morphological perspective, has become less than useful. This chapter will review the gross morphology of the nervous system but will follow a different path at the more precise levels. At those levels, electrophysiology provides much more useful and precise information.

The morphologist has used the term functional in a very nebulous manner, to describe the participation of an engine, circuit, or neuron in the signal processing or manipulation related to a high level modality. This work will use functional in a narrower sense related to the specific operational significance of a single cytological neuron or its equivalent electrical circuit of physiology.

When discussing the morphology of the nervous system, and particularly the central nervous system (CNS), the work of Blinkov & Glezer should not be overlooked2. It is by far the definitive reference on all morphological and histological elements of the CNS.

Young has made a series of very significant observations in a 2000 paper3. They will be developed throughout this chapter. However, some of them deserve early attention.

Under the title, “Inconvenient results for vision-as-analysis,” he makes the following observations. “. . . it is widely assumed that a large proportion of the synapses in primary visual cortex come from neurons in the LGN, the principal relay for signals from the eye to the cortex in primates. But this is not the case.” He goes on to justify his position with a number of citations.

With regard to vision, he notes, “Both types of data indicate that V1 is situated nearest the visual periphery in connectional terms, and that other visual stations are successively more central, culminating in anterior IT and other rostral parts of the temporal lobe, . . .” This work suggests it is the thalamic reticular nucleus (TRN) of the thalamus that is the culminating point prior to transfer of the percept signals to the saliency map associated with area 7. Young concludes, “The old certainties, among them that one can employ a bar or grating in a denuded visual scene and hope to understand normal vision, may be beginning to give way.” To understand the operation of the CNS, it is very important to understand the functional flexibility

1Released: 21 October 2014

2Blinkov, S. & Glezer, I. (1968) The Human Brain in Figures and Tables. NY: Basic Books

3Young, M. (2000) The architecture of visual cortex and inferential processes in vision Spatial Vision vol 13, pp 137-146 2 Neurons & the Nervous System inherent in the neuron as an electrolytic-semiconductor-based circuit (Chapter xxx). The neurons of the retina have been shown to be relatively simple in their internal structure and interconnection architecture4. An important specific feature was that the nucleus and soma played minor roles in the operation of the retinal neurons. It was the active electrolytic device, the Activa, within the soma that was the cornerstone of neural operation. Further analysis showed that many Activa were present in the photoreceptor cells of the retina outside of the soma. When exploring the auditory modality, it was found that the Activa also appeared at what must be described as Nodes of Ranvier along the neurites of the neuron and outside of the soma5. Exploration of the CNS has uncovered another unexpected feature (Section xxx). It appears the branching of axons at Nodes of Ranvier can result in the formation of analog-oriented axon segments as well as phasic-oriented axon segments emanating from the same neuron. Thus, an analog signal can be converted to a phasic signal at a Node of Ranvier in addition to within the hillock of a soma. Appreciating this fact leads to a better appreciation of the physiological architecture of the nervous system. 10.1.1 Establishing the discussion framework

While a general equivalence is recognized between the brains of the higher primates and the human, it must be realized that at the current state of research, many significant differences are being documented that differentiate the human brain from all other (at least primate) brains6. In 2007, Preuss provided an even broader discussion of the homology, analogy and differences between the brains of various species, both primate and non-primate7. His report is indicative of a turning point among the anatomical, morphological and histological communities toward more reliance on the traffic flow patterns among the engines of the CNS. He focuses on the major role of the superior colliculus, but does not quite come to recognize the separation between the SC and the uniquely positioned engine (the perigeniculate nucleus (PGN) located along the Brachia of the Superior Colliculus. It is the PGN that focuses on the sensory functions previously traced to the SC with the remaining portions of the SC focused on the motor activity. The combination of the PGN, the remainder of the SC and the TRN constitute a powerful system for controlling the sensing, reaching and grabbing activity so critical to higher mammal and primate activity. His paper is an important one. It will be cited repeatedly in this chapter.

In the 2007 paper, Preuss notes the lack of uniform attention to the many functional systems employed among the mammals, and the resultant difficulty in drawing precise conclusions in many areas. Two potential phylogenic trees of the primates are described in Section 1.1.3. They differ primarily because of the limited research concerning one of the human’s closest relatives, the orangutans (genus Pongo). It is proposed here that the orangutans and humans share a single family, Hominidae with the chimpanzees (Pan) and gorillas (Gorilla) grouped in the family, Panidae. The monkeys are in a more primitive suborder, anthropoidea.

While the chimpanzee has been widely used in behavioral research and claimed by many to be a model for the human neural system, it is clear it is less than a complete model. The members of Macacus (particularly the Rhesus monkeys) are even more limited. It has been widely reported the Rhesus monkey does not present a V4 analogous to that of humans. The least studied but the most similar of the primates to the human is proposed to be the orangutan. It exhibits a variety of characteristics similar to those of humans (including the only other primate to copulate face-to-face.). Their intelligence is well noted but poorly quantified. Interest in the abilities of the orangutan has increased recently. Oxnard has performed a large number of multivariate analyses across the broader spectrum of the primates that includes many results suggesting a closer relationship

4Fulton, J. (2004) Biological Vision: A 21st Century Tutorial. Vancouver, BC, Canada: Trafford

5Fulton, J. (2006) Biological Hearing: A 21st Century Tutorial. Vancouver, BC, Canada: Trafford

6Preuss, T. (2004) What is it like to be a human? In Gazzaniga, M. ed. (2004) The Cognitive Neurosciences, 3rd Ed. Cambridge, MA: MIT Press pp 5-22

7Preuss, T. (2007) Evolutionary specializations of primate brain systems In Ravosa, M. & Dagosto, M. eds. Primate Origins: Adaptations and Evolution. NY: Springer Chapter 18 System Morphology 10- 3 between the orangutan and homo than previously documented8. Pages 246-247 show alternate primate cladograms depending on his criteria. Hopefully, his material will encourage other researchers to include the orangutan in their studies. The cited work from 1984 includes citations to his earlier work. The limited capability of his multivariate morphometric analysis compared to the later multi-dimensional scaling combined with the associated stress test (is important. Table 3.1 of the 1984 book shows a wide variation in the rank order of the primates based on the number of dimensions employed (ranging from 3 to 17). In keeping with his philosophy of introducing his multivariate analysis without providing details, the criteria for establishing these rank orders were not provided. All of the work in the 1984 book was based on the fossil skeletal record. The human exhibits a perigeniculate nucleus/pulvinar couple that is unique to the human species (unless shared with the orangutan and possibly members of Cetacea). It occurs in two variants the visual and auditory couples. The (vision) perigeniculate nucleus/pulvinar couple is associated with the foveola of the retina, a 1.2 degree diameter disk centered on the line of fixation. This couple is key to the ability of the human to perceive fine spatial detail and to read. The (auditory) perigeniculate nucleus/pulvinar couple is associated with the ability of humans to perceive the fine structure of complex sound patterns, and to appreciate music. No animal is known to compete with the human in fine spatial vision. Therefore, there is no known animal model for this pre-eminent portion of the visual neural system. There is no known animal model for the more sophisticated aspects of the auditory neural system, although Cetacea may equal the performance of the human (and exceed it in specific capabilities). It is possible members of Cetacea may also appreciate the tonal qualities of musical patterns, as frequently associated with the songs of whales. The orangutan has recently been observed spontaneously whistling musical patterns. These songs may suggest it has the ability to interpret musical sequences much like humans (and members of Cetacea probably ) do.

10.1.1.1 Establishing morphology subfields by equipment capabilities

Figure 10.1.1-1 as modified from Iurato provides an excellent framework for the following discussions9. The figure has been modified to incorporate the comments on his page 5. He noted that, while light microscopes of the phase contrast and polarization sensitive types could give valuable information below one micron, the information was indirect. Even optically perfect conventional light microscopes could not give full imagery near or below the wavelength of the light employed. The features of interest in understanding the operation of the electrical elements of the neuron frequently have sizes in the region of 100 Angstrom or less.

8Oxnard, C. (1984) The Order of Man. New Haven, CT: Yale Univ. Press

9Iurato, S. (1967) Submicroscopic structure of the inner ear. NY: Pergamon Press pg 2 4 Neurons & the Nervous System

Figure 10.1.1-1 Instrument resolution versus the subfields of morphology. Special (phase contrast, etc.) light microscopes are required to exceed one micron resolution. Modified from Iurato, 1967.

10.1.2 Identifying individual neurons

Identifying individual neurons can be a problem wherever they are densely packed. In general, investigators use a camera lucida approach; hand drawing the neuron based on what they observe using this device. The resulting drawings show a great deal of artist’s license that is in turn biased by their earlier training and experience. Figures such as figure 2.8 in Rose, and many others, are good examples of a “pretty” montage of neurons useful for pedagogy but of little value in discussing the histology or functional performance of the neurons10.

10Rose, S. (2005) The 21st Century Brain. London: Jonathan Cape pg 47 System Morphology 10- 5 In the retina and CNS, the delineation and identification of each neuron may depend on the type of stain employed. Figure 10.1.2-1 shows the difference in the appearance of similar pieces of the cortex based on three commonly used staining procedures. The drawing prepared from the Golgi method (see below) does not isolate nearly the number of soma or soma parts as does the Nissl method. The Weigert procedure appears to emphasize the presence of myelin and chemically similar materials. This emphasis defines the two bands of Baillarger and the major axes of the projection neuron axons leaving the cortex. The location of these axons probably denotes the centerlines of the columns.

Figure 10.1.2-1 The effect of staining on neuron delineation and identification. Note the significant difference in size of the “pyramid cells” using the Nissl stain. Note the more complex form of the neurons using the Golgi stain. The Weigert stain primarily delineates the myelination associated with the neurons. From Carpenter & Sutin, 1983.

, or blobs, in this region of the cortex.

The above figure does not tell the complete story. The Golgi representation is actually a transcription from the original stained image as illustrated in Figure 10.1.2-2 from Conel. Note the significant difference between these two to the untrained eye. Although these two frames were placed adjacent to each other, as were numerous other pairs in Conel’s books, he made no statement concerning their similarity or colocation on the cerebral cortex. While the size difference is considerable between the neurons in both the left and right frames, there are few that could be described as pyramid cells based on their unprocessed Golgi-Cox appearance or on their drawn 6 Neurons & the Nervous System representations. Conel generally provided an additional pair of images with each pair like the above, resulting in sets of four images. This second pair showed the same cortex region prepared using cresyl violoet and the Cajal method. Each image shows significantly different levels of detail. However only the drawing from the Golgi-Cox image represents an interpretation of the original material by the artist. The use of an artist to interpret the raw Golgi-Cox imagery introduces a significant problem. If the artist is told that a high percentage of the neurons are pyramid cells, he will draw a high percentage of pyramid-shaped cells regardless of the original material. It is interesting that the Conel drawings System Morphology 10- 7

Figure 10.1.2-2 A comparison of the raw image obtained from the Golgi-Cox method and the drawing prepared from the image. From Conel, 1963. based on the Golgi-Cox imagery do not contain a large percentage of pyramid-shaped cells, although Conel apparently assigned that name to a large percentage of the total number of cells. These figures do not capture the variation in laminate organization and content. Figure 10.1.2-3 8 Neurons & the Nervous System shows these variations according to von Economo11. The frames from left to right represent different portions of the human brain based on the Nissl stain and discussed in the following figure. The description of the layers is largely arbitrary and differs from source to source. The labeling attributed indirectly to Brodmann in D. Smith seems most useful12. “Note the six basic layers, but note also how the relative proportion of each varies from one type of cortex to another. Layer I is known as the plexiform (or molecular) layer and contains mainly a densely matted network made up of dendrites from the pyramidal cells in the lower layers. This network runs horizontally, thus allowing information to flow from point to point across a given area of cortex. Layer II is known as the external granular layer and contains stellate cells and a large number of small pyramidal cells. Many of the apical dendrites of the large pyramidal cells in Layer V (see below) synapse here. Layer III is known as the external pyramidal layer and contains stellate cells and both large and medium-sized pyramidal cells. Layer IV is known as the internal granular layer, and contains primarily stellate cells. Where this layer is particularly thick, then the resulting cortex is known as granular cortex (or koniocortex). The primary auditory and visual areas are composed of granular cortex. Where this layer is particularly devoid of stellate cells, then the resulting cortex is known as agranular cortex. The primary motor area and much of the upper frontal lobe are composed of agranular Figure 10.1.2-3 Section architectures found in the cortex. As with Layer I, there is a concentration of human brain compared. Note the three different horizontally arranged fibres, often referred to as the numberings. The total depth in frame 1 & 2 is about external band of Baillarger. Layer V is known as 500-600 microns. See text. From von Economo, the internal pyramidal layer, and is rich in pyramidal 1929 cells. In the primary motor area, these are exceptionally large and go by the name giant cells of Betz. These Betz cells are important because their axons descend to become the corticobulbar and corticospinal tracts. Their apical dendrites are much shorter, however, ascending to Layers I and II before travelling off horizontally in all directions. Layer V contains yet another horizontal network of fibres, often referred to as the internal band of Baillarger. Layer VI is known as the fusiform layer and contains a range of cell types, including callosal neurons, namely those whose axons project into a commissural tract.”

Most of these depictions employ hand drawing of the cross section to emphasize certain features. Such emphasis is not present in photographic records. Figure 10.1.2-4 shows an actual photograph prepared by Brodmann. Note the very subtle differences in the appearance of different numbered regions at this resolution. There are no signs of pyramid shaped cells.

11Von Economo, C. (1929) xxx Oxford Univ Press page 16

12Smith, D.J. (1997). Neuroanatomy for Students of Communication. Cardiff: UWIC. [ISBN: 190066609X - out of print] (available at http://www.smithsrisca.demon.co.uk/neuro-micro.html ) System Morphology 10- 9

Figure 10.1.2-5 reproduces a figure from D. Smith showing the important role of the stage 3 neurons based on use of the Weigert stain. Several observations are required concerning this figure. C The triangular symbols for pyramid cells have been replaced by pentagonal symbols. Cell locations differ marginally. C The titles along the top of the graphic should be considered secondary to the more explicit labels attributed to Brodmann above. They are simplified in order to relate to the following figure. Figure 10.1.2-4 The cytoarchitecture of human visual cortex using Nissl-stained tissue section. The C Labeling in the center and on the right has large arrow near the bottom indicates the border been omitted in favor of the stepped line at between area 17 and area 18. The large arrow is in the bottom. This makes the symbolism in the deep white matter of the cortical mantle. The stage 4 of columns 4 and 5 to appear to be in outer surface of the cortex is at the top (near the laminate 3 in spite of the notes on the right. small arrow). From Brodmann, 1909.

C Layer 1 is described as a dendrite network. However, based on the stain, it is more correctly labeled a local association network employing stage 3 myelinated neurons. C The vertical axon bundles are stage 3 commissure arriving and or departing via association or cortico-cortex projection paths.

C The horizontal structures in layers IV and V represent extensions of the stage 3 commissure in order to form multi-dimensional comparison arrays within the laminates. 10 Neurons & the Nervous System

Figure 10.1.2-5 After Von Economo, with horizontal dendrite systems and vertical axon "columns" added by D. Smith. See text.

Figure 10.1.2-6 shows a gross representation of the different types of laminate structure in the human brain. No effort has been made to identify striated areas or the finer divisions of the cortex used currently. System Morphology 10- 11

Figure 10.1.2-6 A description of the specialization of areas of the human brain from Smith using the nomenclature of Brodmann (but not using Brodmann’s area notation).

10.1.2.1 Defining pyramid cells

No definitive (i.e., precise ) definition of a pyramid cell has been encountered in a broad review of the literature of the last fifty years or more. It may be of interest that Cajal initially described the cells as pyramid or psychic cells13. The term pyramid stuck and the alternative was lost in the ash can of history. Based on the semantic meaning of these two words, it appears obvious that Cajal did not have the term pyramid firmly in mind based on any geometric consideration.

As developed in Chapter xxx, the term pyramid cell is used to define two significantly different types of neurons. The first type operates only in the analog domain, stage 2, 4 or 6) and is typically a differencing neuron (where the arborizations at the base of the neuron form the poditic terminals of the neuron. The second type is a neuron that accepts analog inputs, performs differencing, and then generates action potentials as a stage 3 encoding neuron.

A factor of great importance in discussing individual stage 3 neurons is the diameter of the axon(s). The literature is generally unclear when discussing these axons as to whether the diameter listed is of the axon itself or of the myelinated axon. The myelination is not an integral part of the axon and is frequently provided by a distinctly separate neuroglia. Thus, the combined diameter may be misleading when discussing a specific type of neuron. Whether myelin is present may have a very large impact on the signal transport velocity (and the resultant transport delay) associated with the neuron. However, the underlying axon diameter may not change between the two situations. Thomson & Bannister list a typical delay of 2 ms per mm for unmyelinated axons.

10.1.2.2 Defining the agranular laminates of the pia matter

Layer IV of the cortex is frequently described as the granular layer with layer V described as the pyramidal layer. Many investigators have described portions of the cortex missing layer IV as agranular14.

13Elston, G. (2003) Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function Cerebral Cortex vol 13, pp 1124-1138

14Petrides, M. & Mackey, S. (2006) The orbitofrontal cortex: sulcal and gyral morphology and architecture In Zald, D. & Rauch, S. eds. The Orbitofrontal Cortex. Oxford: Oxford Univ Press. Chapter 2 page 29 12 Neurons & the Nervous System

Barbas & Zikopoulos have given an entirely different description of the layers of the cortex without providing any supporting citation15. In discussing the orbitofrontal cortex, they define, “an agranular area, which has only three identifiable layers, dysgranular areas, which have four identifiable layers, and granular (eulaminate) areas which have six distinct layers. Agranular and dysgranular type cortices are collectively called limbic.” The definitions of Barbas & Zikopoulos do not appear frequently. However, they illustrate the range of terms used for the same conditions within neurology and the neurosciences. 10.1.2.3 Defining commissure destinations

Figure 10.1.2-7 describes the terminal points and principle destinations of neurons commonly found in the CNS.

Figure 10.1.2-7 Diagram of the major cortical neurons of the cerebral cortex. Layers I through IV are usually described as receptive layers. Layers V & VI are described as the discharge layers. From Noback, 1967.

Figure 10.1.2-8 describes the terminal points and principle destinations as presented by Hubel 20 years later. Note the significant differences in layer thicknesses versus the Noback figure. The more conceptual Hubel figure does reflect a more modern subdivision of layer IV. The subdivision of these layers will take on a different form or labeling in Chapter 12. Fetz has reproduced a figure from Jones (1986) similar to Noback’s figure but focused on the tissue

15Barbas, H. & Zikopoulos, B. (2006) Sequential and parallel circuits for emotional processing in primate orbitofrontal cortex In Zald, D. & Rauch, S. eds. The Orbitofrontal Cortex. Oxford: Oxford Univ Press. Chapter 4 System Morphology 10- 13 of the primary motor cortex16. Jones did not show a layer IV at all in his presentation. Obviously, he did not subdivide layer IV. He did describe commissure from layer VI as destined for the thalamus. At the current time, investigators tend to use their favorite template defining the relative widths of the different layers and scale the template length to fit the thickness of the tissue they are examining. The tissue seldom if ever includes any internal markers with which to coordinate with the template.

Figure 10.1.2-8 Terminations and paths of neurons in the CNS TEMP from Hubel99pg99. ADD.

16Fetz, E. Motor functions of cerebral cortex In Patton, H. Fuchs, A. et al. eds. Textbook of Physiology, 21st Ed, Vol. 1. pp 616 14 Neurons & the Nervous System

Figure 10.1.2-9 shows another labeling of the cortical cross section by Jones17 that illustrates several situations related to the current state of the art in this area. First the Jones figure is more detailed than the pedagogy oriented figure of Noback. However, the Jones figure shows that it is becoming necessary to be much more specific concerning the area of the cortex being discussed. Rather than a simple Brodmann area designation, it is important to describe the areas using Talairach coordinates, preferably based on an inflated or flattened cortex. It is also important to suggest the type of cortex area presented, such as whether it exhibits Baillarger bands or not. Baillarger bands are highly suggestive that bands IVb and V are portions of a comparator circuit configuration (Section xxx)..

Figure 10.1.2-9 Targets of projections from pyramidal cells in different layers of primary motor cortex. Cells projecting across the midline are shown at right. Arabic numbers refere to Broadmann’s architectonic designations. SMA; secondary motor area. PMC; premotor motor cortex. VL; nuceus ventralis lateralis. VPLo; nucleus ventralis posterior lateralis oralis. From Jones, 1986.

17Jones, E. (1986) xxx In Jones, E. & Peters, A. eds. Cerebral Cortex, Vol 5. NY: Plenum Press pp 113-184 System Morphology 10- 15 Note all of the commissure of the figure are shown as outgoing. In discussing this figure, Fetz suggests18, “Most of the outputs to subcortical targets arise from pyramidal cells in layer V. The corticospinal cells lie deepest in layer V and include the largest pyramidal cells in motor cortex, the so-called Betz cells. Cells i successively more superficial portions of layer V project to successively more proximal brain-stem targets, namely to the medulla, pons, and red nucleus; the most superficial lyer V cells project to the striatum. A few pyramidal cells send branching connections to more than one of these targets, but the majority project to only one site.” Fetz also notes, “ Layer VI contains smaller pyramidal cells with long apical dendrites, whose axons project to the thalamus, particularly the ventrolateral nucleus. Many layer VI cells also send recurrent connection to upper cortical layers. Fetz is more limited in his remarks concerning inputs to the primary motor cortex. He indicates most inputs are from other cortical areas, many ipsilateral, and the thalamus. [xxx back up here, recognize the histologist tends to think about horizontal diffrences while the Hubel followers tend to think of columns. ] 10.1.2.1Generic structure of the cerebral cortex cross section

Based on these discussions, the typical primary purpose of the layers of the cerebral cortex are: xxx

Layer 1– Layer 2– Layer 3– Layer 4– Layer 5– Layer 6– 10.1.3 Labeling neurons by physical shape

Morphology has had a difficult time segregating and defining different types of neurons. The beginning of the effort is usually attributed to Cajol who first used the term pyramid cells to define the neurons of the cerebral cortex. This single descriptor soon gave way to the dichotomy of pyramid cells and cortical cells. This dichotomy soon became pyramid cells and interneurons.

An alternate naming convention has arisen in parallel with the above dichotomy. It has used the simple notation of the number of “processes” leaving the portion of the soma containing the nucleus. The resulting names have been monopolar, bipolar and multipolar neurons. This nomenclature suffers from at least three problems. Unfortunately, the nucleus and other chemically oriented elements of the soma have no functional relationship to the role of the neuron. They are strictly concerned with morphogenesis and housekeeping. Second, the term bipolar is easily confused with a physiological descriptor where a bipolar cell may or may not process bipolar signals, and may or may not be bidirectional in function. Third, the description multipolar leaves a majority of all neurons of the cortex in a single class (See below).

When working outside the cortex, the morphologically naming of the peripheral neurons of vision and hearing have used entirely different strategies. The names used in hearing are frequently whimsical, suggesting the lack of knowledge of their underlying function. The neurons of the retina show no pattern. Some are named by their specific function (photoreceptor cells), some by their orientation (horizontal cells), some by their presumed structure (amercine cells), and others by names imported from other studies (bipolar and ganglion cells). Some conceptual names that were adopted very early, such as rods and cones, have never been successfully associated with, or successfully differentiated between, specific portion of the photoreceptor cells.

Thomson & Bannister have summarized the situation with regard to pyramid cells19. “Although

18Fetz, E. (1989) Motor functions of cerebral cortex In Patton, H. Fuchs, A. et al. eds. Textbook of Physiology, Vol 1, 21st Ed. Philadelphia, PA: W. B. Saunders pp 609-648

19Thomson, A. & Bannister, A. (2003) Op. Cit. Page 6 16 Neurons & the Nervous System pyramidal cells share many distinctive anatomical features, they are far from a homogeneous group. Even within a layer there are several morphological subtypes, ofter projecting to different cortical and subcortical regions.” The problem of naming neurons of the cortex based on geometry is illustrated in Figure 10.1.3-1 The upper row shows typical shapes based on the profile of the cell (of unknown rotational orientation). The lower row shows the plan view of typical shapes without regard to their profile. The samples are shown with a circular plan view since there is no specification of the pyramidal cell as having a multicornered plan view. It is quickly obvious that no pyramidal cell (with an axon extending from the center of the lower extremity of the cell as shown in the upper row is truly pyramidal in shape. It is also clear that most pyramidal cells do not exhibit a pyramidal planform as shown in the lower row. The pyramidal neurons tend to be spindle-shaped, with a circular planform and with multipolar podite structures at the detailed level. Cells of the right-hand shape in the lower row tend to be called stellate (star-shaped) cells when viewed in planform. Elston has contributed his interpretation of the planform of the pyramidal cells in layer III when projected onto the tangential plane20. While they all are multipolar, he does not show any of them with a multi- cornered configuration reminiscent of a pyramid. Elston’s conclusions regarding the variety and relative complexity of “pyramid cells” with location and probably with detailed function within the cortex are worth reviewing. His paper reiterates that the designation pyramid cell is more conceptual than graphic.

Figure 10.1.3-1 The difficulty of differentiating between neurons based on shape.

20Elston, G. (2003) Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function Cerebral Cortex vol 13, pp 1124-1138 fig 5 System Morphology 10- 17 The shapes encountered in practice within the cortex are much more complex as shown in Figure 10.1.3-221. Note how the names provided by Afifi & Bergman range from the geometric to the pseudo-functional and to hybrids of the two. It should be noted that many of the finer processes of neurons cannot be seen using conventional light microscopy (sample H is probably a good example). Some additional processes can be seen with Nomarski and other special modes of operating light microscopes.

Figure 10.1.3-2 A montage illustrating variations in neuronal size, shape and processes found within the cortex. The orientation of the cells with respect to the surface of the cortex was not specified. A; pyramidal cell. B; flask-shapes Purkinje neuron. C; stellate neuron. D; granular neuron. E; multipolar anterior horn neuron. F; multpolar sympathetic ganglion neuron. G; multipolar parasympathetic ganglion neuron. H; pseudounipolar dorsal root ganglion neurons. Ax = axon. From Afifi & Bergman, 1998

The shapes found within the retina and the auditory nucleus of the peripheral nervous system differ considerably from the shapes shown in the above figure. As noted in Section xxx, the difficulty in labeling neurons uniquely has led to considerable difficulty in defining the number of each type.

21Afifi, A. & Bergman, R. (1998) Functional Neuroanatomy. NY: McGraw-Hill pg 5 18 Neurons & the Nervous System

Noback provided the following numbers of cortical neurons in 1967 ; Total number of neurons (mature adult human) 20 billion Number of pyramid cells 4.5 billion Number of stellate cells 3.5 billion Number of unspecified “other” 12 billion Staining has shown the great difference in pyramid cell size without offering any rationale for this difference. Separation of the pyramid cells into those with and without myelination offers one rationale for differentiating them. A pyramid cell with a myelinated axon is used in the phasic mode associated with stage 3. A pyramid cells without a myelinated axon is probably used in local analog signal manipulation. Signal manipulation is a stage 4 function. A second rationale involves whether the pyramid cell exhibits both one or more dendritic arborizations and one or more poditic arborizations. If it does not have any poditic arborizations, it cannot perform internal differential signal manipulation before encoding. However, it can still accept both differential (bipolar) signals and monopolar signals at its dendritic terminals. Within the engines of stage 4, it appears nearly all myelinated pyramid cells exhibit podite arborizations. Swanson gave a similar set of numbers in 2003. 3-14 billion neurons and ten times as many glial cells within the CNS.

10.1.5 Describing neurons by fanciful names

The use of abstract names for neurons has been quite common, specifically with regard to research into hearing. Many authors have provided fanciful names for the interneurons of the CNS. Thomson & Bannister noted several types of these. They listed chandelier cells (or axo-axonic cells), basket cells (covering a vast range of morphologies), and double bouquet cells (first named for their bitufted dendritic arbor. They noted the double bouquet cells “are most readily identifiable by their narrow bundles of unmyelinated, vertically oriented, descending and sometimes ascending axon collaterals.” They went on to identify Martinooti cells and spider web cells. It tells a very highly trained eye to distinguish between many of these cell types when presented as two-dimensional views on paper.

Thomson & Bannister describe one important feature of these cells by the target of their axons

Name Target Features Chandelier cells Proximal part of pyramid cells Horiz or oblique axonal branches with vert. collat. Basket cells “ ” Preferential innerv. of somata and prox. dendrites

Double bouquet cells Dendrites of pyramid cells Narrow bundles of unmyelinated vert axons Martinooti cells “ ” Prominent unmyelinated axon projection to layer 1 spider web cells “ ” Late spiking, frequently concentric processes The major features of these cell types are far from definitive and exclusionary. As Thomson & Bannister noted, “while many of the interneurons belonging to the classes described above are readily identifiable if well filled with reaction product, there are many that do not comply with these classifications, neurons that meet one or two, but not all the criteria for a particular classification or whose near-spherical axonal and dendritic arbours defy classification on gross morphological criteria.”

10.1.5 Describing neurons by size distribution

Many authors have attempted to show the neurons of a specific type are distributed “normally” in System Morphology 10- 19 size. However, neurons are the result of a biological growth process. Biological growth processes are not the result of a random process and are not governed by the Gaussian Law. Such neurons exhibit a log-normal distribution, i.e., their size is represented by a normal distribution plotted using a logarithmic horizontal axis. Blinkov et al discussed this question briefly but succinctly (page188). They note the necessity of separating the size distributions associated with different layers in order to avoid multimodal distributions. They also made an observation that may have suffered in translation. “Thus, in the cortex also, besides the laws of probability, strictly determined relationships operate, not based on random factors.” In fact, the growth laws are also laws of probability, but they are not the familiar Gaussian Laws. 20 Neurons & the Nervous System

10.2 Cytoarchitecture of the CNS

DeSalle & Tattersall have provided a profile of the development of the Homo brain, along with an estimate of its total volume, during the last six million years22. . Professor Triarhou has written a comprehensive history of the development of the cytoarchitecture of the brain in a 2009 paper on the internet at the impossible address of: http://www.scitopics.com/Cytoarchitectonics_and_the_Morphofunctional_Parcellation_of_the_Hu man_Cerebral_Cortex_From_the_44_Brodmann_Areas_of_1909_to_the_107_Economo_Koskinas_ Areas_of_1925.html This address must be entered into the address field without carriage returns. [xxx in my files it is an archival file at C:/Whneuron/Triarhou_cytoarchitecture.mht ] He points out the pluses and minuses of the different labeling systems developed over the years. 10.2.1 Anatomy, sulci & gyri of the cerebral cortex

In the past, it was common to illustrate only one lateral view of the cerebral cortex on the assumption it was symmetrical. This has been found untrue at the detail level available today through either dissection or medical imaging techniques. Preuss discusses these asymmetries in some detail23. Figure 10.2.1-1 shows the major gyri and sulci of the left hemisphere of the human brain (with the exception of the prefrontal lobe) as described by Jones & Peters in 1990. The prefrontal lobe is located largely on the underside and medial surface of the cerbral cortex. These locations are detailed more fully in Section 10.2.2 and in Chapter 12. As they noted, under a heading “2.4 Standardization of Nomenclature,” there is little standardization at this time. Even recent papers differ significantly in labeling all but the most major sulci and gyri. It has also become obvious that the folding of the cerebral cortex is not precise and repeatable across the human species. It is particularly difficult to show that a specific engine of the brain always appears in a specific sulcus and not on the nearby gyri in some individuals.

22DeSalle, R. & Tattersall, I. (2012) The Brain: Big Bangs, Behaviors, and Beliefs. New Haven, CT: Yale Univ Press. page 271

23Preuss, T. (2004) What is it like to be a human? In Gazzaniga, M. ed. (2004) The Cognitive Neurosciences, 3rd Ed. Cambridge, MA: MIT Press pp 12-14 System Morphology 10- 21

Figure 10.2.1-1 Labeling of the sulci and gyri of the human brain. This figure may not represent the majority view (See text). Top; lateral view of left hemisphere with prefrontal lobe on the left. Bottom; medial view of left hemisphere with prefrontal lobe on the right. Note the medial view (lower frame) is facing opposite the upper frame. Major gyri and sulci are labeled by conventional terms for primates. From Clemente, 1985 & reproduced in Jones & Peters, 1990.. 22 Neurons & the Nervous System

A rotating 3D representation of the human brain within the context of the face and jaw is available at https://en.wikipedia.org/wiki/File:Lateral_sulcus.gif . The lateral sulcus is also known as the Sylvan sulcus or the lateral fissure of Sylvius. It also shows the distinct separation of the cerebellum from the cerebral cortex. Figure 10.2.1-2 aids in the definition of a variety of additional features using a cross section of the human cerebral cortex. The purpose is to define the nomenclature. Assuming the cerebral cortex is symmetrical about the midline is not warranted. Preuss presents a different view showing the gross asymmetry of the human brain (page 13). As noted in Jones & Peters, there is a general consensus regarding the nomenclature shown in this group of figures for the human and a few other primates. However, different sets of nomenclature are used for most other frequently studied carnivores. They discuss the reasons for this. The primary reason is an inadequately determined homologous relationship between these animals.

Figure 10.2.1-2 Diagram of human cerebrum in transverse section. The several gyri that compose part of the frontal and temporal opercula mushroom out over the insula from slender stalks of white matter (indicated by stars). From Roberts et al. 1987 and reproduced in Jones & Peters, 1990.

Figure 10.2.1-3 shows additional details related to the areas in white in the above figure from Sheperd (1998, pg 330). The labeling differs from that used elsewhere in this work. The striatum of the detailed view is labeled the putamen in the smaller inset. The large volume of white matter can be compared to the tissue of the cerebral cortex (which is shown greatly enlarged). The latter is typically only 600 xxx microns thick System Morphology 10- 23

The total surface area of the human brain is open to speculation. Values from two to ten square feet appear in the literature. James provides an appraisal of the shape of the brain and its size prior to the expansion of computerized analyses24. He notes, “The cerebral cortex looks like a large flexible bag which has been crumpled up to fit into a smaller container. What shape would it adopt if it were allowed to expand until all the folds were removed? There is no record of any previous attempt to determine the unfolded shape of the entire human cerebral cortex.” He provides a brief history of unfolding the brains of other species. He goes on, “Another matter of interest is the fact that the combined area of the two unfolded cortices is about 0.89 m2 (about ten square feet), two and a half times larger than the currently accepted figure, also about eight-ninths of the Figure 10.2.1-3 A section through the human cortical area lies within the sulci.” cerebral cortex showing the basal ganglia and the major interconnections in this region. The region James illustrated how the sulci are formed labeled cortex is the insula. Gpe; globus pallidus, when a sheet of material is compressed in- external segment. Gpi; globus pallidus, internal plane from two orthogonal directions segment. Thal; thalamus. Sth; subthalamic simultaneously. Y-folds will form. The nucleus. Snr; substantia nigra, pars reticulata. Snc; existence of numerous Y-folds on the cortical substantia nigra, pars compacta. From Shepherd, surface supports the view that the unfolded 1998. shape will be free of bumps or constrictions.

It is worth noting again the human brain is not limited to the cerebral cortex.

10.2.1.1 Redefining the aversive motor and perceptual sensory areas of the human cerebral cortex

A functional analysis of the human cerebral cortex suggests a different labeling of the major lobes of the brain from the historical frontal, parietal, temporal and occipital lobes. Figure 10.2.1-4 shows a description of the cerebral cortex from Fetz25. It shows the occipital lobe on the right as commonly defined, extending up to the parietal-occipital sulcus. The temporal lobe nominally extends forward from the preoccipital insicure. The problem comes in the front areas of the brain. Fuchs & Phillips have addressed this subject briefly and gone with the historical anatomical view26. The texture of the regions of the historical frontal lobe vary as do the paths of the commissure to those regions. They define the areas 8 and 44 are transitional areas that are “dysgranular” as opposed to the prefrontal lobe that is granular. Defining the frontal lobe as extending back to the central sulcus is entirely arbitrary based on historical anatomical practice. The figure clearly shows the region from the superior frontal sulcus to the parietal occipital sulcus is populated by high level sensory and motor functions generating adversive and cognit type signals. These signals are not associated with the cognitive processes of the frontal lobe.

24James, B. (1992)The unfolded shape of the brain J Roy Soc Med vol 85 pp 551-552

25Fetz, E. Motor functions of cerebral cortex In Patton, H. Fuchs, A. et al. eds. Textbook of Physiology, 21st Ed, Vol. 1. page 609

26Fuchs, A. & Phillips, J. (1989) Association cortex In Patton, H. Fuchs, A. et al. eds. Textbook of Physiology, 21st Ed, Vol. 1. page 677 24 Neurons & the Nervous System

In this work, the frontal lobe will be defined as extending to the superior frontal sulcus. A new central lobe will be defined as the orofi lobe extending from the superior frontal sulcus to the parietal-occipital sulcus. This orofi lobe includes all of the high level sensory signals accessible by the cognitive functions of the frontal lobe (1 through 5 & 7) and the destination of all high level motor instructions from the cognitive function (areas 4, 6 & 8) . These high level instructions are converted into operational instructions in the orofi lobe before being further expanded into motor commands by the cerebellum and superior colliculus. [xxx coordinate with any changes in Clemente figure Some maps show the superior frontal sulcus as running fore and aft. Figure 10.2.1-4 Major areas of the cerebral cortex Zillmer & Spiers have provided an alternate from the functional perspective. See text. description of the cyto-architecture of the brain attributed to Pinel & Edwards (1998) and shown in Figure 10.2.1-5. While providing more detailed labelling, it omits the Broadmann numbers and presents a totally different rendition of the sulci and gyri. System Morphology 10- 25

Figure 10.2.1-5 Cortical motor processing areas. From Zillmer & Spiers, 2001. 26 Neurons & the Nervous System

Modern medical imaging equipment and the computing power available, in the hands of a knowledgeable map maker, can produce a realistic map of the unfolded human brain. Such a map can uncover relationships previously difficult to demonstrate. Connolly et al. have provided an inflated view of the medial surface of the right cerebral hemisphere suggesting the degree of neural tissue hidden from most studies27. Hurdal has undertaken a major program in unfolding the brain using conformal transformation principles. Figure 10.2.1-6 shows an unfolded map of the right hemisphere of the human cerebral cortex from Hurdal. The black fringe is an artifact of the editorial process. As suggested by James, it shows minimal distortions (bumps or constriction) in the reconstructed surface. Such distortions are indicated by the size of the circles used in the reconstruction process. The distortions may represent problems with the resolution of the MRI technique rather than true distortion. The labeling is drawn from watching the surface unfold on Hurdal’s website28. Several unidentified cut lines were used to prepare this map. She has also prepared maps of the unfolded cerebellum. Future work will embed labels into the fabric of the maps. The work will also expand to include the entire brain rather than just one hemisphere of the cortex or the cerebellum. The map is incomplete with regards to the elements of the insula, the diencephalon and other internal structures that are also part of the unfolded brain.

Van Essen has provided a very useful review of the various potential maps and databases for describing the human brain29. He also includes an annotated bibliography that is very helpful.

Chalfin et al. have offered their values for the volume of the human brain and compared it with many others within the morphology

Figure 10.2.1-6 Unfolded cerebral cortex. Occipital cortex, including underside, on left in red. Purple portion along top represents the medial face of the frontal and parietal lobes. From Hurdal, 2009.

27Connolly, J. Andersen, R. & Goodale, M. (2003) fMRI evidence for a “parietal reach region” in the human brain Exp Brain Res vol 153, pp 140-145 (also pg 468 in Gazzaniga )

28Hurdal, M. (2009) http://www.math.fsu.edu/~mhurdal/ Click on Visualizing flat maps of the human brain

29Van Essen, D. (2002) Windows on the brain: the emerging role of atlases and databases in neuroscience Cur Opinion Neurobiol vol 12, pp 574-579 System Morphology 10- 27 oriented group of investigators30. Their numbers appear to be much larger than those of the histology community. Talairach & Tournoux have prepared flat maps of the human brain using a new set of coordinates that is gaining wide acceptance within the MRI community31. Unfortunately, their entire atlas was based on one brain. This well known problem is illustrated in figure 5 of Walters et al32. The Talairach coordinate system offers a means of exploring areas of the brain with higher precision. Van Essen has noted, “individual areas can vary two-fold or more in their absolute size and in their location relative to gyral/sulcal landmarks.” Citing Watson, Myers et al. (1993), Walters et al. note the motion sensitive area, human V5, has a range of 27 mm in location. Walters et al. used a very high resolution MRI with a 4.7 Tesla magnet and a clear bore of only 30 cm in their early attempts to associate structure with function. Gusnard & Raichle have provided a figure showing Brodmann’s areas superimposed on a flat representation of the cerebral cortex as part of a broader study of oxygen utilization during neural activity33. Unfortunately, the areas were not numbered in the version published even though the caption suggests they were. Holmes et al. have demonstrated the utility of overlaying individual MRI images when adequate care is taken in registering the images34. While the limiting resolution is not increased, the contrast and associated visibility of many structures is measurably enhanced.

The Walters et al. and similar work is likely to produce new maps showing the standard deviation in the location and the size of functional features of the brain in the near future.

Based on the above sources, the surface area of the human brain appears to vary about ±12 to ±15% between adults. The total area of the human brain is usually taken as about two square meters but the numbers found in the literature for the average area can vary by a factor of ten, 0.15 to 2.0 sq. meters. Some investigators may not know how to convert square cm to square meters.

The Fischl group has published a wide range of papers exploring the area and volume of the human brain from a variety of perspectives35. Im et al. have provided a large statistical analysis of the human and other primate brains36. As an example, they give the surface area of the left lobar occipital lobe as 127.59 ± 12.06 sq. cm based on 148 human subjects. For a nominally circular left lobar, the diameter of the lobar is about 6.35 cm.

30Chalfin, B. Cheung, D. Muniz, Jose. et al. (2007) Scaling of neuron number and volume of the pulvinar complex in new world primates: comparisons with humans, other primates, and mammals J Comp Neurol vol 504(3), pp 265-274

31Talairach, J. & Tournoux, P. (1988) Co-planar Stereotaxic Atlas of the Human Brain. Stuttgart: Thieme [xxx missing from UCI stacks

32Walters, N. Egan, G. Kril, J. Kean, M. et al. (2003) In vivo identification of human cortical areas using high-resolution MRI: An approach to cerebral structure–function correlation PNAS vol 100(5), pp 2981–2986

33Gusnard, D. & Raichle, M. (1989) Functional imaging, neurophysiology, and the resting state of the human brain In Patton, H. Fuchs, A. et al. eds. Textbook of Physiology, 21st Ed, Vol. 1. Chapter 91

34Holmes, C. Hoge, R. Collins, L. eta al. (1998) Enhancement of MR Images Using Registration for Signal AveragingJ Comput Assist Tomogr vol 22, pp 324-333

35Fischl, B. Salat, D. Busa, E. et al. (2002) Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain Neuron vol 33(3), pp 341-355

36Im, K. Lee, J-M. Lyttelton, O. et al. (2008) Brain Size and Cortical Structure in the Adult Human Brain Cer Cortex vol 18, pp 2181-2191 28 Neurons & the Nervous System

Toro et al37. have also provided a statistical analysis but on a smaller scale than Im. It is difficult to find data for just V1 alone (ca., 2014). 10.2.1.3 Precision measurements of cortical thickness

A 2000 paper by Fischl & Dale is particularly valuable38. It describes the precise thicknesses and standard deviations for many areas of the cortex. In particular, it notes that many of the “primary” sensory areas are typically thinner than average while many of the associative areas of the cortex are typically thicker, Figure 10.2.1-7.

Figure 10.2.1-7 Average cortical thickness across 30 subjects, with primary auditory (A1), sonatosensory (S1) and visual (V1) cortices indicated by the white arrows. Lateral view of left hemisphere on the left. Reddest area is approximately Brodmann areas 44, 45 & 47. Medial view of left hemisphere on right. Upper reddest area is approximately area 32. Lower reddest area is approximately areas 35, 36 & 38. From Fischl & Dale, 2000.

They show a very good statistical uniformity between similar areas among individuals and the use of two separate MRI machines. They also note some large variations in thickness between the tissue on opposite walls of a sulcus.

37Toro, R. Perron, M. Pike, B. et al. (2008) Brain Size and Folding of the Human Cerebral Cortex Cer Cortex vol 18, pp 2352-2357

38Fischl, B. & Dale, A. (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. PNAS vol 97, pp 11050-11055 doi: 10.1073/pnas.200033797 System Morphology 10- 29

10.2.2 Cytoarchitecture of the cerebral cortex

Figure 10.2.2-1 from Noback shows the labeling of the lateral projection of the external surface of the cerebral cortex according to Brodmann. Areas 12-14 are not shown in this figure. These numbers are assigned to the underside of the frontal lobes. See Section 12.1.2.

Figure 10.2.2-1 Cytoarchitectural map of the left lateral surface of the human cortex, with numbering according to Brodmann.

[xxx note missing numbers described in Afifi & Bergman, not well ] Zillmer & Spiers have provided a cytoarchitectural map from Banich stressing the difficulty of annotating various regions of the CNS based only on lateral views of the brain39.

39Zillmer, E. & Spiers, M. (2008) Principles of Neuropsychology. US: Wadsworth pg 113 30 Neurons & the Nervous System

Figure 10.2.2-2 from Noback shows the labeling of the projection of the medial surface of the cerebral cortex according to Brodmann.

Figure 10.2.2-2 Cytoarchitectural map of the medial surface of the human cortex, with numbering in accordance to Brodmann.

Baars & Gage have provided Figure 10.2.2-3, a colored version of the above two figures with auxiliary lines delineating the numbered regions. They describe the prefrontal cortex areas as Brodmann areas 8, 9, 10, 11, 12, 13, 44, 45, 46 and 47. They note, “these areas are characterized by the predominance of the so-called granular neural cells found mostly in layer IV.” These cells are not included in the neurons defined on page 65 of the 2nd edition of Baars & Gage as the center of focus of their text. They are in fact the actual dominant form (over 95%) of neurons in the CNS. The granular neural cells are analog (non-action potential generating) neurons involved in the actual information extraction and processing within the CNS.

The functional aspects of the prefrontal cortex will be discussed in Chapter 12, Cognitive Engines. System Morphology 10- 31

Figure 10.2.2-3 Brodmann areas in the frontal lobes. Areas forward of motor cortex (BA 4 & 6) are considered to be prefrontal. “It is often useful to think of a gradual transition between more ‘cognitive’ areas and primary motor cortex.” Adapted by Baars from Dubin. 32 Neurons & the Nervous System

Petrides & Mackey provided an early plan view of the rostral basal surface of the human brain showing Brodmann’s area notation in 199440. The area is known as the orbitofrontal cortex. They noted, more subjects must be examined to more precisely specify the boundaries of each area. Figure 10.2.2-4 reproduces a more detailed graphic from Ongur in 200341. The notation and designated areas vary from the Petrides & Mackey paper. Based on differential staining, they noted, “Although the sulcal and gyral patterns showed significant variability, notably between the right and left sides as well as between different brains, the distribution of cortical areas varied only slightly from brain to brain.” A suggested subsequent paper has not appeared in the literary indexes.

Figure 10.2.2-4 Architectonics of the orbital and medial prefrontal cortex. Note the asymmetry between the left and right lobes in both sulci and in area designations. From Ongur, Ferry & Price, 2003.

10.2.2.1 Labeling of areas not addressed by Brodmann

Brodmann’s numbering system was designed to address the lateral and medial views of the brain without undue attention to the more interior gyri and sulci. Figure 10.2.2-5 shows a collection of these areas as annotated by different specialists.

40Petrides, & Mackey, (2006) The orbitofrontal cortex: sulcal and gyral morphology and architecture In Zald, D. & Rauch, S. eds. The Orbitofrontal Cortex. Oxford, UK: Oxford Univ Press pg 31

41Ongur, D. Ferry, A. & Price, J. (2003) Architectonic subdivision of the human orbital and medial prefrontal cortex J Comp Neurol vol 460, pp 425-449 System Morphology 10- 33

Figure 10.2.2-5 A mosaic of labels for internal areas of the cortex. Top; bottom of the medial temporal lobe with areas associated with major subregions for memory labeled along with the rhinal areas associated with olfaction (smell). Buckley & Gaffan, 2006. Left; Medial temporal lobes, insula and cingulate cortex as discussed on page 256 of Baars & Gage, 2007. Right; areas associated with the auditory cortex and showing the typical asymmetries, discussed on page 193 of Baars & Gage. Standring, 2003.

10.2.2.2 A flat representation of the cerebral cortex

Swanson has provide Figure 10.2.2-6 showing the cerebral cortex as a flat map emanating from the top of the diencephalon (the thalamus and hypothalamus). The diencephalon is labeled the interbrain in this figure. 34 Neurons & the Nervous System

Figure 10.2.2-6 A flat map topological representation of Brodmann’s regionalization of the cerebral cortex of the human brain. Not necessarily to scale. Annotate. AH; Ammon’s horn. AON; anterior olfactory area. COA; cortical amygdalar area. DG; dentate gyrus. INS; insular area. OB; olfactory bulb. SBC; subicular complex. Primary sensory areas are shown in darker gray (1-3, somatosensory; 17, visual; 41, auditory; olfactory, AON). The large area to the right of the hindbrain is the cerebellum. From Swanson, 1995..

The large space between the diencephalon and the BA 51 of the cerebral cortex is occupied by what is variously labeled the basal ganglia or the striatum and its elements (Swanson, page 176). It is shown as extending all of the way to the midline, thereby blocking any direct surface path from the diencephalon to the cerebral cortex, and implying that all interconnections between these two bodies must be by point to point commissure (white matter), primarily via the thalamic radiation.. The distance of BA 17 from the thalamus should be noted. BA 17 is not relied upon for detailed information extraction from the foveola. The time delay associated with two way stage 3 signaling is unacceptably long. 10.2.3 Cytoarchitecture of the diencephalon

Human neuroanatomy by Carpenter & Sutin appears to be the authority on the morphology and System Morphology 10- 35 cytoarchitecture of the human diencephalon42. As they note, “it has long been regarded as the key to the understanding of the organization of the central nervous system (page 493).” At the level of detail in Carpenter & Sutin, their morphologically defined reticular nucleus, caudate nucleus, and possibly the intralaminar nuclei, may be equivalent to the functionally defined thalamic reticular nucleus (TRN) of this work. The use of the term relay neuron is overstressed in that work. Many of the neurons so labeled perform significant association functions in addition to their apparent relay functions, particularly within the MGN and LGN. At finer levels of detail, the human diencephalon has not been mapped unambiguously. Most of the mapping has been based on chemical stains to differentiate between different areas. This technique does not lead to differentiation based on functional relationships.

Borostyankow-Baldauf & Herczeg have recently attempted to rationalize the nomenclature of the human and non-human pretectal complex without reliance on cyto-topography43. The names discussed remain geographical rather than functional in character.

10.2.3.1 Cytoarchitecture of the thalamus

Figure 10.2.3-1 has been widely reproduced since its first appearance in a CIBA document of 195044.

42Carpenter, M. & Sutin, J. (1983) Human Neuroanatomy, 8th Ed. London: Williams & Wilkins Chap 15

43Borostyankoi-Baldauf, Z. & Herczeg, L. (2002) Parcellation of the human pretectal complex: a chemoarchitectonic reappraisal Neurosci vol 110(3), pp 527-540

44Chusid, J. (1982) Correlative Neuronanatomy & Functional Neurology. NY: Appleton & Lange pp 19-20 and in Zillmer, E. & Spiers, M. (xxx ) Principles of Neuropsychology. US: Wadsworth pg 93 36 Neurons & the Nervous System

Figure 10.2.3-1 Thalmo-cortical radiations and labelling. From Zillmer & Spiers, 2001.

10.2.4 Cytoarchitecture of the cerebellum System Morphology 10- 37

Ganong has provided a graphic description of the cerebellum and its functional segmentation in Figure 10.2.4-145. The figure includes a somatotopic representation overlaying the cerebellum. Jacobson and Marcus have provided an alternate representation of the left frame of this figure. Both authors credit Snider (1950) as the source of an underlying graphic. While Ganong does not point out the fact, his homunculi is overlaid on the cerebellum of a monkey according to the latter authors. Note the duplicate organization of the cerebellum. This is quite likely associated with the fact the cerebellum is involved in recording information received from the stage 4 afferent neural circuits and the conversion of stage 5 instructions into stage 6 operational commands in the efferent neural circuits. Swanson has addressed in conceptual form the role of the cerebellum as described in this work, including its operation based on the reflex mode as well as in responding to the stage 5 instructions by generating a proliferation of individual commands to multiple muscles46.

Figure 10.2.4-1 The cerebellum unfolded. Left: Cerebellar homunculi. Proprioceptive and tactile stimuli are projected as shown in the figure above and the split figure below. The striped area represents the region from which evoked responses to auditory and visual stimuli are observed. Right: Projection of the body on the cerebellum. Areas I and II (above and below the dashed line) are the two areas where auditory and visual stimuli are projected. From Ganong, 1975.

[xxx add more on the cerebellum ] There is a large clinical bibliography describing diseases of the cerebellum in considerable detail. The areas dedicated to the visual and auditory modalities are relatively small in the cerebellum. This is attributed to the fact the pulvinar performs much of the information extraction activity

45Ganong, W. (1975) Review of Medical Physiology, 7th Ed. Los Altos, CA: Lange Medical Publ. page 145

46Swanson, L. (2003) Brain Architecture. NY: Oxford Univ Press pp 135-137 38 Neurons & the Nervous System associated with the cerebellum in other modalities. It appears much of the area associated with the visual and auditory modalities in the cerebellum are related to the oculomotor and pinna-motor functions within these modalities. 10.2.5 Importance of point-to-point commissure paths

The cytoarchitecture, and particularly the flatmaps of the CNS show the various major engines of the brain are not connected by short signaling paths within the plain of cortex tissue. The major signaling paths are defined by the commissure that follow point-to-point paths between the major engines. This architecture minimizes the time delay between critical engines and reduces the thickness of the required neural cortex considerably. 10.2.6 Morphogenesis of the neural system

[xxx cite brief material in 4.2.2 and/or 5.1.2 showing dual neural paths within spinal cord. ] Neuroscientists frequently speak of the dorsal surface of the amnion (early embryo) forming an initial tube that becomes the spinal cord around day 2147. Broader morphologists speak of the a second tube formed on its ventral surface that becomes the gastro-enteric (digestive) system. Thus, two distinct tubes are formed that are conjoined. Before these two tubes are closed (not later than 20th day), the amnion can divide along its median axis and form identical twins. After the 20th day, the subdivision is likely to result in conjoined twins.

At the level of detail required by this work, the initial amnion rapidly forms two conjoined tubes at about day 21 in humans. The tube forming the neural system is initially open at both ends as shown in (B) of Figure 10.2.6-1.

47Scammon, E. (1953) Developmental Anatomy in Morris' Human Anatomy. NY: Schaeffer (reproduced in Noback) System Morphology 10- 39

Figure 10.2.6-1 Morphogenesis of human embryo beginning about day 18. A; a compilation from multiple sources. B; additional details. See text.

Very quickly, the upper end of the spinal cord tube pinches to form two tubes that then turn so their end faces turn toward each other. Individual neurons begin to populate the inner surface of the neural tube and exit through its open ends. The neurons exiting from the two faces at the top tend to join and form commissure between the two tube elements. These commissure increase in number to form the corpus callosum. The neurons exiting from the face at the bottom tend to exit as the tube extends its formation, with the numbered nerves tending to exit the tube more or less in sequence (although the assigned nerve numbers were not assigned based on morpho-genetic considerations). As the tube extends, the nerves tend to group into initially two distinct bundles, along opposite sides of the tube, closely related to their function as shown schematically in (xxx fig 4.2.2-x or 5.1.2-x). These bundles then group into sub-bundles associated with specific functions, generally before they leave the spinal cord tube. The heavy arrows in (A) related to vision and hearing have frequently been shown as features of the mesencephalon. On closer examination, these nerves are shown to exit from a “fold” of the posterior diencephalon above the cephalic flexure and overlaying the mesencephalon. This fold forms the lateral and median geniculate nuclei and related structures as shown on the right. Randall (1997, pg 417) equates the adult mesencephalon with the label “Tectum” and notes both the thalamus and hypothalamus arise within the diencephalon. Tectum is not often used in discussion of human anatomy. He also notes the Pons and cerebellum arise within the metencephalon while 40 Neurons & the Nervous System the medulla oblongata arises within the myelencephalon. He also notes, “Thus, although morphogenetic changes in the brain obscure its segmental origins, the pattern of information processing echoes early segmentation.”

10.2.6.1 Morphogenesis at birth

Clinicians and anatomists have long pondered the challenge faced by the large head of the human passing through the birth canal. They have often noted the freedom of the cranial plates to move individually prior to birth with fusion occurring postnatal. Of even greater functional significance is the absolute volume of the brain during this period. The number of neurons in the CNS is rapidly expanding as birth approaches. However, the total available volume must be constrained to accomplish a successful birth. This condition is achieved by restricting the level of myelination of the CNS commissure prior to birth. Myelination proceeds rapidly following birth in order to achieve efficient communications between the engines of the CNS and with the peripheral system. xxx has described the order of myelination during morphogenesis. Rose has provided a comprehensive discussion of brain morphogenesis in humans48. Figure 10.2.6-3 from Dobbings provides a comparison between the growth rate of the brain in a variety of species49. The vertical scale is in percent change per time period indicated for the species, e.g., a peak rate near 6%/month for humans. The integral of this curve shows a distinct plateau just prior to and including the time of birth. The human brain weighs about 350 grams at birth compared to its adult weight of between 1300 and 1500 grams. Ranging from 23 to 7 percent at birth, it will reach 50% at six months, 60% at one year, 75% at two and one- half years, 90% at six years and 95% at ten years.

Rose provides a discussion of the relative development of individual portions of the neural system pre and post natal (pages 192- Figure 10.2.6-2Human brain growth rate compared 195) that generally follows xxx. It with other species. The age scale varies with species specifically addresses the limited extent of as indicated. From Dobbings & Sands, 1970 myelination of the nerves.

10.2.6.2 Detailed development of cortical laminate

Rakic, Ang & Breunig have prepared a paper on morphogenesis within the cerebral cortex, including the migration of groups of neurons50. It draws on many previous papers by Rakic and colleagues. Although complex, Figure 10.2.6-3 from their work is important. It shows the development of the cerebral cortex as a migratory process from a ventricular zone distinct from the pia matter. The nomenclature is complex. The reader is referred to the source. An important feature to note is the high level of both ipsilateral and contralateral cortical-cortical (CC) connections and the high level of thalamic radiation (TR). A majority of these paths are bidirectional. The scale (E40 through E100

48Rose, S. (1976) The Conscious Brain. NY: Vintage Books Chap 7

49Dobbings, J. & Sands, J. (1970) Nature vol 226, pp 639-640

50Rakic, P. Ang, E. & Breunig, J. (2004) Setting the stage for cognition: genesis of the primate cerebral cortex In Gazzaniga, M. ed. (2004) The Cognitive Neurosciences, 3rd Ed. Cambridge, MA: MIT Press Chap. 3 System Morphology 10- 41 shown) refers to date during gestation (embryo age). [xxx expand ]

Rakic, Ang & Breunig note, “After all cortical neurons have been generated and have attained their final positions, their differentiation, including the formation of synapses, proceeds for a long time, reaching a peak only during the second postnatal year (page 44).” They reference a review of synaptogenesis by Bourgeois et al. in the second edition of Gazzaniga.

Figure 10.2.6-3 A cartoon of early corticogenesis. VZ; ventricular zone (adjacent to inner surface of cortical layer).. CC; coritco-cortico nerves. CP; cortical plate. MA; monoamine subcortical centers. MN; migrating neurons. NB; nucleus basalis. TR; thalamic radiation. See source for details of nomenclature. From Rakic, 1988.

Kornack has given similar information on neurogenesis in the primate forebrain51. At the next level of detail in the morphogenesis of the brain, Figure 10.2.6-4 from Fuster provides a comprehensive description of the histogenesis of the human prefrontal cortex.

51Kornack, D. (2004) Adult neurogenesis in the primate forebrain In Gazzaniga, M. ed. (2004) The Cognitive Neurosciences, 3rd Ed. Cambridge, MA: MIT Press Chap. 2 42 Neurons & the Nervous System

Figure 10.2.6-4 Development of neuronal architecture in human prefrontal cortex. Top; prenatal period from 10.5 weeks to birth. Attributed to Mrzljak et al, 1990. Bottom; 3, 6, 15, and 24 months after birth attributed to Conel, 1963. Note the significantly different appearance of neurons in the same layer at the detail level over time. From Fuster, 2008.

10.3 The cross section of the cortex

Only a few areas of the cortex are so tightly folded that they are typically described as volumetric in character. The thalamus is one such body that contains multiple regions described as solid objects rather than folded planar surfaces. In the case of the pulvinar, it is tightly folded and appears to include commissure entirely within its outer envelope.. Typically, the cortex consists of multiple layers of neural cells enclosed within an outer shell generally described as the pia matter. All of the neural tissue is accessed from the inner surface via commissure, with the exception of some short distance commissure traveling predominantly in the layer closest to the pia matter. System Morphology 10- 43 10.3.1 A comparison of nomenclature

Swanson (page 166) has provided a short summary of the nomenclature used to describe sections of the neural cortex tissue. He notes that Brodmann recognized two distinct types. He described tissue that clearly went through a six-layer stage during development and tissue that did not. Note, this is different than saying the tissue that went through a six-layer stage ended in a six-layer configuration. Later investigators adopted different terms for what appears to be the same tissue classifications. Tissue Brodmann Oskar & Vogt Others had a 6-layer stage homogenetic isocortex neocortex no 6-layer stage heterogenetic allocortex paleo- & archicortex (combined)

The terminology in the other column has been used in other contexts, was not supported by Swanson and is not supported here. While preferred at this time, even the isocortex and allocortex appear less than descriptive or exclusive to this context. Swanson used a sample bridging the area 18, area 18 junction to illustrate the difference between these two tissue types, Figure 10.3.1-1. The example does not include either one or both Bands of Baillarger. Brodmann provided two distinct numbering systems for these adjacent pieces of cortical tissue. Note the difficulty in discussing the numerical layers of the cortex unless the specific portion of cortex is defined. Note also Swanson’s comparison on page 168 (not shown) where Cajal’s layer 5 corresponds to Brodmann’s layer 4. On page 170, Swanson illustrates a section based on Nissl staining by Lorento that includes sublayers of layers V and VI of isocortex that do not appear in Swanson’s earlier figures. The figure attempts to define seventeen unique neuron types. After 100 years, the subject of layer numbering is clearly subject to a lot of confusion and needs an alternate methodology.

Swanson made some observations on pages 169-171 that are useful but not necessarily conclusive. He asserts, “In the isocortex there are very few neurons in layer 1; layers 2 and 3 are characterized by relatively small pyramidal neurons (along with local circuit neurons, layer 4 consists almost entirely of local (granule) cells, and layers 5 and 6 are characterized by larger pyramidal neurons (along with local circuit neurons). Interestingly, the smallest pyramidal neurons tend to be localized to layer 2, and they typically generate association projections to other cortical areas within the same hemisphere. Layer 3 pyramidal neurons tend to be somewhat larger, and they typically generate commissural projections to the opposite hemisphere, as well as Figure 10.3.1-1 The cytoarchitecture of human association projections to the same visual cortex using Nissl-stained tissue. The large hemisphere. The largest pyramidal neurons arrow at the bottom defines the border between the are found in layers 5 and 6, and they are two areas. Layers are identified by the Roman responsible for generating most of the numerals at either end. The large arrow in in the descending cortical projections to the cerebral deep white matter of the cortical mantle. The outer nuclei, brainstem (including the thalamus), surface of the cortex is at the top. From Brodmann, and spinal cord.” 1909 He further asserts, “This arrangement also suggests a fundamental organization of isocortex into three ‘super layers’: supragranular, granular (layer 4), and infragranular. Layer 4 is characterized by a dense input from the thalamus and much of the local circuit output of layer 4 stellate neurons is directs toward the supragranular layers. The supragranular layers of relatively small pyramidal neurons generate primarily intracortical 44 Neurons & the Nervous System projections. In essence, the supragranular layers generate the immensely complex network of connections between cortical areas, . . . The supragranular layers also provide a major input to the infragranular layers of relatively large pyramidal neurons that generate most of the output of cerebra cortex to other parts of the brain. In other words, the infragranular layers are essentially the ‘motor’ part of the cerebral cortex.” Shepherd provided a distinctly different set of sections in 1998. Figure 10.3.1-2. shows sections of four areas. The differences between these areas is not obvious to this analyst and the numbering appears quite arbitrary..

Figure 10.3.1-2 The laminar organization of neurons in different cortical areas of the macaque monkey cortex (inset). A; area 17 (striate visual cortex). B; area 18 (extrastriate cortex). C; area 4 (motor corex. D; area 9 (frontal cortex). A basic six-layer structure can be identified in all areas. The pia matter covers layer 1; the white matter is below layer 6. Note the marked difference in cell size and density among the different areas, but additional layers are apparent in some areas (e.g., area 17). Stained for Nissl substance. From Shepherd, 1998. System Morphology 10- 45

Rakic has offered a set of more descriptive, but still less than functional, names for the six-layer cerebral cross section found during the first half of gestation in primates52. It is fair to assume based on the above description that the smaller pyramidal neurons are stage 4 signal manipulation neurons (potentially labeled local circuit neurons) and the large pyramidal neurons are stage 3 projection neurons. The neuroscience literature seldom describes the structure of the cortex related to the non-neural region between the pia matter and the outer dura matter.. Carpenter & Sutin provide such a visual description53. 10.4 The blood-brain barrier and cardiovascular circulation 10.4.1 The blood-brain barrier and cardiovascular circulation

Carpenter & Sutin have addressed the very complicated subject of the blood-brain barrier in detail54. 10.4 2 The cardiovascular circulation

Zillmer & Spiers have collected diagrams describing the vascular system of the CNS55. The figures show how different CNS areas are supported. They show the Circle of Willis and the areas it supports in detail.

10.5 The morphology of the dorsal brainstem and spinal cord EMPTY

10.5.1 The complex structure of the dorsal brainstem

Figure 10.5.1-1 from Noback shows the visual appearance of the dorsal brainstem with the cerebellum of [Figure 10.2.4-1] cut away . The Putamen has been added to the figure in accordance with a more detailed figure focused on the cerebellum in Kandel et al56.

[xxx show folding of the LGN, probably including fig from Livingstone & Hubel or Hubel book ] [xxx include my drawing of folding ] [xxx the tegmentum is the surface behind the inferior colliculi, above and below the peduncles ] [xxx discuss the functional name for the brachium of SC, particularly the mound shown.] [xxx define the Corpora quadrigemina as the four colliculi ] [xx discuss the horseshoe shaped pulvinar behind this surface supporting both halves of the quadrigemina.]

52Rakic, P. (1995) A small step for the cell—a giant leap for mankind: a hypothesis of neocortical expansion during evolution Trends Neurosci vol 18, pp 383-388

53Carpenter, M. & Sutin, J. (1983) Human Neuroanatomy, 8th Ed. London: Williams & Wilkins

54Carpenter, M. & Sutin, J. (1983) Human Neuroanatomy, 8th Ed. London: Williams & Wilkins pp 18-22

55Zillmer, E. & Spiers, M. eds. (2008) Principles of Neuropsychology. US: Wadsworth page 80

56Kandel, E. Schwartz, J. & Jessell, T. eds. (1991) Principles of Neural Science, 3rd Ed. NY: Elsevier, page 628 46 Neurons & the Nervous System

Figure 10.5.1-1Dorsal surface of the brainstem showing the quadrigemina. The row of structures containing the lateral geniculate nuclei serves the visual sensory modality. The row containing the medial geniculate nuclei serves audition. From Noback, 1967. System Morphology 10- 47

Figure 10.5.1-2 shows an alternate representation from Gray’s Anatomy because of the importance of the metathalami in understanding the operation of the visual and auditory ensory modalities.. The terminology surrounding this region of the brain varies by author. In this work, the vision (auditory) perigeniculate nucleus lies along the brachia between the lateral (medial) geniculate nucleus and the superior (inferior) colliculus. In the 40th Edition of Gray’s Anatomy, it is described briefly as the pregeniculate nucleus on the side opposite the hilus in an non-attributed figure 21-657. Thomson & Bannister have used the designation “nucleus reticularis thalami (or in LGN the peri-geniculate nucleus)” for what is called the perigeniculate nucleus in this work. xxx semantics? A new organization has appeared on the internet that promises to bring a new standard of uniformity to the morphology of the brain (by its ubiquity alone)58. The Brainmaps.org is based at the University of California, Davis and is funded by the National Institute of Health. It will take Figure 10.5.1-2 The major elements adjacent to one some time before the literature converges on of the metathalami, formed of the inferior and the recommended terminology. A set of superior colliculi and the lateral & (vision) para– acronyms is used that will be unfamiliar to and medial & (auditory) para–geniculate nuclei. many investigators. Most of the data consists From Gray’s Anatomy, IX Ed. figure 719. of visual images of brain slices and equivalent MRI slices. Very little data is included for Homo sapiens.

Carpenter & Sutin have provided additional illumination regarding the structure of the diencephalon and thalamus (page 502), including describing the thalamic reticular nucleus..They also show cross sections of the LGN showing the location of the projection of the blind spot (page 528).

57Standring, S. ed. (2008) Gray’s Anatomy, 40th Ed. NY: Elsevier pg 315

58http://brainmaps.org/abbrevslist.php?cmd=reset 48 Neurons & the Nervous System

10.5.2 The complex structure of the spinal cord

Figure 10.5.2-1 shows the nominal organization of the human spinal column and including the spinal cord. An MRI of the spine and spinal cord of the author of this work (78 years old) is available if details not found in major texts are desired. However, the images are difficult to interpret by the untrained observer. They show the expected degradation in the spine with age. 10.5.2.1 Longitudinal organization of the spinal column ADD

The top of the figure shows the nominal arrangement of the spine longitudinally.

The vertebra S1 through S5 are generally fused into a single structure forming the dorsal portion of the pelvic cavity.

Near T11, the character of the spinal cord changes into what is called the caudal equina (horse’s tail). The neurons associated with a specific area below that level of the spinal cord begin to fan into individual groupings long before they leave the protection of the spinal cord. 10.5.2.2 Cross section of the spinal column

The bottom of the figure shows the cross sectional organization of the spinal column and the clear separation of the descending motor neurons associated with the ventral horn and the ascending sensory neurons associated with the dorsal horn. Both sensory and motor neurons tend to have their soma collected into root ganglia external to the spinal column to conserve space within the protected volume. Beyond the root ganglia, the neurons associated with a single distant area are generally grouped into bidirectional “spinal nerves.” Figure 10.5.2-1 The human spinal cord and spinal column RESCAN AT HIGHER RESOL.. From While it is possible to conceptualize reflex Lambert & Kinsley, 2011. circuits occurring within the spinal nerves, it is generally believed that reflex paths are formed within the interconnections between the dorsal and ventral horns near where the neurons associated with a specific area enter and leave the spinal cord. 10.6 Stage 3 connections within the cortex

Recently, a new brain imaging technique has appeared that identifies the major neural paths within System Morphology 10- 49 the living brain (including those of humans)59. The technique is a variant of MRI known as “diffusion tensor” magnetic resonance imaging (dtMRI). An alternate description is diffusion type functional magnetic resonance imaging (d-fMRI). It tracks the movement of water molecules as they move along the axons of stage 3 neurons. This movement has long been documented60 but without the benefit of the MRI machine to collect the data in a highly graphic manner. The velocity of the water molecules has been reported to vary between 1-10 and up to 400 mm/day. The technique does not record individual non-myelinated neurons within an individual engine of the CNS. Figure 10.6.1-1 shows a sample of this imagery from the laboratory of Wedeen, using false color techniques. Other images of his work are available at http://Smithsonian.com/brainimages The imagery does not represent well the neurons of specific engines of stage 4, 5 or 6 as these neurons do not have extended axons that can be easily tracked by this technique. Note the absence of neurons shown at the termini of the axons near the crown of the cortex. This crown is the home for the vast majority of the neurons of the cortex. Within the limitations of the technique, the image strongly supports the hypothesis of a central switching and control function within the TRN of the thalamus (lower center of the image) and the primary radiation from that engine. Simultaneously, it does not support the long hypothesized dorsal pathway connecting the area V1, V2 and V4 of the human brain traveling from the right to the upper right near the surface of the cortex. No dimensions, particularly the depth of the region images or the number of axons in an individual commissure (parallel families), were provided in the magazine article. Nor was the voxel resolution of the imagery given. The warp and weave character of the combined commissure is evident. Note also the convergence of the red axons in the image on the purple axons at a 90 degree angle. Wedeen has published several of these images, including at least one from a rhesus monkey showing a similar warp and weave pattern and potentially commissure interconnecting engines of the cortex that do not pass through the TRN control center.

59Helmuth, L. (2012) Order in the Cortex. Wash. DC: Smithsonian page 11 based on the work of Wedeen

60Ottoson, D. (1983) Physiology of the Nervous System. NY: Oxford Press pp 44-47 50 Neurons & the Nervous System

Figure 10.6.1-1 A lateral view of the human cortex using dtMRI in false color from the Laboratory of Wedeen, M. D. at Massachusetts General Hospital. .Occipital lobe on the right. From Wedeen, 2012.

Additional imagery from Wedeen is available61,62. The paper in Science provides considerable discussion of their findings but little information on methods. The “sheet” character of the commissure associated with specific paths is suggestive of multiple parallel neurons providing word serial/bit parallel signal projection between major engines of the cortex. Figure 10.6.1-2 shows a more artistic representation but the grouping of commissure is largely lost. Only stage 3 signal projection neurons are shown using this technique which relies upon the presence of myelin.

61Wedeen, V. et al. (2012) The Geometric Structure of the Brain Fiber Pathways Science vol 335, 1628; DOI: 10.1126/science.1215280

62Wedeen, V. et al. (2013) The Orderly Brain Discover June, pg 10 System Morphology 10- 51

Figure 10.6.1-2 Stage 3 cabling (commissure) of the human brain. Each strand is a nerve (commissure) consisting of multiple stage 3 neurons. False color from a state of the art MRI imager. From Wedeen, 2013.

Figure 10.6.1-3 shows another example that is particularly applicable to the question of whether there is a literal dorsal signal path between the portions of the occipital and parietal lobes known as V1, V2, V3 and V4 or merely a conceptual path. No circumferential commissure are seen along the upper right portion of this image parallelling the cranium. All of the relevant commissure are traveling back and forth between the above labeled areas and the casule containing the thalamus and TRN. Thus the concept of a dorsal and a ventral signal stream is primarily a semantic convenience that is falsified by more detailed experimental results. 52 Neurons & the Nervous System

Figure 10.6.1-3 White bundles of myelinated axons run in all directions to and from the capsule of the human brain. There are no commissure traveling obviously circumferential paths paralleling the cranium. The lower packet of purple traces appear to relate to the optic nerve. As a result, the “dorsal signal path is primarily conceptual. From Lazar as reproduced in Baars & Gage, 2007 System Morphology 10- 53

Figure 10.6.1-4 provides an additional image using dtMRI that addresses whether there are intimate relations between the two halves of the occipital lobe or whether most of the information extracted in each lobe is returned to the TRN and the thalamus for combining and further processing. The bulk of the long distance signal paths are fore and aft but with significant lateral signal exchange between the two hemispheres in the region of the corpus callosum. More details are needed with regard to the specific geometry used to create this image. Marzi et al. have noted the lack of direct inter occipital lobe commissure based on earlier pathology (Section 17.9). [xxx following table elements belongs in chapter 11 where it also appears ] [xxx see pages 344-347 of Afifi & Bergman Describe as Specific afferent paths (terminating within the brainstem) (terminating within the cerebral cortex) Internal association paths (totally within the laminates of the tissue) Short (u-fiber) paths (generally serving only one gyrus) association paths (generally between different gyri within same hemisphere)

Commissure (generally between gyri of different hemispheres)

Projecting efferents To other cerebral cortex areas (also commissure) To deep structures in brain (cortico-spinal) (cortico-thalamic) etc.

- - - - -

A set of images of the human brain using a 7.0 Tesla machine is now in press and should

Figure 10.6.1-4 Plan view of human CNS showing its fore & aft organization except in the area of the corpus callosum. See text. From Wedeen, 2013. 54 Neurons & the Nervous System offer even higher resolution63. 10.6.1 The ratio between white matter (stage 3) and grey matter in the CNS

The ratio between the stage 3 white matter (considering only the myelinated axons) and the gray matter of stages 4, 5 & 6 have long been studied with increasing levels of precision. Zhang & Sejnowski have presented the latest comprehensive study and reviewed the earlier work64. Their basic premise was, “the cerebral cortex of a larger brain tends to have disproportionally more long-distance connection fibers or white matter (dark regions) than the gray matter (folded outer surface).” They omitted consideration of the internal capsule and employed a global average for the thickness of the cortex itself. They did not address the ventricular space within the typical cerebral cortex. They also noted that several very small mammals were omitted from their considerations because they did not seem to follow the same power law as the larger animals. Their figure 2 data for a wide range of animals did not include error bars for individual species but showed a regression line suggesting a power law with a fixed exponent of 1.23 ± 0.01 (mean ± SD) versus an anticipated 1.33. However, the sequence appears reasonable, especially when the variations shown in their figure 3 are examined. They do note that their data was generally acquired for only a very few animals of a given species and in many cases by different investigators. They note, “for the mouse brain, which is also quite small, an estimate of fiber length in white matter gives the average L . 3 mm (figure 62 in ref. 30). Together with G . 112 mm3, this data point would be close to the regression line in Fig. 3. Therefore, more experimental data would be required to test whether the cubic relation may fail for the smallest brains.

Based on this work, white matter is only associated with signal projection and the amount of volume employed by stage 3 neuron axons (white matter) should approach zero when the average commissure length required went below a nominal 2 millimeters. Thus, the slope of piece-wise best fit power law should increase dramatically in animals smaller than the pygmy shrew (approaching a vertical asymptote at very low gray matter volumes in figure 2). Figure 10.6.1-5 shows a projected extension of their regression line to smaller animals for their figure 3. because of a reversal of scales, the asymptote in this figure is horizontal. It should be noted that stage 3 axons (white matter) are not believed to be used in insects and molluscs but these phyla have not been adequately explored with regard to this question. There are some indication in the literature that octopus employs at least some stage 3 neurons between nodes of its “distributed brain.” 10.7 Identification of stage 4 neurons within the cortex Figure 10.6.1-5 Projected gray/white matter This section will differentiate between some regression line to smaller animals (dash-dot line) of the neurons of the cortex based on their where stage 3 signal projection is seldom found (or identifiable operations. Only a few neuron required based on this work). See text. Modified from Zhang & Sejnowski, 2000.

63Cho, Z-H. Calamante, F. & Chi, J-G. (2013-14) 7.0 Tesla MRI Brain White Matter Atlas. Panmun.

64Zhang, K. & Sejnowski, T. (2000) A universal scaling law between gray matter and white matter of cerebral cortex PNAS vol 97(10), pp 5621–5626 System Morphology 10- 55 types can be identified by this means at this time. 10.7.1 The pyramid cells

Myelinated pyramid cells are clearly of the projection type associated with stage 3 signal projection. Unmyelinated pyramid cells are also clearly associated with stage 4 signal manipulation. As a general rule, the unmyelinated pyramid cells are smaller than the myelinated pyramid cells. However, the size of the myelinated cells are not proportional to their axon length. The axons of myelinated pyramid cells contain Nodes of Ranvier at intervals on the order of two millimeters along their entire length. These Nodes of Ranvier regenerate the action potentials traveling along them. Thus, the regeneration process removes any need for the axons to be larger when longer. A myelinated axon could be of indefinite length as long as it is served by its Nodes of Ranvier. An axon of six meter length is not uncommon in elephants. Myelinated axons in whales can be much longer. Blinkov & Glezer noted the difficulty in differentiating between pyramid cell and stellate cell subtypes in 196865. “. . . for the types of cells can be distinguished reliably only by the investigation of their processes, i.e., in preparations impregnated with silver by Golgi’s method. Blinkov & Glezer (page 211) have defined four types of pyramid cells based on their connections with other structures within the cerebral cortex.

P1– pyramid cells with an unbranched axon running into the white matter of the brain, 31%. P2– pyramid cells with a branching axon but without retrograde collaterals, 25%. P3– pyramid cells with an axon possessing retrograde collaterals, 14% P4– pyramid cells possessing only retrograde collaterals, without a main trunk running into the white matter, 4.8%.

It is proposed that the P1 pyramid cells, 31% of the total, are stage 3 projection neurons based on the character of their axons. 10.7.2 The stellate cells

Stellate cells receiving their primary input from myelinated axons are clearly associated with stage 3 signal projection. They are typically operating as decoding circuits with time constants dependent on the detailed function they are performing. They frequently have very few dendritic contacts and may or may not have poditic arborizations.

Stellate cells receiving their inputs primarily from other unmyelinated sources are typically performing stage 4 signal manipulation functions. These cells tend to have very elaborate arborizations at both their dendritic and poditic terminals.

Blinkov et al (page 211) have defined three types of stellate cells based on their connections with other structures within the cerebral cortex.

S1– stellate cells with an axon ramifying in the dendritic area of the cell, 14%. S2– stellate cells with a long axon and no collaterals, 4.7-4.8%. S3– stellate cells with an axon running into the layer of the cortex lying above, 1.8%.

10.8 Architectures of the CNS

The most important fact to appreciate when discussing the organization of the CNS is illustrated by Figure 10.8.1-1 from Swanson66.. All neural paths to and from the cerebral cortex pass through or are relayed by the thalamus and hypothalamus. Similarly, all glandular activity is controlled by neural signals passing through or relayed by these two entities. Swanson provides more detailed illustrations, including one of his flatmaps for the human brain with Brodmann’s areas identified

65Blinkov, S. Glezer, I. (1968) The Human Brain in Figures and Tables. NY: Basic Books pg 210

66Swanson, L. (2003) Brain Architecture. NY: Oxford Univ Press page 77 56 Neurons & the Nervous System

(page 164). Swanson notes the area associated with the olfactory bulb is at the very junction of the cerebral cortex and the thalamus (but does not identify the thalamic reticular nucleus). It becomes arbitrary when an investigator says the olfactory bulb connects directly to the cerebral cortex without passing through the thalamus (or TRN). While this may be true on one reading of the morphologically identified areas, it does not necessarily relate to the functional performance of different neural areas. At the next level of detail, the current listing of the gyri (islands) and sulci (valleys) names for the human cerebral cortex are

Figure 10.8.1-1 A flat map of the CNS split along the vertical axis showing the basic arrangement of the major parts or regions of the mammalian nervous system. All paths to the cerebrum pass through the thalamus and/or hypothalamus. Based on the rat. From Swanson, 2003. System Morphology 10- 57 available on line67.

10.8.1 Cytoarchitectures of the cerebral cortex

Currently, a rough hierarchy of the cerebral cortex can include the following types. Most of the dimensional data is based on Macaque monkeys. Title Source Diameter Cent./cent. spacing Neuron count gyri anatomical level engines (Fulton) 4 million hypercolumns Lund, et al/Huble77 1-2 mm “visible columns”Lund, et al 250-300 μm 570 μm columns Hubel columns Mountcastle 300-500 μm [50-80 minicolumns combined ] minicolumns Mountcastle 40-50 μm 80-100 microcolumns Linden et al

Mountcastle considers the minicolumn as a basic building block that is replicated, with internal variations, throughout the cerebral cortex.

[xxx see figure 7 in Lund03. ]

[xxx Special edition of Cerebral Cortex on this subject Vol 13(1) ] [xxx Hubel88 describes their view of columns that need not penetrate the full thickness of the cortex laminate Use Hubel figure showing partial depth columns]

[xxx Mountcastle03 discusses minicolumnns in an excellent overview ]

[xxx Lund et al03 review the history of columns and discuss a visible column of 250-300 microns diameter and hypercolumns of 1-2 mm. Is figure 7 useful? Several other dimensions68]

[xxx Thomson & Bannister69 provided an excellent review in 2003 What is role of square neurons within layers 4 of the cortex? Are these meant to be myelinated Bailarger white matter?]

Figure 10.8.1-2

67http://en.wikipedia.org/wiki/Template:Cerebral_cortex

68Lund, J. Angelucci, A. & Bressloff, P. (2003) Anatomical substrates for functional columns in macaque monkey primary visual cortex Cerebral Cortex vol 12, pp 15-24

69Thomson, A. & Bannister, A. (2003) Interlaminar connections in the neocortex Cerebral Cortex vol 13, pp 5-14 58 Neurons & the Nervous System

Figure 10.8.1-2 Major afferent and efferent projections between the cerebral cortex and the diencephalon. Stage 4 encoding neurons are described as pyramid cells and are indicated by open triangles with their axons emanating from their flat bottoms. From Thomson & Bannister, 2003.

Linden & Schreiner provide an interesting figure showing bidirectional data between auditory cerebral cortex and the MGN areas70. Figure 10.8.1-3

70Linder, J. & Schreiner, C. (2003) Columnar transformations in aiditory cortex? A comparison to visual and somatosensory cortices Cerebral Cortex vol 13, pp 83-89 System Morphology 10- 59 Linden & schreiner give a more detailed definition of the term koniocortex as they use it, referencing (Winer, 1992). “The basic characteristics of koniocortex; a promininet layer I, dense and well-developed layers II and III, a somewhat granular layer IV with strong thalamic input, a relatively cell-sparse layer V populated by large pyramidal neurons, and a layer VI with smaller cell bodies. Baars & Gage provided a 2nd Edition of their book in 201071 The new chapter 8 stresses the two-way communications intrinsic to virtually all thalmo-cortical and trans-cortical commissure via the corpus callosum in line with the assertions of this work. The new Figure 8.10A and B are interesting with regard to the dorsal visual path. Frame A shows the thalmo-cortical paths identified by MRI but frame B relies upon a cartoon to identify the putative cortico-cortical paths within a given hemisphere (even though an associated inset does not justify the cartoon). Figure 10.8.1-3 anatomical connections within a They then note (page 250), “Keep in mind column of primary auditory cortex. From Linden & also that the thalamus is the major input hub Schreiner, 2003. for the cortex, and also the major cortex-to- cortex traffic hub. . .However, the basal ganglia operate as a major output hub, for motor control and executive functions.” The subject of two- way communications is also addressed on page 252 relative to vision with “In fact, about 90% of the LGN-V1 fibers are ‘running the wrong way’. Above the LGN, everything is a two-way highway. This is a dominant feature of the brain, and it is a great challenge to understand how two- way connections work.” The emphasis was added because of the critical importance of this statement. It is in agreement with the hypothesis of this work.

71Baars, B. & Gage, N. eds. (2007) Cognition, Brain, and Consciousness: Introduction to Cognitive Neuroscience, 2nd Ed. NY: Academic Press 60 Neurons & the Nervous System

[xxx Tanaka03 describes both the size and movement of the output region of a column in response to a structured stimulus ] A feature of Figure 10.8.1-4 is that the isolated signals do not remain fixed in location and are not necessarily contiguous. These suggest that the signals recorded do not constitute the final signal representing a percept. It is likely that these signals are only an intermediate step in the percept formation process or are only a few of the signals of a larger set of signals comprising the final parallel word defining the complete percept.

Figure 10.8.1-4 Map of activation evoked by xxx From Tanaka, 2003. System Morphology 10- 61 Figure 10.8.1-5 shows the results of some interesting experiments with monkeys. Here again, it is important to note the region of correlation signal output is not small, unique, or fixed in location. These features suggest the signals recorded are not indicative of the completion of the percept generation activity. It is quite likely the signals recorded are only a few of the parallel signals comprising the final parallel word defining a percept.

Figure 10.8.1-5 Systematic movement of the activation area with object rotation. From Wang et al., 1996.

10.8.1.1 Conventions used in CNS architectures

Two conventions have arisen that need to be mentioned. The MRI community has adopted the practice of illustrating slices of the brain as if it was viewed from below. In the typical presentation, the right hemisphere is shown on the left side of the graphic. When discussing more detailed images of small pieces of the cortex, it is common to speak of “horizontal” neural fibers. The convention appears to have arisen from the tendency to display sections of cortex with the pia matter surface shown horizontal at the top of the graphic. This allows the designation of other “laminates” of the cortex by horizontal lines below the pia matter. Unfortunately, “horizontal” has no functional meaning in this presentation. The various layers remain coplanar with the pia matter regardless of the position of the tissue in the brain (on gyri or in sulci) and the posture of the subject. Thus, “horizontal” actually refers to tissue or features of the cortex that are parallel to the local pia matter. This situation is illustrated in figures 2(iii) and 3(iii) 62 Neurons & the Nervous System of Walters, et al. and many other sections displayed at low (visual) magnifications. Layers of considerable curvature at this magnification are described as horizontal when they are clearly curved and parallel to the local pia matter. Several labels have been applied to various portions of the numerical laminate layers commonly used in neuroscience. The stria of Gennari is frequently used to describe a portion of layer IVb. Baillarger’s bands (inner and outer) are frequently used to describe the stria of Gennari (outer band) and an internal band found within layer V. While these bands are frequently shown as dark bands in MRI images, they are in fact associated with the white myelinated neurons of the cortex. The white myelinated material is frequently described as white rami when they leave theese layeres of the cortex. It is becoming common to create a “mask” of the white matter in MRI work that can be subtracted from other imagery to create a higher contrast record of the non-myelinated features (Walters, pg 2982).

10.8.2 Cytoarchitectures of the diencephalon

[xxx quadirgemina is an interesting historical designation that can be replaced by an expanded representation showing both geniculate nuclei (all of them including PGN’s) and SC ]

Jacobson & Marcus have provided the best information on the cytoarchitecture of the diencephalon72. Their chapter 6 provides a clear description of the diencephalon and its anatomical role within the neural system. They provide a breakdown of the entity into its major components, including the thalamus and the pulvinar, and provide a list of the nuclei within the thalamus. They also describe the major connections (commissure) between most regions of the brain (See Section 10.8.4 xxx).

10.8.3 Cytoarchitectures of the prefrontal lobe

[xxx See Section 12.1.2 xxx ]

72Jacobson, S. & Marcus, E. (2008) Neuroanatomy for the neuroscientist. NY: Springer System Morphology 10- 63

10.8.4 Cytoarchitecture of the limbic system & basal ganglia

The limbic system and basal ganglia play a different role than the stage 4 signal manipulation neurons associated directly with sensory information extraction, the stage 5 cognition neurons, and the stage 6 motor neurons. In the context of this work, they appear to provide signal manipulation of a second order and provide additional information to the cognition stage. They could therefore be considered a second portion of the signal manipulation activity, a stage 4b. Furster has suggested that the basal ganglia are associated most directly with the premotor and primary motor portions of the cortex73. If true, they would be more appropriately associated with a motor manipulation activity that could be labeled stage 6b as described earlier in Section 4.6.3 and more fully in Section 12.5.1. As noted in the introduction to this section, Baars & Gage described the basal ganglia as the “hub” for motor control and executive functions. For this initial discussion, both the limbic system and basal ganglia will be considered elements of a second order signal manipulation activity, stage 4b. The specific circuits of the limbic system and the basal ganglia remain obscure primarily because there is no obvious and identifiable signal that is applied to either system and no specific output is known to emanate from either group. Thus their association with specific sensory channels or states of awareness have usually been determined by lesion experiments and other indirect evidence.

Carpenter & Sutin (page 579) have chosen to define the basal ganglia as consisting of two distinctive parts: the corpus striatum, concerned with somatic motor function, and the amygdaloid nuclear complex (also known as the archistriatum), regarded as a component of the limbic system. They go on to identify two major elements of the corpus striatum: the neostriatum (commonly referred to as the striatum) and the paleostriatum which lie next to each other, lateral to the internal capsule. The neostriatum consists of the caudate nucleus and putamen. The paleostriatum portion of the corpus striatum is labeled the globus pallidus. These structures are identified in Figure 10.8.4-1. The morphological continuity between these elements helps explain the duplication of names that have appeared in the literature. While they tend to surround the diencephalon, they are in turn surrounded by the cerebral cortex.

[xxx address the roles of these elements based on Carpenter & Sutin, pg 638 + . Then rewrite the above introductory remarks. ]

10.8.4.1 The elements of the Figure 10.8.4-1 Semischematic drawing of the Limbic System isolated striatum, thalamus, and amygdaloid nucleus showing: the continuity of the putamen and head of the caudate nucleus rostrally, and the Figure 10.8.4-2 presents a view from relationships between the tail of the caudate nucleus DeSalle & Tattersall of the limbic system in and the amygdaloid nucleus. From Carpenter & context with the CNS but using slightly Sutin, 1988.

73Furster, J. (1988) The Prefrontal Cortex. NY: Lippincott-Raven page 220 64 Neurons & the Nervous System different nomenclature74. [xxx make consistent and correlate with 10.8.4.2 ]

Carpenter & Sutin have described the elements of the limbic system (citing MacLean, 1952) as including the limbic lobe and a series of subcortical nuclei, such as the amygdaloid complex, septal nuclei, hypothalamus, epithalamus, anterior thalamic nuclei and parts of the basal ganglia. They define the limbic lobe as including subcallossal, cingulate and parahippocampal gyri, as well as the underlying hippocampal formation and dentate gurus. They note, “Although the cortical areas designated as the limbic lobe have some common structural characteristics, the extent to which they form a functional unit is not clear.”

Figure 10.8.4-3 illustrates the limbic system according to Carpenter & Sutin.

Figure 10.8.4-2 The cytoarchitecture of the limbic system in context. From DeSalle & Tattersall, 2012.

74DeSalle, R. & Tattersall, I. (2012) The Brain: Big Bangs, Behaviors, and Beliefs. New Haven, CT: Yale Univ Press. System Morphology 10- 65

Figure 10.8.4-3 The medial surface of the human cerebral cortex showing the limbic lobe (shading) surrounding elements of the basal ganglia and thalamus (the upper brainstem). “Although the cortical areas designated as the limbic lobe have some common structural characteristics, the extent to which they form a functional unit is unclear.” From Carpenter & Sutin, 1988. 66 Neurons & the Nervous System

10.8.4.2 The elements of the Basal Ganglia

The role of the basal ganglia remains difficult to quantify and its complexity at the histological level makes it difficult to describe. Parent has attempted to simplify earlier terminology related to the basal ganglia75. Parent attempts to differentiate clearly between the basal ganglia and the limbic structures (chapter 10). He provides a definitive description of the basal ganglia ca. 1986 in Figure 10.8.4-4.

Parent reviews the early assertions by histologists that the striatum was homogeneous with the more recent investigations that have described groups of small neurons surrounding larger neurons with significant branching structures. He suggests there are as many as seven cytologically different neurons in mammalian striata based on Golgi studies (page 135). However, he indicates as many as 95% of these fit his “spiny I” classification. These are clearly pyramid cells using the language of this work with up to seven poditic structures radiating from the soma.

Parent makes a very strong statement, “The entire cerebral cortex is known to project topographically to the striatum (page 140).” He softens this statement in his following sentence where he says, “Input from the sensorimotor cortex is extensive and bilateral, whereas that from the visual cortex Figure 10.8.4-4 The basal ganglia in mammals ca. is minimal.” He goes on but fails to provide a 1986. From Parent, 1986. consistent detailed picture of the situation. He notes, “the thalmostriatal projection is the second most prominent striatal afferent projection.” He does not discuss the relative density of the projections from different areas or the character of their information.

Parent switches focus in his chapter eight to note the pallidum represents the efferent side of the basal ganglia. It consists of large numbers of large fusiform shaped projection neurons (20-60 microns in diameter) with smooth dendrites that are as long as 1000 microns. These are highly suggestive of correlation elements in the context of this work. He notes a massive projection from the pallidum to the ventromedial thalamic nucleus via the entopeduclular nucleus.

Summarizing Parent, the striatum receives signals from a wide variety of cortical areas and the pallidum delivers signals to a variety of cortical areas but primarily to the thalamic elements of the brainstem. The delivered signals appear to result from a correlation mechanism similar to that found in many striated areas of the brain. Parent concludes in 1986, “Despite many years of serious investigation, the exact role played by structures of mammalian basal ganglia is still a matter of controversy. Most researchers agree, of course, that the basal ganglia are involved in motor function, but there is no general consensus on the exact contribution of the basal ganglia to the overall motor organization of the brain.” He goes on, “In fact, the data reviewed in this chapter strongly supports the idea that the striatum, as well as other basal ganglia components, may be involved in nonsensorimotor functions, such as those associated with motivational, emotional, and cognitive types of behavior.”

75Parent, A. (1986) Comparative neurobiology of the basal ganglia. NY: John Wiley & Sons System Morphology 10- 67 Figure 10.8.4-5 from Swanson (page 121) gives an important description of the cortical architecture of the basal ganglia defined above. The location of the striatum and pallidum are clearly at the junction between the telencephalon and the diencephalon. In the context of this work, the striatum is a part of stage 4 (labeled 4b in Section 12.5.1 because of a lack of adequate knowledge of its operation). Similarly, the pallidum is described as part of stage 6 but temporarily labeled stage 6b pending further definition of its functions. The flat map representation shows how short distance association circuits are limited in the breadth of their connections (typically less than a few millimeters within the plane of the cerebral flat map). For interconnection over longer distances, a commissure must leave the surface of the flat map near its origin and travel to a point near its terminus outside the plane of the cerebral flat map. The billions of these longer stage 3 commissure paths dominate the interior (white space) of the cortex. The nomenclature of the Swanson figure is extensive but the detailed structures within the hypothalamus are not of immediate interest. They are related to the behavioral state of the animal discussed in Section xxx. The figure is shown to illustrate how the basal ganglia, including the amygdalar are associated with the portion of the telencephalon immediately adjacent to the diencephalon. Their inclusion in the label cerebral cortex is entirely one of morphological convenience. AAA, anterior amygdalar; CEA, central amygdalar; MEA, medial amygdalar; . Figure 10.8.4-5 Flat map of the CNS showing the relationship of the basal ganglia to other elements. Shepherd has provided a cross section of the The basic organization of the hypothalamus and human brain showing the same region76. The caudally adjacent regions of the midbrain is shown actual folding of the brain results in a much in this flat map. The black strip on either side of the more complex picture when presented in midline represents the neuro endocrine motor zone cross section. It is much more difficult to (in the right rostral tip, the white asterisk, *, interpret from an architectural perspective. indicates the GnRH region). The light gray region between the neuro endocrine motor zone and the medial nuclei (MN) is the periventricular region (PR), which contains a visceromotor pattern generator network and the suprachiasmatic nucleus (the master circadian clock in the brain). See text. From Swanson, 2000.

76Shepherd, G. (1998) The Synaptic Organization of the Brain, 4th ed. NY: Oxford University Press page 330 68 Neurons & the Nervous System

Figure 10.8.4-6, also from Swanson, places these elements in a broader perspective. Inexplicably, the basal ganglia are labeled cerebral nuclei in this figure. 10.8.5 Interconnections within the brain

Marcus & Jacobson have published an extensive textbook and associated pedagogical aids77. While a valuable resource, The book is in its first edition and suffers from a variety of editorial problems (particularly involving internal cross- references). Marcus & Jacobson have provided a graphic critically important to the theory of this work. It defines the key role of the thalamus, and particularly the TRN in controlling the stage 4 and 6 portions, but not the stage 5 (cognition) portion, of the cerebral cortex.

Figure 10.8.5-1 shows the major thalamic projections to the major areas of the lateral left hemisphere of the cerebral cortex. The following figure shows the projections to the medial right hemisphere. Of particular interest is the large areas exhibiting projections from the pulvinar. These are areas proposed in this work to be performing high level percept (cognit) creation based on the low level percepts created by the pulvinar. Subdivisions of these areas are most frequently associated with various visual and auditory tasks.

In the case of vision, these areas accept high resolution information from the foveola via the visual PGN/pulvinar couple rather than the low resolution information from areas 17, Figure 10.8.4-6 Flat map of the CNS showing the 18 & 19. separation of the cerebral cortex from the diencephalon and other major elements. The basal ganglia are labeled cerebral nuclei in this figure. From Swanson, 2003.

77Marcus, E. & Jacobson, S. (2003) Integrated Neuroscience. NY: Kluwer System Morphology 10- 69

Figure 10.8.5-1 Major thalamic projections onto the lateral surface of the left hemisphere of the human cerebral cortex. From Marcus & Jacobson, 2003. . 70 Neurons & the Nervous System

Figure 10.8.5-2 shows the projections to the medial right hemisphere.

Figure 10.8.5-2 Major thalamic projections to the medial surfaces of the right hemisphere of the human cerebral cortex. From Marcus & Jacobson, 2003. . System Morphology 10- 71 Preuss has provided an alternate representation, Figure 10.8.5-3, of the major paths between the thalamus and the cerebral cortex limited to the visual modality. There appears to be a transcription error in both frames of this art. A troica of paths should be shown from the P,M & K nerve bundle from the retina to the Brachia of the Superior colliculus (actually the separate engine known as the perigeniculate nucleus in this work.). As shown there are two parallel paths from the K neurons of the retina to the Superior colliculus. The paths from the PGN lead into the two areas of the Pulvinar as labeled. With these changes, the LGN/occipital lobe couple and the PGN/pulvinar couple discussed in Section 15.6 of “Processes in Biological Vision” become compatible with the Preuss figure.

10.8.6 Interconnections between the CNS and PNS

Marcus & Jacobson have provided a comprehensive discussion of the connections between the brain and the peripheral nervous system. It begins with a discussion of each cranial nerve and their separation into motor and sensory portions where appropriate. They treat nerves I and II separately from the other cranial nerves. The discussions of the targets of the sensory portions of these nerves (at least nerves I, II & VIII) can be expanded based on this work.

The conventional cranial nerve numbers are given here, without expansion, based on Noback (page 122);

I. Olfactory Smell II. Optic V i s i o n (afferent, sensory) III. Oculomotor V i s i o n (efferent, oculomotor) IV. Trachlear Vision (afferent, eye movements) V. Trigeminal Mastication & ear muscle control VI. Abducens V i s i o n (efferent, eye movement) Figure 10.8.5-3 Major thalamic projections to both VII. Facial Muscles of frontal, parietal and occipital lobes of the cerebral face and ear cortex related to the visual modality. See text for bones proposed correction to artwork. From Preuss, 2007. VIII. Vestibulocochlear H e a r i n g & equilibrium (afferent, sensory) IX. Glossopharyngeal Swallowing movements X. Vagus Swallowing below larynx, respiration and digestion XI. Spinal accessory Movement of shoulder and head XII. Hypoglossal Movement of tongue

10.8.6.1 CNS to PNS interconnections in humans 72 Neurons & the Nervous System

Figure 10.8.6-1 shows the dermatomes of the human associated with the root ganglia of the spinal cord and the major nerves emanating from the root ganglia. The mapping of the external physique onto the parietal lobe, both the sensory and motor portions, are frequently labeled a homunculus (See Section xxx). The labeling of the nerve roots follows the conventions used to describe the vertabra of the spinal cord presented in Section 1-.5.2.1.

Figure 10.8.6-1 Dermatomes of human RESCAN. Areas innervated by nerve roots (center panels) or peripheral nerves (outer panels). From Kandel et al., 2000>

10.8.6.2 Interconnections in Macaque

Figure 10.8.6-2 shows the dermatomes of the Macaque and their representation in the parietal lobe System Morphology 10- 73 of the brain from Nelson et al78. “The heavy lines mark the borders of the two representations. Cortex activated by designated body surfaces are outlined. The representation of individual digits of the hand and foot are outlined and numbered (D,-Ds); shaded areas correspond to the representations of the hairy dorsum of the digits. The dotted line indicates the position of the central sulcus. The dashed line indicates the region along themedial wall where portions of the representation in Areas 3b and 1 are contained in the cortex on the medial wall of the hemisphere (see Fig. 2). This summary was constructed from cortical maps obtained in several cases in which more than one region was completely mapped in both Areas 3b and 1. Individual maps were combined, based on their overlap.” The paper is extensive and includes many citations.

78Nelson, R. Sur, M. Felleman, D. & Kaas, J. (1980) Representations of the Body Surface in Postcentral Parietal Cortex of Macaca fascicularis J Comp Neurol vol 192 , pp 611-643 [xxx in ref. folder ] 74 Neurons & the Nervous System

Figure 10.8.6-2 Dermatomes of Macaque. The organization of the representations of the body surface in Areas 3b and 1 of the cynomolgus macaque. The representations are shown on a dorso-lateral view of the brain (left) and as they appear “unfolded” from the central sulcus and medial wall of the hemisphere (right). See text. From Nelson, et al., 1980. System Morphology 10- 75

10.8.7 Interconnections between the CNS and glandular system

Figure 10.8.7-1

Figure 10.8.7-1 The interface between neural and glandular systems in Chordata. The two divisions of the neuroendocrine interface are illustrated in this parasagittal view of the hypothalamus (at upper left) and the pituitary gland (lower right) of the rat. Axons of magnocellular neurons (Magno) end in the postrior lobe of the pituitary, where they release vasopressin (VAS) or oxytocin (OXY) into the general circulation. Axons of parvicellular neurons (Parvi) end in the external lamina of the median eminence (e). Their neurotransmitters are released into hypophysial portal vessels that transport them to the anterior pituitary, where they exert endocrine effects on five classic cell types that in turn secred hormones into the general circulation. See text or Swanson for more definitions. From Swanson, 2003.

10.8.8 Interconnections between elements of the somatosensory system within the CNS

Figure 10.8.8-1 appears in Kandel et al. (page 453) with an extensive caption that is not reproduced here. The somatic sensory signals from the spinal cord are delivered to the thalamus, both the VPL portion as shown as well as the command and control section of the thalamic reticular nucleus (TRN) covering the thalamus and not shown. The accompanying text notes, “The S-II cortex projects to the insular cortex, which in turn innervates regions of the temporal lobe believed to be important for 76 Neurons & the Nervous System tactile memory.” Their text goes on to elaborate the specific areas of the hand and their associated areas in the somatic sensory cortex in considerable detail.

Figure 10.8.8-1 Location of somatosensory channels on the cerebral cortex. A; the surface of the cerebral cortex dedicated to somatic sensing. B; coronal section as indicated in A. C; a more detailed section as defined in A showing the major channels reaching the cotex from the thalamus. Most of the paths shown involve stage 3 neural paths between stage 4 engines because of the distances involved. S-1; primary somatic sensory cortex. S-II; secondary somatic sensory cortex. Other numbers correspond to Brodmann’s areas. See text. Modified from Jones & Friedman, 1982 in Kandel et al., 2000.

10.9 Correlation of functions with the cytoarchitecture of the CNS

[xxx expand to show strings (in block diagram form) associated with vision and hearing. While investigators have passed through the period of correlating bumps on the external skull with psychological traits, many still assert the concentration of one or more psychological traits with one hemisphere of the brain or the other. With the advent of modern non-invasive imaging techniques, and the correlation of more data using computers this situation has also changed. It is now recognized that one trait may exhibit a hemisphere related dominance, it is seldom strong enough to keep the subject from operating effectively in the arena of that trait in the absence of any contribution from that hemisphere. It is also recognized that it requires a concatenated string of cortical areas to accomplish any significant physiological task. Figure 10.9.1-1 from Fuchs & Phillips System Morphology 10- 77 gives a recent description of the situation at a relatively coarse level79.

10.9.1 Broca’s and Wernicke’s areas

Based on lesion data, Broca’s area and Wernicke’s area are both associated with the speech aspects of verbal communications. However, this is an oversimplification. It is now clear that Broca’s area is a stage 6 motor area associated primarily with the implementation of adversive instructions related to speech generation. Wernicke’s area, on the other hand is a stage 4 analytical area primarily concerned with information extraction related to the perception of speech. Fuchs & Phillips have described the functional shortfall in stage 4 information extraction associated with Wernicke’s area as “receptive aphasia (also called fluent, or sensory, aphasia).” Clearly, this condition has nothing to do with the sensory system of stage 1 or 2 and sensory aphasia is an inappropriate label. . They describe functional shortfalls related to Broca’s area as expressive aphasia (also called nonfluent, or motor, aphasia).” The label nonfluent appears inappropriate. The condition is an expressive aphasia Figure 10.9.1-1 Recent representation of functional resulting from a stage 6 motor neuron role of areas of the human brain. From Fuchs & aphasia. Phillips, 1989.

79Fuchs, A. & Phillips, J. (1989) Association cortex In Patton, H. Fuchs, A. et al. eds. Textbook of Physiology, 21st Ed, Vol. 1. pp 687-690 78 Neurons & the Nervous System

Figure 10.9.1-2 shows the best available rendition of the areas of Broca and Wernicke. It includes BA 40 based on the belief that it contributes to the perceptual aspects of language. This work takes the view that the perceptual aspects are extracted by the auditory PGN/pulvinar.

Figure 10.9.1-2 Areas associated with spoken language. Area 22 is part of the larger association area of the temporal lobe. It is responsible for extracting the “information” from a sentence before combining the information with other (non-audio) sensory inputs. Area 44 is responsible for creating a string of words (a sentence) in the neural code needed to drive the large number of muscles involved in vocalization. The instructions to the individual muscles are prepared in area 6. From Fuster, 1993. System Morphology 10- 79

Figure 10.9.1-3 shows a somewhat more detailed rendition of the areas of Broca & Wernicke. Fuchs & Phillips seek to associate the areas of Broca and Wernicke via the arcuate fasciculus. However, the primary paths between these two areas are via the frontal lobe and the thalamic reticular nucleus (TRN). There is no requirement for a normal Wernicke’s area in support of speech generation. Similarly, there is no requirement for a functional Broca’s area in support of speech perception. However, there are many documented caveats associated with specific situations within these generalities. Zillmer & Spiers show several more recent cyto-architectural maps that stress the extension of Wernicke’s area into both the temporal or parietal lobe and how many major areas are frequently hidden from the conventional lateral views of the brain80.

80Zillmer, E. & Spiers, M. (2008) Principles of Neuropsychology. US: Wadsworth pp 22 & 113 80 Neurons & the Nervous System

Figure 10.9.1-3 Temporal and frontal language areas of the left human hemisphere and their connecting fibers. See text. On the complete brain, Broca’s area is indicated by sparse stipple, and the temporal language area, which includes Wernicke’s area and the angular gyrus, is indicated by dense stipple. Drawings above and below that of the complete brain represent horizontal sections through the left (below) and right (above) temporal language area, revealing the larger left planum temporale (tippled area) that occurs in 65% of normal human brains. From Patton et al., 1989. System Morphology 10- 81 The areas immediately adjacent to Wernicke’s area are very important. The angular gyrus is believed to associate visual, tactile and auditory information. Fuchs & Phillips characterize this area (page 687). “Lesions of the angular gyrus, or the neighboring supramarginal gyrus, produce alexia with agraphia. These patients can neither read nor write and have difficulty converting visually, tactually, or orally presented symbols into language. For example, they cannot spell, nor can they recognize words that are presented one letter at a time.” They provide a broad background in various aphasias associated with listening, reading, writing. and speaking.

10.9.2 The inferotemporal cortex

Romero et al. have provided a review of the functions associated with the inferotemporal cortex without introducing fMRI81. xxx ADD What is its specific location.

10.9.3 The storage of short and long term memory in the cortex

Chapter 17 will discuss the storage of memory in detail. A paper in Section 17.1.2 by Quiroga et al. is particularly relevant to our state of knowledge in this area. They develop whether a minimal group of cells represent an explicit representation of “Grandmother” or whether they merely represent a “concept of Grandmother.” At the current time, the basic code used to store memories is unknown. The spatial distribution of memory storage is unknown and whether the memory is stored in a unitary bit per memory concept or a multi-bit per memory concept us unknown. Only the gross description of the areas related to the formation, overall storage and retrieval of memory elements are known.

81Romero, M. Bermudez, M. Vicente, A. et al. (2008) The inferotemporal cortex: an integration module for complex visual analysis In Portocello, T. & Velloti, R. eds. Visual Cortex: New Research New York: Nova Science Publ. pg 227+ 82 Neurons & the Nervous System

10.10 The neuroglia (or glia)

10.10.1 The proposition of Fields

Fields has provided a recent popular book on the neuroglia based on his experience and purview from his position within the NIH82. He has also published more academic material on the subject83. The paper by Wake et al. focuses on the histological relationship between the axon segment and its becoming myelinated by the action of oligodendrocytes. They note, “Unique to vertebrates, formation of the myelin sheath must be highly regulated temporally during development and targeted specifically to appropriate axons.’ They also note, “Myelin, the multilayered membrane of insulation wrapped around axons by oligodendrocytes, is essential for nervous system function, increasing conduction velocity by at least 50 times. This increase in speed of propagation (a more specific term than conduction) is a major subject of Chapter 9 of this work. A major premise of Fields’ book (suggested by his title) is that the glia play a significant role in glia signaling (as distinct from neural signaling) within the CNS. However, he does not exclude neural signaling as the dominant signaling mechanism.

Fields has mentioned the velocity of neural signals several times in his book, with some variation. Page 19 suggests a velocity increase of 100 times, from 2 mph to 200 mph. On page 295, he again suggests 100 times based on velocities of one and 100 mph. These are round numbers appropriate for a popular book. They are not tied to a specific neural path. However, the increase of 50 times, and a maximum of a nominal 100 mph (37 m/sec) can be compared with the measured value of 44 m/sec documented in Section 9.xxx. While the value of 44 m/sec is taken from the slope of a graph at a temperature of 37C, it is not likely to be off by a factor of two. It should be noted, 44 m/sec is an average saltatory velocity between Nodes of Ranvier, and includes the delay of one node. The actual propagation velocity of a neural signal along an axon segment (measured by the same investigator) is much higher, nominally 4,400 m/sec. (Fig 7.4.5-1 in Hearing xxx).

Fields does not address the intimate relationship between the schwann cells in particular and the neuron that leads to his noted increase in propagation velocity of neural signals. This intimate relationship leads to the conversion from signaling via diffusion within the axoplasm to a propagation phenomenon involving the marriage between axon segment and Schwann cell. Neither does he address the role of the Node of Ranvier in separating axon segments and requiring the interruption of the myelination in order to achieve access to the chemical constituents of the extra neural matrix–the primary reason for his string of squashed pearls analogy. The role of the myelination of axon segments is much more important than his suggested listening by the oligodendrocytes to the signals traveling along the axon segments.

Fields makes the unabashed statement that “The synapse is the transistor of the brain, the fundamental switch connecting neurons into circuits that allows us to think and feel, remember and hope (page 52).” This is in complete agreement with this work but the synapse is only one representation of the Activa, the true transistor of the neural system (Chapter 2). Figure 10.10.1-1 attempts to distill many of the points in Fields related to the histological role of glia. It omits the medicinal and disease aspects of glia. The book focuses on the brain and leaves the PNS under-discussed. While noting Schwann Cells are present in the end plates at the neural- muscular interfaces of the PNS, he does not address the myelination of the remaining stage 3 neurons of the PNS. Fields does focus on the great number of glia within the CNS, suggesting they outnumber the actual neurons by as much as 6:1 (page 24). Like others, Fields is now estimating the total number of neurons within the CNS at 100 billion, up a factor of ten from a decade ago

82Fields, R. (2009) The Other Brain. NY: Simon & Schuster

83Wake, H. Lee, P. & Fields, R. (2009) Control of Local Protein Synthesis and Initial Events in Myelination by Action Potentials Sci Express, www.sciencexpress.org / 4 August 2011 / Page 1 / 10.1126/science.1206998 System Morphology 10- 83 thanks to higher resolution tissue examination, along with up to 100,000 synapses per neuron (page 211). This close examination has documented individual myelinated neurons with an axon diameter of only one nanometer (page 40). When counting glia versus neurons, the count criteria is important. Is the count based on axon segments and equivalent myelination of those segments or is it based on counting cell nuclei? The intertwining of glia and neurons is quite complex. A single glia may support multiple neurons,frequntly up to 50 axon segments. It may also support multiple smaller neurons which Fields describes as fists of glial material penetrated by small axons. Conversely, a single neuron may be supported by multiple glia. Are we counting by weight or volume? Fields asserts, “Glia outnumber neurons up to 100:1 in white matter tracks and nerves (page 24).”

Fields notes myelination is Figure 10.10.1-1 The roles of glia within the neural system. Only unique to the family the Schwann cells and the oligodendrocytes support myelination of Chordata (a.k.a, Vertebrata). the axon segments of neurons. From Fields, 2009. Other orders, and particularly the Squid, employ very large diameter neurons and tightly grouped neurons to achieve increased signal velocity over small diameter neurons (page 39).

The velocity of signal propagation within Chordata (Section 9.xxx) is not related to the diameter of the axon segment per se, as frequently suggested in the past. It is determined by the ratio of capacitance/unit length to inductance/unit length.

Fields identified three types of Schwann cells used to myelinate neurons of the PNS, the squashed pearls configuration with one squashed pearl per axon segment along a stage 3 neuron, the fist like Schwann cells penetrated by many small axons and the terminal Schwann cells forming the outer envelope of the neuron-muscle interfaces known as end plates (page 31). He notes, “anatomists call fist like Schwann Cells non-myelinated to distinguish from the stretched pearl type myelination. This is an awkward label as the axons penetrating the fist remain myelinated but potentially not individually wrapped. In a single illustration, Fields like others, shows each squashed pearl including a nucleus and constituting a single cell. These three variants of Schwann cells look entirely different but “assure that no (stage 3) axons of neurons are ever left bare.” Fields notes the absence of Schwann cells from the brain and spinal chord (page 32) when introducing the oligodendrocytes that he asserts only occur within the CNS and spinal chord. He notes the shape of the individual oligodendrocyte generally morphs from a cocklebur to an octopus as it extends to myelinate multiple axon segments. Based on his description, many of the oligodendrocytes appear to be immature glia that ultimately emulate Schwann cells within the CNS and spinal chord. They are dominant in the white matter supporting stage 3 neurons of the commissure, just as Schwann cells are supportive of the stage 3 neurons of the nerves of the the PNS. This author was unable to find any delineation between Schwann cell and oligodendrocyte in Fields’ words; however his figure 18 is presented here as Figure 10.10.1-2. It shows the primary difference between an oligodendrocyte supporting multiple axon segments within the CNS and a series of individual Schwann cells supporting individual axon segments within the PNS. It has been modified 84 Neurons & the Nervous System slightly to account for the nucleus shown off to the side of the PNS neuron. As a general rule, such a neuron does not normally exhibit a myelinated dendritic structure prior to a synapse and before the soma is encountered. In addition, finding the soma isolated from the signaling structure is unusual (a monopolar neuron in the archaic language of the histologist). The point of action potential generation is typically a region labeled the hillock within the soma of a “bipolar neuron” of histology.

There is a reported exception to these two conditions that has been reported, but minimally documented with respect to the neurons immediately following the sensory neurons in the hearing modality. It appears that due to volumetric constraints, this neuron is a stage three neuron and its first encoding conexus as well as one or more subsequent units, consisting of a myelinated axon segment and a Nodes of Ranvier, may occur before reaching the soma. The figure does not suggest any method of signaling between the intentionally isolated Schwann cells associated with the PNS axon segments. Communications between the oligodendrocytes appears equally limited within the CNS. Most discussions of glia suggest the myelin is laid down in thin layers that lack any interior fluid path that could support signaling. Such a fluid path would defeat the principle reason for myelin encasing axon segments.

Quoting the current Wikipedia page for background (with rewording at the end), “Myelinating Schwann cells begin to form the myelin sheath in mammals during fetal development and work by spiraling around the axon, sometimes with as many as Figure 10.10.1-2 The oligodendrocyte versus Schwann cells. Left; 100 revolutions. A one oligodendrocyte supporting three axon segments from three well-developed Schwann cell different neurons. Right; three distinct Schwann cells supporting is shaped like a rolled-up two neurons on each side of a synapse. Modified minimally, by sheet of paper, with layers of adding a synapse, from Fields, 2010. myelin in between each coil. The inner layers of the wrapping, which are predominantly membrane material, form the myelin sheath while the outermost layer” includes a region of cytolemma enclosing the nucleus immersed in a cytoplasm For completeness, Figure 10.10.1-3 describes a nominal fist type of glia/neuron interface from a very early representation. Note that it is attributed to a Schwann cell by Wyburn84 and subsequently by Ganong (1975). It more closely resembles the arrangement used in non-mammals (such as the squid) to reduce the capacitance between the axoplasm of individual axon segments and the surrounding external neural matrix.

84Wyburn, xxx. (1960) The Nervous System. NY: Academic Press System Morphology 10- 85

The primary purpose of myelination, regardless of source is to isolate the axon segment from the fluids of the extra neural matrix by a tightly contacting low dielectric material. Whether it is a wrapping or a knot of material is largely incidental (Section 9.xxx). Fields appears to estimate the number of glia cells aa between six and 100 times the number of neurons in the CNS, a number running into the 1-10 trillion range (a number only exceeded by the current USA national debt). Fields notes several other unfortunate remnants of the early days of histology; a lack of uniquely specific names for specific functional types of glia, and even a lack of specific names for significantly different types Figure 10.10.1-3 Early caricature of a fist of glia of glia assigned the same generic histological engulfing multiple axon segments. Original caption name. The designation oligodendrocytes has in 1960 and repeated in 1975 was “Relation of axons an unfortunate tone that suggests these cells to Schwann cell in unmyelinated nerve.” The have some association with the dendrites of mesaxon is irrelevant to this discussion. From neurons which they do not. Nor do the Wyburn, 1960. oligodendrocytes share an internal structure with dendrites.

Fields does make the interesting point that cancer is virtually non-existent among the neurons because they do not normally subdivide during a lifetime (page 69). 2.3 The organization and mixed coordinate systems of the chordate brain

The morphogenesis of the human brain is well illustrated in figure 3-17 of Carpenter & Sutin85.

[xxx moved previous part of 2.3 to new chapter 4 ] For the higher primates, the top caudal part of the thalamus is designated the pulvinar as shown in Figure 10.11.1-1.

85Carpenter, M. & Sutin, J. (1983) Human Neuroanatomy. London: Williams & Wilkins pg 80 86 Neurons & the Nervous System

Figure 10.11.1-1 CR Caricature showing the position of the Pulvinar, LGN and Thalamus in relation to the old brain. Note the rostral part of the thalamus is to the left. The optic nerve (commissure) merges with the brain at a caudal location. Note also the separation of the commissure proximal to the optic chiasma into two separate bundles going to the LGN and to the brachium and Superior Colliculus. From Mettler, 1948.

It is very difficult to locate an actual photograph of the elements of the thalamus at the level of detail shown in this caricature. The best pictures were found in Nolte & Angevine and in Jackson & System Morphology 10- 87 Duncan86. Both of these works showed both photographic and MRI imagery of these areas. Nolte & Angevine provide annotated pictures that will be expanded upon later in this work87. The Jackson & Duncan text showed a more extensive series of slices through the brain that allow the relevant structures to be tracked from slice to slice. Orrison shows a coronal MRI image and a caricature of the image showing the relative distance between and the isolation of the Superior Colliculus and the thalamus88. When expanding on the figures in the above works, it is necessary to differentiate between the many nuclei of the thalamus and assign them primary roles. This is difficult to do with the amount of exploratory work already reported in the literature. To circumvent this problem, the term pretectum will be appropriated from the non-primate chordate literature and used to describe those portions of the thalamus that are related to the visual process but do not include the lateral geniculate nuclei. A precise functional distinction between the pretectum and pulvinar may not be possible at this time. As defined, the pretectum includes the so-called pulvinar-LP complex (LP = lateral posterior nucleus), the lateral dorsal neucleus and the ventral posterolateral nuclei (terms not necessarily used consistently by all current authors. The text in parenthesis [ xxx what figure, maybe brodal or pansky ] is designed to describe the principle function of the various elements with respect to vision. No vision related notation is given under some of the elements. The notation under the various morphological lobes will be addressed below. They differ significantly from Nolte, particularly with respect to the frontal (anterior) lobe. The major task of the frontal lobe is cognition. One result of this process is the generation of high level commands to the parietal lobe to implement actions. These actions are not limited to motor functions. They also include changes in operating mode of a variety of feature extraction engines.

Nolte has drawn attention to the fact that the functional characteristics of the various elements do not respect morphologically defined boundaries. This is particularly true where the functional element (engine) is found to extend deep into sulci and occasionally reappear on the other side. The folding of the surface of the brain is primarily to aid in the packaging of a large thin sheet of neural material in a minimal volume shielded by bone while maintaining minimum signal delay between various neural engines (functional elements) . The minimal volume reflects the requirement in advanced chordates to minimize the moment of inertia of the head in order to achieve high angular rates of rotation.

Any relationship between a given gyrus and a functional neural engine is a flimsy one. The same situation arises in the thalamus and other elements of the midbrain. As Nolte noted in connection with his figure 15-3 describing the brainstem, the precise location of many of the morphologically defined neural engines spill over into adjacent areas defined at the next higher morphologically level.

Further definition of the morphological areas of the thalamus are given in Table 16-1 of Nolte. Both their names and a common abbreviation are given. Interestingly, because it has not been as widely studied, the pulvinar is not associated with a common abbreviation.

It is important to note Nolte’s emphasis on the dual character of the neural signals related to the thalamus (and generally true throughout the neural system). Although he does not address the signal processing neurons present as such, he indicates that projection neurons operating over short distances operate in the tonic mode while those operating over longer distances (commissure neurons) operate in a burst mode (i.e., phasic mode associated with action potentials).

2.3.2 Coordinate transformations within the visual system

86Jackson, G. & Duncan, J. (1996) MRI Neuroanatomy NY: Churchill-Livingstone

87Nolte, J. & Angevine, J. (2000) The Human Brain in Photographs and Diagrams, 2nd ed. St. Louis, MO: Mosby pp 124-125

88Orrison, W. (1995) Atlas of Brain Function. NY: Thieme Medical Publishers pp 142-143 88 Neurons & the Nervous System

See Section xxx in neural material.

2.3.2.1 The transition from retinotopic to abstract mapping

The organization of the visual system begins to lose its retinotopic character as the signal paths progress away from the retinas. Within the parietal, temporal and anterior lobes, the organization is not retinotopic. It is essentially abstract and described in terms of a saliency space where the information is in vector form. The vector related to each piece of information contains a tag that relates to its spatial origin. However, this spatial tag is not retinotopic. It defines the location of the source of the information in inertial space as computed from all of the sensory inputs of the animal. Conflict between the various sensory inputs results in the well known vertigo since the higher feature extraction engines are not able to arrive at an unequivocal location tag in inertial space.

2.3.2.2 The transition from abstract to inertial-topic mapping

Many experiments related to the afferent command signals arriving at or leaving the superior colliculus, SC, have suggested a retinotopic relationship. However, this relationship is not in terms of absolute spatial position on the retina. It is more closely related to the absolute position of the excitation source in object space. It is more directly related to the distance of the absolute spatial position from the line of fixation of the eyes. These signals are used to command the oculomotor, and other, muscles as required to achieve a desired line of fixation. These commands can be generated autonomously or in response to the volition of the anterior lobe. In most experiments, the animal has been constrained to prevent head and body motion. As a result, the investigator has found the SC signals only indicative of eye motion. Care must be taken in interpretation of such results.

2.3.3 Initial embroyology of the visual system

2.3.3.1 Initial embroyology of the brain

{xxx copied this section to 4.2.3.2.1 ] Figure 10.11.3-1 assimilates some of the terminology in the 5th edition of Torrey89, Pansky, et. al90. and the new edition of Afifi & Bergman91. Many of the figures in these works are taken from the older text by Noback92. The material to the left of the vertical centerline is generally from Torrey. Hamilton has also provided a figure similar to the left half of the above figure93. The material to the right of the centerline is an expansion based on this work using the nomenclature of Afifi & Bergman. The opening paragraph of Afifi is particularly relevant to the following discussion. The figure attempts to show the morphogenesis of the brain of a higher chordate as a function of gestation time using three common anatomical forms. The most comprehensive discussion of morphogenesis appears in Noback. However, even this discussion does not address the difference in morphogenesis related to the foveola found in a broad range of higher chordates. The literature has generally presented two different topographies for the brain of the chordates depending on their level of morphological development. When examined more closely from a

89Feduccia, A. & McCrady, E. (1991) Torrey’s Morphogenesis of the Vertebrates. NY: John Wiley & Sons.

90Pansky, B. Allen, D. & Budd, G. (1988) Review of Neuroscience. 2nd ed. NY: Macmillan Publishing Co.

91Afifi, A. & Bergman, R. (1998) Functional Neuroanatomy. NY: McGraw-Hill

92Noback, C. (1967) The Human Nervous System. NY: Blakiston Div. of McGraw-Hill

93Hamilton, L. (1976) Basic limbic system anatomy of the rat. NY: Plenum Press. pg. 30 System Morphology 10- 89 functional perspective, this dichotomy is not supported here. Torrey has exemplified this dichotomy by drawing the three heavy arrows indicating the general areas associated with the senses and then saying that the retinas connect to the diencephalon in the higher chordates and to the mesencephalon in the lower chordates. Hence the left side of the five-part anatomy of the higher chordates show the retinas interfacing with the diencephalon. This was as far as Torrey went. The arrows in the above figure are drawn at slightly different locations than the arrows (obviously added during editorial review) of Torrey. Since the brain has not completed its genesis at the three-part anatomy stage, the arrows point only to general areas. To go further based on only a two- dimensional drawing is difficult. As an example, the optic chiasm cannot be shown easily within the context of the above drawing. In addition, there is another level of detail that is critical to the understanding of vision in the higher chordates. These species exhibit a morphological fovea. Of greater importance, they exhibit an physiological foveola within the fovea. The presence or absence of a foveola is a significant physiological dichotomy among the chordates. This dichotomy influences the final morphological implementation of the visual system. Whereas the neural interface between the optic nerves associated with the tectum is called the pretectum in the lower chordates, some authors call it the corpora quadrigemina in the higher chordates. The difference in this case is almost entirely morphological and not functional. Afifi discuss this matter in terms of the pretectum being reabsorbed as the 90 Neurons & the Nervous System

Figure 10.11.3-1 OLD DUPL The morphogenesis and gross anatomy of the brain related to vision. The progression from two-part to five-part anatomy traces the morphogenesis of all brains. The figures to the left of the vertical centerline are similar to the fifth edition of Torrey. The four arrows differ from the three pen and ink entries made in Torrey by the new editors of that volume. In this case, the arrows refer to the location of the initial interface between the sensory neurons and the brain. Torrey has the lower arrow pointing to the lowest ventricle in the three-part anatomy, the Rhombencephalon. This area relates more directly to the vestibular than the auditory function. The figure to the right of the centerline represents the proposed interface between the retinas and the brain in greater detail. Paths A and B are afferent paths while path C is efferent. While the shaded area is frequently discussed in terms of ventricles or “spaces”, they are generally filled with the association fibers and commissures connecting the various engines (Torrey describes as centers) of the brain. corpora quadrigemina is formed. There is an additional problem in accounting for the portion of the tectum associated with the audio interface. This paired structure (not shown) is located within the area of the corpora quadrigemina. The area is analogous to an area of hills and mountains. The question becomes where do you draw the line between a hill and a mountain. The area could be called the corpora sexigemina equally well. The structures of both the thalamus and tectum that relate to vision are generally paired and arranged laterally from the sagittal plane (Pansky, et. al, pg. 325).

Torrey ends its discussion by suggesting that the anterior pair of the corpora quadrigemina are related to vision and the posterior pair are related to hearing. Noback presents the exact opposite System Morphology 10- 91 impression when discussing the audio system94. He does not differentiate between the nerves coming from the ears and those coming from the nearby vestibulary system. This work takes a different view. It suggests corpora sexigemina is a better functional description of the roof of the tectum in all animals. It proposes that the two anterior bodies, the inferior colliculi are directly related to vision, the middle pair (which might be a part of the inferior colliculi based on Noback ) are related to audition and the posterior pair, the superior colliculi are related to the oculomotor functions of vision as well as the motor functions of the body. This structure has a close tie to the vestibular system. This position is consistent with a merging of the figures on page XXX & 325 of Pansky, et. al. The graphical description of the above relationships is further clouded by the three flexure points found particularly in the higher chordates. The brain cannot be properly presented on a 2- dimensional surface because of these flexures. These flexures are used to allow the brain to be packaged within a skull compatible with a face parallel to the ventral surface of the bipeds and quasi- bipeds. These flexures evolve in humans up to the time of birth. As shown, only the cephalic flexure is collocated with an isthmus. The cervical and pontine flexures actually reverse during the final genesis of the human. On initial examination, most of the neurons of the optic nerve are found to interface with the thalamus. However, this conclusion is not relevant to the functional performance of the visual system. When explored in detail, the retinas are seen to interface simultaneously with both the bottom of the diencephelon (the lateral geniculate nuclei of the thalamus, labeled A in the figure) and with the top of the mesencephalon (the roof of the tectum). The interface with the roof of the tectum actually consists of two distinct interfaces in the case of at least the higher chordates. There is an interface with the inferior colliculus (usually labeled the pretectum in the lower chordates and labeled B in the figure) and with the superior colliculus (labeled C in the figure). These interfaces are shown explicitly in Pansky, et. al95. (Pansky, et. al. pairs the terminology pretectum and superior colliculus in their 1988 book and this terminology is frequently used in this work.) The inferior colliculus interface is associated with the neurons emanating from the foveola and being processed by the Precision Optical System. The superior colliculus interface is associated with the few motor neurons of the ocular globes which also travel within the optic nerve and support the iris, lens, etc. The neurons interfacing with the inferior colliculus provide the fine spatial resolution associated with the foveola and so important to the visual system of humans and other advanced chordates (including birds). Hence, while most of the neurons of the optic nerves interface with the thalmus, the most important neurons of the optic nerves interface with the tectum. 2.3.3.2 Initial embryology of the eye

[xxx just cite section 2.3.3.2 in Processes in biological vision book and drop 2.3.3.2 and 2.3.3.3. ] As noted above, although most neuroscientists think of the retinas as integral parts of the CNS, a broader view based on morphogenesis would suggest the eyes, including the retinas, are parts of the PNS that happen to be located within the scull in vertebrates. Section 4.5.1 presents more details on the embryology of the eyes. 2.3.3.3 Initial embroyology of the retina

The initial formation of the retina is documented by Reh, writing in Ryan, et. al96. He notes that the ganglion cells appear to form first. Lam & Bray develop the fact that large numbers of ganglion cells die during development97. The available facts suggest that a large number of ganglion cells are formed before the signaling architecture of vision is completely implemented. Subsequently, unneeded ganglion cells atrophy.

94Noback, C. (1967) Op. Cit. pg. 6

95Pansky, B. Allen, D. & Budd, G. (1988) Op. Cit. pg. 137

96Reh, T. in Ryan, et. al. (2001) Retina, 3rd ed. Vol. One, St. Louis, MO: Mosby, Chap 1

97Lam, D. & Bray, G. (1992) Regeneration and Plasticity in the Mammalian Visual System. Cambridge, MA: The MIT Press, pg 31 92 Neurons & the Nervous System

2.3.4 The connections between elements of the brain

With the retinas recognized as brain tissue, it is important to also recognize the historical term optic nerve actually refers to a commissure of the brain. A commissure is a major bundle of neurons connecting distant locations of the central nervous system, CNS. The largest commissure, the corpus callosum includes over 300 million individual axons. The optic nerve, optic tract and optic radiation can be considered commissure. Commissure connect areas of the brain separated by more than a few millimeters. Commissure is the morphological name for elements of the projection stage of the neural system found within the CNS. These neurons employ phasic signal transmission (action potentials). Over shorter distances, the signals are transmitted within the brain using tonic signaling (analog waveforms). Within this work, all signals traveling from sensor neurons will be considered afferent until they reach the anterior lobe of the cerebral cortex or are redirected by the pretectum. Conversely, all neural signals emanating from the cerebral cortex, and those assembled by the pretectum, will be considered efferent. These terms will de defined more completely in Chapter 11. 2.3.4.1 The connection architecture of vision

In discussing the connections within the brain, it will be shown in Section 15.2.4 that it is critical that the functional (topological) architecture be understood before assignments can be made based on morphology of topography. The visual system is so sophisticated, that many inappropriate assertions can be made lacking such background. 2.3.4.1.1 The block diagram

While the visual system can be described based on many morphological features, the fact that the higher level chordates exhibit two distinctly different signaling paths between the old brain and the new brain is crucial. The second signaling path is the mark of a highly developed brain containing a fovea. The well known path is from the LGN of the thalamus, through the geniculocalcerine fissure, to area 17 of the cerebral cortex. It is primarily concerned with the visual awareness of the space surrounding the animal and has been labeled the awareness path. This path is fundamentally extrafoveal. The second path is less well known and extends from the pulvinar, along the pulvinar pathway to area 7 of the cerebral cortex. It is concerned with the analysis of the details of a scene projected onto the foveola. It is labeled the analytical path and is only concerned with the neurons emanating from the foveola. The coordinated movement of the eyes, involving both major and minor saccades (including tremor) over short intervals of time allow the system to analyze important elements of the surrounding environment in a sequential manner.

These pathways are not related to the so-called M– and P–pathways which both follow the above awareness path. Figure 10.11.4-1 reproduces [Figure 15.2.4-3] to illustrate the overall topology of the visual system in the higher chordates (which does not necessarily include the monkeys). This figure will aid the reader in following the remainder of this section and the references cited. In this context, the term higher chordates refers to the sophistication of their foveas. This group includes many hunters among the mammals and aves.

The purpose of the figure is to differentiate between the awareness path along the top of the figure and the analytical path below it. The signals from these two afferent paths are formed initially in the retina and are ultimately merged in area 7 of the cerebral cortex. Note also the efferent path labeled the command path leaving the POT and arriving at the superior colliculus. The Parietal-Occipital-Temporal lobe junction area, POT, is a major signal exchange point within the visual system and probably between all of the major sensor systems. This path highlights the role of the superior colliculus in vision. It clarifies the fact that the superior colliculus is primarily involved in output command (efferent signal) generation regardless of whether the initial stimuli came from an external source or from the cerebral cortex via the volition path. The alarm path is important in this discussion because it frequently introduces responses in the superior colliculus (a part of the POS) not anticipated by the researcher. The stereo path is shown for completeness. System Morphology 10- 93

Figure 10.11.4-1 Reproduction of Figure 15.2.4-3 to illustrate the top level topology of the visual system in the higher chordates. The Pretectum incorporates a series of nuclei, including the pulvinar.

Note the delays shown by the sausage shaped symbols throughout the figure. These delays are functional features of the signal projection circuits (commissure). These delays have a profound effect on the operation of the visual system even though they have not been recognized in the morphology (or to a great extent in physiology) of the visual process. The commissure employ phasic signaling as a power saving mechanism and accept the associated time delay. The neural engines employ analog signaling to minimize time delay, in the much more complex circuits, and minimize the distances between circuits to minimize power consumption. There are also significant delays associated with Meyer’s loop and the related Reyem’s loop.

2.3.4.1.2 The morphological picture up to the cerebral cortex

There are many caricatures available describing the brain as applicable to vision. This is primarily because the major vision pathways are so prominent and so much of the brain is devoted to visual processing. However, these caricatures are difficult to correlate because of the different perspectives of various authors. Newell republishes three different figures describing these pathways, (figures 1-47, 1-54 and 2-24) plus a selection of line drawings of the same areas. His figure 1-47, from Glaser98, is reproduced here as Figure 10.11.4-2. It shows the

98Glaser, J. (1978) Neuro-Ophthalmology, Hagerstown, MD: Harper & Row Also reproduced in Newell Op. Cit. 94 Neurons & the Nervous System geniculocalcarine tract in some detail. It also introduces the fact that Meyer’s radiation actually divides into a bundle going to the occipital lobe and a bundle going to the parietal lobe. It does not show a separate bundle from the pretectum to the parietal lobe following the pulvinar tract which will be introduced below.

Figure 10.11.4-2 The visual-sensory system viewed from the left side. The left cerebral hemisphere has been removed except for a portion for the occipital lobe and the ventricular system. The arrow beneath the third ventricle points to the lateral geniculate body. From Glaser, 1978.

2.3.4.2 The connections between the eyes and the midbrain

Most people are familiar with the optic nerves and their interdigitation that occurs at the optic chiasm. However, they are not generally familiar with the retinotopic localization of afferent nerves within the optic nerve (commissure) and seldom think of the efferent nerves within this bundle that control the iris and lens system of the eyes. Few people are aware of the additional segmentation of the optic tract posterior to the chiasm. These segmentations were shown in the earlier figure and labeled A, B & C. While A & B are afferent, C is efferent. At the detailed level, the terminus of these various bundles within the midbrain are quite diffuse. Some appear to extend into the pons and probably relate to the vestibular system. 2.3.4.2.2 The morphological picture for afferent paths System Morphology 10- 95 Figure 10.11.4-3 presents the clearest caricature of the afferent neural paths from the eyes to the midbrain99. While it was drawn by Miller to focus on the pupillary light reflex, it shows many other paths.

Figure 10.11.4-3 Caricature of the afferent neural paths between the eyes and the midbrain. Miller notes the probability of a collateral of the visual axons leaves the optic tract before the visual axons synapse in the lateral geniculate body. From Miller, 1985.

The bulk of the optic nerve is shown proceeding to the two lateral geniculate nuclei. However, Miller notes in his caption the probability of a collateral path of vison axons proceeding elsewhere. It is a proposal of this work that this collateral path is actually a key path in the ability of humans to interpret fine detail. It is proposed that approximately 2.5% of the neurons of the optic nerve follow this path to the pretectum. There, the signals from these neurons are processed in a two-dimensional correlator in order to extract the initial interpretation of the content of the scene applied to the foveola. It is proposed that this collateral path is one of the distinguishing features of the human visual system. While it may be shared with the other higher apes, it is probably not shared widely with the lower mammals. Miller suggests there is a distinct path from specialized sensors in the retina to the pretecto-oculomotor tract that aid in the control of the iris. This is a plausible but not well documented position. An alternate position would assume the necessary information to control the iris was extracted from the information passed to the pretectum over the visual neurons. In either case, signals from the pretectum pass back to the muscles via a series of nuclei. A similar situation arises with regard to control of the lens for purposes of accommodation. It appears probably that signals to control the lens are extracted from the signals from the foveola in the pretectum. Based on this analysis, three types of signals are extracted by the pretectum, the signals describing the fine detail in the scene projected on the foveola, the signals required to command the oculomotor muscles for purposes of

99Miller, N. (1985) Walsh and Hoyt’s clinical neuro-ophthalmology, 4th ed. vol. 2, Baltimore, MD: Williams & Wilkins. Also reproduced in Newell, Op. Cit. pg 107 96 Neurons & the Nervous System pointing, and the signals required to control the iris and lens. 2.3.4.1.2 The morphological picture for efferent paths

There are two sets of efferent neural paths from the midbrain. The oculomotor group controls the motions of the eyes. The second group controls the iris and the lens inside of the eye. Both of these groups are associated with the servomechanisms that will be described as portions of the Precision Optical System (POS) of the visual system. The POS was formerly known as the auxiliary optical system because its purpose was unknown.

Figure 10.11.4-4 shows the principle neural elements and paths between the midbrain and the eye100. The nomenclature in this figure is somewhat different than used elsewhere in this work. However, the correlation between terms can be made visually. E-W, Edinger-Westphal parasympathetic sub-nucleus; IR, inferior rectus muscle nucleus; IO, inferior oblique muscle nucleus; MR medial rectus muscle nucleus; SR, superior rectus; SO, superior oblique; CCN, caudal nucleus; LR, abducent nucleus for lateral rectus muscle.

2.3.4.3 The connections between the midbrain and the cerebral cortex

There are two separate and distinct visual pathways between the old brain (thalamus, pons & medulla) and the new brain (the cerebral cortex). The well known geniculocalcerine pathway leads from the lateral geniculate nuclei to area 17 of the occipital lobe. Historically, area 17 has been considered the primary visual cortex. This is an archaic designation. The alternate pulvinar pathway, between the pulvinar portion of the thalamus (or more specifically the pretectum) and area 7 of the cerebral cortex, plays a crucial role in the superior Figure 10.11.4-4 Organization of the oculomotor vision and analytical capabilities of those animals nucleus viewed from above, left posterior. See text. with a fovea. A human can function in the modern From Glaser, 1978. world with severe damage to area 17. However, he is greatly constrained by damage to the afferent visual area of area 7 or to the pulvinar and pulvinar pathway. This signal path constitutes the analytical path in human vision. This signal path is most highly developed in Homoinoidea (man and the higher, anthropoid, apes). While the rhesus monkey (Cercopithecoidea macacus) is widely used in vision research, this family does not exhibit the full capabilities of the analytical path found in the great apes and man. 2.3.5 Ultimate morphological and topological organization of the brain 2.3.5.1 The morphological environment of the midbrain

To interpret the major signal pathways of the brain in Section 2.6.1, it is important to explore the anatomical terminology associated with the brain. This terminology is very confused at the detailed level at the current time because of the variety of approaches to the subject. The new text by Nolte, referenced above, provides an abundance of information concerning the brain. However, the text is introductory and does not focus specifically on the details of the visual system. It is not in close agreement with the authors referenced above. 2.3.5.2 Correlating the optic tectum

Vanegas has edited a comprehensive volume comparing the optic tectum in different species. Unfortunately, much of the comparison is left to the reader as each chapter addresses the optic tectum in a different species101. The text

100Glaser, J. (1978) Op. Cit. Also reproduced in Newell, Op. Cit. pg 59

101Vanegas, H. (1984) Comparitive Neurology of the Optic Tectum. NY: Plenum System Morphology 10- 97 does not address signaling directly. It relies primarily on the introduction of lesions to ascertain the visual role of different regions. In this respect, the text is concerned primarily with the retinotopic aspects of vision. In reviewing Vanegas, one rapidly discerns a pattern. As the immature brain matures, the midbrain differentiates into multiple regions associated with vision. While the morphological names applied to these regions may vary between species, their topological function is more consistent. The lateral elements at the front (posterior most in humans) of the tectum receive the corresponding ipsilateral fields from both eyes. They are generally described as the lateral geniculate bodies. In animals with a fovea, there is a separate area at the front of the tectum that receives and merges the images from the foveola of both eyes. This area has been labeled the pretectum in many of the lower animals and the pulvinar in humans. The vision related areas posterior to the above areas are generally divided into two lateral pairs, the inferior and superior colliculi. The roles of the superior colliculi are quite clear, they are a major part of the neural system controlling the pointing of the eyes relative to inertial space. In this role they control the oculomotor system as well as the head and other body muscles controlling the direction of the line of fixation of the eyes. The superior colliculi direct the operation of the various terminal nuclei of the auxiliary optical system. These nuclei directly control the oculomotor system. Because of the importance of this signal path, the auxiliary optical system will be designated the Precision Optical System, POS, in the remainder of this work. The POS is a major component of the Precision Optical Servo-System, POSS, that controls the spatial pointing of the eyes and the extraction of precise information used to perceive, interpret and recognize elements of the visual field. The complete functional description of the POSS and POS will be found in Section 15.2. 2.3.5.3 The lateral geniculate nuclei

The lateral geniculate nuclei, LGN, have been studied for a very long time. They have been mapped extensively by morphological and physiological investigators. They will be discussed more fully in Section 2.8.1.4. There are two primary functions of these nuclei. First, these nuclei correlate the images from the corresponding fields of view of the two eyes, primarily outside of the foveal area. Second, they detect rapid movement in the retinal image due to motion in object space. The results of both of these functions are passed to the pretectum/pulvinar over the stereo path and the alarm path. The signals passed over the alarm path are absolutely critical to the survival of most animals regardless of phylum or species.

The fact that the signal processing carried out within these structures is highly dependent on the time delay introduced by Reyem’s loops has not been recognized until now. Reyem’s loops introduce a time delay that is proportional to the distance from the line of fixation of element of the scene. By attempting to merge the corresponding signals from the two eyes, this time difference is easily measured and the information is transmitted to the pulvinar/pretectum area to establish stereo convergence of the eyes. Rapid motions in the scene also generate time differences that are easily measured in the LGN. These time differences are also passed to the pretectum/pulvinar for immediate action.

The time delays due to Reyem’s loops are not of use after the processing in the LGN Therefore, these delays are removed by the corresponding Meyer’s loops before the signals reach the cerebral cortex along the awareness path. 2.3.5.4 The Pulvinar, analog of the Pretectum

In recent primate literature, the important role in vision of the region of the thalamus labeled the pulvinar has become clearer. Chalupa has presented considerable material relative to this region102. Nolte has also noted the supervisory role of the pulvinar (page 381). Nomenclature remains a problem in delineating the pulvinar and the associated structures. As indicated above, the pretectum (or optic tectum) may consist of a majority of the anterior part of the thalamus (other than the lateral and median geniculate nuclei) and include both the pulvinar and the lateral posterior nucleus plus other components. In addition, there are a great many caricatures of this region but very few photographs and micrographs. The collage of photographs in Nolte (page 385) and attributed to Nolte, et. al103. and to Chen, et. al. are the best available. They show the location of one lateral zone consisting of a pulvinar, lateral geniculate and medial geniculate and reticular nuclei simultaneously and also their location within the broader context of one of the two thalamus structures. These photographs can be correlated with the caricatures of Chalupa and of Brodal. The details shown in the caricature of Brodal, Figure 10.11.5-1, form a good

102Chalupa, L. (1991) Visual function of the Pulvinar. Chapter 6 in Leventhal, A. ed. The Neural Basis of Visual Function. vol. 4 of Vision and Visual dysfunction, Cronly-Dillon, xxx general ed.

103Nolte, J. & Angevine, J (1995) Op. Cit. 98 Neurons & the Nervous System reference for further discussion104. Further details, based on sectioning of the structure, are shown in Figure 16-16 and Table 16-2 of Nolte.

Figure 10.11.5-1 CR (edit) Three dimensional view of the right human thalamus seen from the dorsolateral aspect. XXX Callouts LM should probably be MG Add PGN if appropriate. From Brodal, 1981.

Standring has presented a colorized version of the Brodal illustration expanded to show the gross interconnections with the associated areas of the cerebral cortex105, Figure 10.11.5-2. It was not further expanded to show the more complex region near the MGN and LGN and the functional role of the pulvinar. The envelope of the thalamus is labeled the reticular nucleus rather than the thalamic reticular nucleus (TRN) in this figure. It is shown in cutaway form rather than detailing its association with the MGN, the LGN and the other omitted elements.

Standring notes (pg 315), “Little is known of the function of the pulvinar. The inferior pulvinar nucleus contains a complete retinotopic representation, and lateral and medial pulvinar nuclei also contain visually responsive cells. However, the latter nucleus , at least, is not purely visual–other modality responses can be recorded, and some cells may be polysensory.” This observation is consistent with the proposals of this work and is suggestive of the complex role of the pulvinar in both precision visual information extraction and in multisensory integration leading to a sophisticated saliency map. The Standring figure appears and is discussed in more detail in Chapter 5 by Baars (page 143-145) and in Chapter 12 by Goldberg & Bougakov in Baars & Gage. Baars figure 5.39 from Mario Lazar shows the actual commissure extending from the thalamus to multiple areas of the cerebral cortex using the diffusion fMRI technique of Wedeen’s laboratory. The caption of the version in Goldberg & Bougakov is more informative and describes the close intimacy between the thalamus and the cerebral cortex, suggesting the thalamus can be considered to be additional layers of cortex, and

104Brodal, A. (1981) Neurological anatomy in relation to clinical medicine. New York: Oxford Univ Press

105Standring, S. ed. (2008) Gray’s Anatomy, 40th Ed. NY: Elsevier pg 313 System Morphology 10- 99 stresses the “thalamo-cortical system.” The unfolding of the cerebral cortex discussed in Section xxx demonstrates unequivocally that the thalamus is an intimate portion of a single sheet of neural material. Their figure 12.7, attributed to Schneider & Chein (2003), also illustrates the bidirectional paths of the commissure between the thalamus and the various regions of the cerebral cortex. The caption stresses, “The thalamus serves as a hub for multiple functions.”

Figure 10.11.5-2 The main nuclear masses of the thalamus (viewed from the lateral aspect color coded to indicate gross interconnections with the areas of the cerebral cortex. Standring, 2007. 100 Neurons & the Nervous System

Schall106 defines the pulvinar as consisting of four nuclei, the medial, lateral, inferior and anterior–that are distinguishable based on their connectivity and functional parameters. [xxx what about functional parameters. how does figure compare to Brodal.] Schall makes the interesting observation that the increase in size of the pulvinar in primates parallels that of the extrastriate visual cortex (presumably following the definition of Spear). When only looking at the primates, this correlation, whether volumetric or area related, may not be that good. Schall also provides an extensive bibliography on connectivity between the pulvinar and other regions of the brain as well as the more general connectivity between regions. His figure 15.11 is believed to contain too many reciprocal paths between engines of the brain. Otherwise it shows a strong familial resemblance to [Figure 2.3.4-1] above. It may be that many of the antidromic circuits in these reciprocal paths are what are called supervisory circuits in communication. Supervisory circuits are low capacity paths only used to report the operational status of an engine to, in this case, the pulvinar. These paths will be discussed further in Section 2.8 & 15.2.4. In Section 15.2.4, the critical role of the pretectum/pulvinar as supervisor of visual signal processing will be stressed. In the context of figure 15.11, the pretectum might be defined as incorporating his pregeniculate nucleus, his pulvinar and his central thalamus. Further discussion of the functional characteristics described in Schall will be found in Chapters 15 and 17. 2.3.5.5 The superior colliculus

The nuclei of the superior colliculus , SC, are of significant size and perform a wide range of complex signal manipulations. These manipulations are complex because the signal received from the POT are fully vectorized in saliency space while those received from within the POS are more retinotopic in character. The SC must process both types of signals as well as those received from the vestibular system. It is frequently proposed that the signals at the output of the SC are retinotopic. However, in general, they relate to the relative position of the elements of a scene relative to the line of fixation rather than the absolute position of the scene elements. These relative values are used to generate the signals used to control the oculomotor muscles shown in the box labeled Plant in the above figure. 2.3.5.6 The cerebellum

The role of the cerebellum will be discussed in more detail in Chapters 11 and 15. It has not offered the morphologist much to work on. Its functional role is highly time sensitive and difficult to determine based on past investigatory techniques. Its role has been determined previously primarily from functional limitations following serious laceration of the element. Nolte has noted the recent proposals that the cerebellum is involved in cognitive functions. In this work, that assertion will be reworded to propose the cerebellum is involved in perceptual and interpretive activities, in association with the pretectum/pulvinar, leading to cognition within the cerebral cortex. Brodal has provides an annotated topographic view of the cerebellum in humans (also reproduced in Brown107) as well as showing some of the main interconnections with other elements of the brain. The primary area associated with vision is believed to be the vermis. Schall provides references to the vision related activities of the vermis.

The major role of the cerebellum is in interpretation of the image projected onto the foveola, where it acts as a very fast two dimensional correlator. In this role, it receives information from the 23,000 photoreceptors of the foveola that is time correlated and attempts to match previously encountered patterns. Individual distinct patterns are received continuously at intervals of only 10-30 milliseconds. When the cerebellum accomplishes a match, it reports the fact to the cerebral cortex (probably by way of the pretectum/pulvinar) via a message in vectorial form. If it fails to recognize an image, it may record the correlation factor obtained for future correlation purposes. 2.3.6 The morphological environment of the cerebral cortex

It is not often recognized that the cerebral cortex (new brain or neo-cortex) is not a three-dimensional or volumetric structure. The cerebral cortex is basically a large thin sheet (thickness equal to a few sheets of paper) that has been folded extensively to fit into the relatively small volume available and thereby accommodate other operational constraints involving signaling delays and moment of inertia requirements relative to the motion of the animal.

106Schall J. (1991) Neural basis of saccadic eye moovements in primates. Chapter 15 in Leventhal, A. Op. Cit.

107Brown, A. (1991) Nerve Cells and Nervous Systems. NY: Springer-Verlag pg 193 System Morphology 10- 101 The arrangement of the brain within the skull is a prime example of the fact that form follows functional requirements in the anatomy of an animal, contrary to the common view of morphologists that function follows form. The entire surface of the sheet is available to support engines (large groups of neurons focused on a specific task) without regard to the folding process. While investigators have historically differentiated between the gyrus –gyri (plateaus between the fold) and the sulci (the folds), recent work has noted the importance of the tissue within the folds in neural activity. It has also become more widely known that the location of the sulci are similar to finger prints, they are not common at the detailed level. Only the location of the main sulci between the individual lobes appear to be consistent within a species. Across species, they reflect the difference in packaging requirements. While the human cerebral cortex is bilateral, it is usually described as formed of five or six lobes. Most of these lobes exhibit a bilateral symmetry of their own. Only the temporal lobes do not since they are a lateral pair that do not individually cross the line of symmetry. The limbic lobe is essentially hidden within the outer corona of the cerebral hemispheres. The posterior portion of the occipital lobe (area 17 in Brodmann’s notation) exhibits a unique morphological surface that has given this region the alternate title of the striate of the cerebral cortex. However, this striate appearance also appears elsewhere in the brain. Since this area has long been known to be involved in vision, the extrastriate areas were originally thought to not participate in vision. It is now recognized that neural engines impacting the overall visual process are found throughout the brain. This is also true of the individual lobes of the cerebral cortex. Recently, the critical importance of area 7 of the cerebral cortex and the pulvinar to the visual process has deprecated the title “primary visual cortex” associated with area 17.

The functional role of area 17 is not unlike that of the LGN. It performs relatively low level image information correlation. In this role, it exhibits a high level of retinotopicity. As the signals are passed from area 17 to areas 18-22, they progressively lose this retinotopicity as the information is translated into saliency vectors that are employed in cognition.

Binzegger et al. have followed a long tradition of attempting to categorize the neurons of the cerebral cortex using light microscopy and without regard to actual function108. They have relied upon some limited statistics related to boutons and dendrites to categorize 39 neurons primarily by cortical layer. The results are obviously less than statistically relevant and disregard the large number of neurons (and dendrites) not observable by light microscopy. Their data does give some insight as to the percentage of axons or dendrites interfacing with another layer of the cortex. 2.3.6.x The definition of extrastriate visual cortex

The character of the surface of area 17 of the occipital lobe is probably related to its correlation function. This low level function also calls for a high degree of retinotopicity. It may be that the striations (corrugations on a small scale) are another way to increase the amount of surface area available in a restricted space. In any case, it has been common to speak of the extrastriated area of the cerebral cortex in a morphological context. Spear has provided a definition for purposes of a specific discussion that is not wholly satisfactory in a general context109. He limits the extrastriate visual cortex to areas that respond to light and contain a retinotopic relationship to the original retinal image. This definition restricts this term to primarily the areas near 17 of the occipital lobe and possibly some areas of the temporal lobes depending on ones criteria for the degree of retinotopicity. There are many areas of the cortex that are critical to the visual process. These areas respond to light but operate entirely in a vector space devoid of retinotopicity. In some cases, they exhibit a topographical relationship to object space in the context of an inertial system but not to the coordinates of the retina. The term extrastriate is probably archaic at this time. It does not differentiate between the functional areas of the cortex involved in vision from other areas. While providing an annotated caricature of the cat brain, he also shows the great disparity between the cat and human brain. It is safe to conclude that the cat brain does not exhibit or contain a highly developed

108Binzegger, T. Douglas, R. & Martin, K. (2004) A Quantitative Map of the Circuit of Cat Primary Visual Cortex J Neurosci vol 24(39), pp 8441– 8453

109Spear, P. Functions of extrastriate visual cortex in non-primate species. Chapter 13 in Leventhal, A. ed. The Neural Basis of Visual Function. Vol. 4 of Leventhal, A. general ed. of Vision and Visual Dysfunction. Boca Raton, FL: CRC Press pg 339 102 Neurons & the Nervous System pretectum/pulvinar and the associated analytical path found in the human brain. Motter has discussed the ramifications associated with areas beyond the extrastriated cortex as defined by Spear110. His discussion was largely conceptual and was introductory to a discussion by Schall111. While primarily discussing the functional aspects of parts of the brain, it contains many additional morphological details.

110Motter, B. (1991) Beyond extrastriate cortex: The parietal visual system. Chapter 14 in Leventhal, A. ed. The Neural Basis of Visual Function. Vol. 4 of Leventhal, A. general ed. of Vision and Visual Dysfunction. Boca Raton, FL: CRC Press pg 339

111Schall, J. (1991) Neural basis of saccadic eye moovements in primates. Chapter 15 in Leventhal, A. Op. Cit. System Morphology 10- 103

Table of Contents 21 October 2014

10 The Morphology of the Neural system ...... 1 10.1 Introduction...... 1 10.1.1 Establishing the discussion framework...... 2 10.1.1.1 Establishing morphology subfields by equipment capabilities . . 3 10.1.2 Identifying individual neurons...... 4 10.1.2.1 Defining pyramid cells...... 11 10.1.2.2 Defining the agranular laminates of the pia matter...... 11 10.1.2.3 Defining commissure destinations...... 12 10.1.2.1Generic structure of the cerebral cortex cross section ...... 15 10.1.3 Labeling neurons by physical shape...... 15 10.1.5 Describing neurons by fanciful names...... 18 10.1.5 Describing neurons by size distribution...... 18 10.2 Cytoarchitecture of the CNS...... 20 10.2.1 Anatomy, sulci & gyri of the cerebral cortex ...... 20 10.2.1.1 Redefining the aversive motor and perceptual sensory areas of the human cerebral cortex ...... 23 10.2.2 Cytoarchitecture of the cerebral cortex ...... 29 10.2.2.1 Labeling of areas not addressed by Brodmann ...... 32 10.2.2.2 A flat representation of the cerebral cortex...... 33 10.2.3 Cytoarchitecture of the diencephalon...... 34 10.2.3.1 Cytoarchitecture of the thalamus...... 35 10.2.4 Cytoarchitecture of the cerebellum...... 36 10.2.5 Importance of point-to-point commissure paths ...... 38 10.2.6 Morphogenesis of the neural system ...... 38 10.2.6.1 Morphogenesis at birth...... 40 10.2.6.2 Detailed development of cortical laminate...... 40 10.3 The cross section of the cortex ...... 42 10.3.1 A comparison of nomenclature...... 43 10.4 The blood-brain barrier and cardiovascular circulation ...... 45 10.4.1 The blood-brain barrier and cardiovascular circulation...... 45 10.4 2 The cardiovascular circulation...... 45 10.5 The morphology of the dorsal brainstem and spinal cord EMPTY...... 45 10.5.1 The complex structure of the dorsal brainstem...... 45 10.5.2 The complex structure of the spinal cord...... 48 10.5.2.1 Longitudinal organization of the spinal column ADD...... 48 10.5.2.2 Cross section of the spinal column...... 48 10.6 Stage 3 connections within the cortex ...... 48 10.6.1 The ratio between white matter (stage 3) and grey matter in the CNS . . 54 10.7 Identification of stage 4 neurons within the cortex ...... 54 10.7.1 The pyramid cells...... 55 10.7.2 The stellate cells ...... 55 10.8 Architectures of the CNS...... 55 10.8.1 Cytoarchitectures of the cerebral cortex ...... 57 10.8.1.1 Conventions used in CNS architectures...... 61 10.8.2 Cytoarchitectures of the diencephalon...... 62 10.8.3 Cytoarchitectures of the prefrontal lobe...... 62 10.8.4 Cytoarchitecture of the limbic system & basal ganglia...... 63 10.8.4.1 The elements of the Limbic System...... 63 10.8.4.2 The elements of the Basal Ganglia...... 66 10.8.5 Interconnections within the brain ...... 68 10.8.6 Interconnections between the CNS and PNS...... 71 10.8.6.1 CNS to PNS interconnections in humans ...... 71 10.8.6.2 Interconnections in Macaque ...... 72 10.8.7 Interconnections between the CNS and glandular system...... 75 10.8.8 Interconnections between elements of the somatosensory system within the CNS...... 75 10.9 Correlation of functions with the cytoarchitecture of the CNS...... 76 10.9.1 Broca’s and Wernicke’s areas ...... 77 10.9.2 The inferotemporal cortex...... 81 104 Neurons & the Nervous System

10.9.3 The storage of short and long term memory in the cortex ...... 81 10.10 The neuroglia (or glia)...... 82 10.10.1 The proposition of Fields...... 82 2.3 The organization and mixed coordinate systems of the chordate brain ...... 85 2.3.2 Coordinate transformations within the visual system ...... 88 2.3.2.1 The transition from retinotopic to abstract mapping ...... 88 2.3.2.2 The transition from abstract to inertial-topic mapping ...... 88 2.3.3 Initial embroyology of the visual system ...... 88 2.3.3.1 Initial embroyology of the brain...... 88 2.3.3.2 Initial embryology of the eye...... 91 2.3.3.3 Initial embroyology of the retina ...... 91 2.3.4 The connections between elements of the brain ...... 92 2.3.4.1 The connection architecture of vision...... 92 2.3.4.1.1 The block diagram...... 92 2.3.4.1.2 The morphological picture up to the cerebral cortex . . 93 2.3.4.2 The connections between the eyes and the midbrain ...... 94 2.3.4.3 The connections between the midbrain and the cerebral cortex ...... 96 2.3.5 Ultimate morphological and topological organization of the brain...... 96 2.3.5.1 The morphological environment of the midbrain ...... 96 2.3.5.2 Correlating the optic tectum...... 96 2.3.5.3 The lateral geniculate nuclei...... 97 2.3.5.4 The Pulvinar, analog of the Pretectum ...... 97 2.3.5.5 The superior colliculus ...... 100 2.3.5.6 The cerebellum...... 100 2.3.6 The morphological environment of the cerebral cortex...... 100 2.3.6.x The definition of extrastriate visual cortex ...... 101 System Morphology 10- 105

Chapter 11 List of Figures 10/21/14 Figure 10.1.1-1 Instrument resolution versus the subfields of morphology ...... 4 Figure 10.1.2-1 The effect of staining on neuron delineation and identification ...... 5 Figure 10.1.2-2 A comparison of the raw image obtained from the Golgi-Cox method and the drawing prepared from the image ...... 7 Figure 10.1.2-3 Section architectures found in the human brain compared...... 8 Figure 10.1.2-4 The cytoarchitecture of human visual cortex using Nissl-stain...... 8 Figure 10.1.2-5 After Von Economo, with horizontal dendrite systems and vertical axon "columns" added ...... 10 Figure 10.1.2-6 A description of the specialization of areas of the human brain ...... 11 Figure 10.1.2-7 Diagram of the major cortical neurons of the cerebral cortex...... 12 Figure 10.1.2-8 Terminations and paths of neurons in the CNS TEMP...... 13 Figure 10.1.2-9 Targets of projections from pyramidal cells in different layers of primary motor cortex ...... 14 Figure 10.1.3-1 The difficulty of differentiating between neurons based on shape ...... 16 Figure 10.1.3-2 A montage illustrating variations in neuronal size, shape and processes .... 17 Figure 10.2.1-1 Labeling of the sulci and gyri of the human brain...... 21 Figure 10.2.1-2 Diagram of human cerebrum in transverse section...... 22 Figure 10.2.1-3 A section through the human cerebral cortex showing the basal ganglia..... 23 Figure 10.2.1-4 Major areas of the cerebral cortex from the functional perspective ...... 24 Figure 10.2.1-5 Cortical motor processing areas...... 25 Figure 10.2.1-6 Unfolded cerebral cortex ...... 26 Figure 10.2.1-7 Average cortical thickness across 30 subjects...... 28 Figure 10.2.2-1 Cytoarchitectural map of the left lateral surface of the human cortex...... 29 Figure 10.2.2-2 Cytoarchitectural map of the medial surface of the human cortex...... 30 Figure 10.2.2-3 Brodmann areas in the frontal lobes...... 31 Figure 10.2.2-4 Architectonics of the orbital and medial prefrontal cortex ...... 32 Figure 10.2.2-5 A mosaic of labels for internal areas of the cortex ...... 33 Figure 10.2.2-6 A flat map topological representation of Brodmann’s regionalization of the cerebral cortex of the human brain...... 34 Figure 10.2.3-1 Thalmo-cortical radiations and labelling ...... 36 Figure 10.2.4-1 The cerebellum unfolded ...... 37 Figure 10.2.6-1 Morphogenesis of human embryo beginning about day 18 ...... 39 Figure 10.2.6-2Human brain growth rate compared with other species...... 40 Figure 10.2.6-3 A cartoon of early corticogenesis...... 41 Figure 10.2.6-4 Development of neuronal architecture in human prefrontal cortex ...... 42 Figure 10.3.1-1 The cytoarchitecture of human visual cortex using Nissl-stained tissue ..... 43 Figure 10.3.1-2 The laminar organization of neurons in different cortical areas ...... 44 Figure 10.5.1-1Dorsal surface of the brainstem showing the quadrigemina ...... 46 Figure 10.5.1-2 The major elements adjacent to one of the metathalami...... 47 Figure 10.5.2-1 The human spinal cord and spinal column RESCAN...... 48 Figure 10.6.1-1 A lateral view of the human cortex using dtMRI in false color...... 50 Figure 10.6.1-2 Stage 3 cabling (commissure) of the human brain...... 51 Figure 10.6.1-3 White bundles of myelinated axons run in all directions...... 52 Figure 10.6.1-4 Plan view of human CNS showing its fore & aft organization ...... 53 Figure 10.6.1-5 Projected gray/white matter regression line to smaller animals...... 54 Figure 10.8.1-1 A flat map of the CNS split along the vertical axis ...... 56 Figure 10.8.1-2 Major afferent and efferent projections between the cerebral cortex and the diencephalon ...... 58 Figure 10.8.1-3 anatomical connections within a column of primary auditory cortex...... 59 Figure 10.8.1-4 Map of activation evoked by xxx ...... 60 Figure 10.8.1-5 Systematic movement of the activation area with object rotation ...... 61 Figure 10.8.4-1 Semischematic drawing of the isolated striatum, thalamus, and amygdaloid nucleus ...... 63 Figure 10.8.4-2 The cytoarchitecture of the limbic system in context...... 64 Figure 10.8.4-3 The medial surface of the human cerebral cortex showing the limbic lobe . . . 65 Figure 10.8.4-4 The basal ganglia in mammals ca. 1986 ...... 66 Figure 10.8.4-5 Flat map of the CNS showing the relationship of the basal ganglia to other elements...... 67 Figure 10.8.4-6 Flat map of the CNS showing the separation of the cerebral cortex from the 106 Neurons & the Nervous System

diencephalon ...... 68 Figure 10.8.5-1 Major thalamic projections onto the lateral surface of the left hemisphere . . . 68 Figure 10.8.5-2 Major thalamic projections to the medial surfaces of the right hemisphere . . . 70 Figure 10.8.5-3 Major thalamic projections to both frontal, parietal and occipital lobes...... 71 Figure 10.8.6-1 Dermatomes of human RESCAN...... 72 Figure 10.8.6-2 Dermatomes of Macaque ...... 74 Figure 10.8.7-1 The interface between neural and glandular systems...... 75 Figure 10.8.8-1 Location of somatosensory channels on the cerebral cortex ...... 76 Figure 10.9.1-1 Recent representation of functional role of areas of the human brain ...... 77 Figure 10.9.1-2 Areas associated with spoken language ...... 78 Figure 10.9.1-3 Temporal and frontal language areas of the left human hemisphere...... 80 Figure 10.10.1-1 The roles of glia within the neural system ...... 83 Figure 10.10.1-2 The oligodendrocyte versus Schwann cells...... 84 Figure 10.10.1-3 Early caricature of a fist of glia engulfing multiple axon segments ...... 85 Figure 10.11.1-1 CR Caricature showing the position of the Pulvinar, LGN and Thalamus in relation to the old brain...... 86 Figure 10.11.3-1 OLD DUPL The morphogenesis and gross anatomy of the brain related to vision...... 90 Figure 10.11.4-1 Reproduction of Figure 15.2.4-3 to illustrate the top level topology of the visual system ...... 93 Figure 10.11.4-2 The visual-sensory system viewed from the left side...... 94 Figure 10.11.4-3 Caricature of the afferent neural paths between the eyes and the midbrain ...... 95 Figure 10.11.4-4 Organization of the oculomotor nucleus viewed from above ...... 96 Figure 10.11.5-1 CR (edit) Three dimensional view of the right human thalamus ...... 98 Figure 10.11.5-2 The main nuclear masses of the thalamus...... 99 System Morphology 10- 107

(Active) SUBJECT INDEX (using advanced indexing option) 3D...... 22 95%...... 30, 40, 66 action potential...... 30, 84 Activa...... 2, 82 area 4...... 44 area 6...... 78 area 7...... 1, 92, 96, 101 attention ...... 1, 2, 32, 87 axon segment...... 82-85 axoplasm...... 82, 84 Baillarger’s bands ...... 62 basal ganglia...... 23, 34, 59, 63-68 blood-brain barrier ...... 45 Brachium...... 45, 86 bray ...... 91 Broca’s area...... 77, 79, 80 Brodmann ...... 8, 9, 11, 14, 20, 28-32, 43 cerebellum...... 22, 24, 26, 34, 36-39, 45, 100 cerebrum...... 22, 56 chord ...... 83 Circle of Willis ...... 45 colliculus ...... 2, 24, 47, 71, 86-88, 91, 92, 100 conduction velocity...... 82 conexus ...... 84 consciousness ...... 59 DG ...... 34 diencephalon...... 26, 33-35, 39, 47, 58, 62, 63, 67, 68, 89 discharge layers ...... 12 disparity ...... 101 Edinger-Westphal...... 96 endocrine...... 67, 75 executive ...... 59, 63 fasciculus...... 79 flat map...... 33, 34, 56, 67, 68 fMRI...... 26, 49, 81, 98 ganglion neuron ...... 17 Gaussian ...... 19 Grandmother...... 81 homogeneous...... 16, 66 homunculus...... 72 hypothalamus...... 33, 39, 55, 56, 64, 67, 75 inferior colliculus ...... 91 intelligence ...... 2 larynx...... 71 lateral geniculate ...... 46, 87, 91, 94-97 lgn/occipital...... 71 limbic system...... 63, 64, 88 listening...... 81, 82 local circuit ...... 43, 45 long term memory...... 81 LOT ...... 43 major nerves ...... 72 medial geniculate ...... 46, 97 mesencephalon ...... 39, 89, 91 midbrain ...... 67, 87, 94-97 morphogenesis...... 15, 38-41, 85, 88, 90, 91 108 Neurons & the Nervous System

MRI ...... 26-28, 47-49, 51, 54, 59, 61, 62, 87 multi-dimensional...... 3, 9 myelin ...... 5, 11, 50, 82, 84 myelinated...... 9, 11, 18, 49, 52, 54, 55, 57, 62, 82-84 Myelination...... 5, 11, 18, 40, 82, 83, 85 nerve numbers ...... 39, 71 neurites...... 2 Node of Ranvier...... 2, 82 Orangutan...... 2, 3 orbital ...... 32 orbitofrontal cortex...... 11, 12, 32 orofi ...... 24 pallidum ...... 66, 67 parietal lobe...... 72, 79, 87, 94 percept...... 1, 60, 61, 68 perigeniculate...... 2, 3, 47, 71 perigeniculate nucleus ...... 2, 3, 47, 71 pgn/pulvinar ...... 68, 71, 78 pituitary gland ...... 75 plasticity ...... 91 poditic ...... 11, 18, 55, 66 pons ...... 15, 39, 94, 96 POS ...... 92, 96, 97, 100 POSS ...... 97 Pretectal ...... 35 Pretectum ...... 87, 89, 91-97, 100, 102 propagation velocity...... 82 pulvinar...... 3, 26, 37, 42, 45, 62, 68, 71, 78, 85-87, 92-94, 96-98, 100-102 Pulvinar pathway...... 92, 96 putamen...... 22, 45, 63 pyramid cell...... 11, 16, 18, 55 quadrigemina ...... 45, 46, 89, 90 reading...... 56, 81 receptive layers...... 12 resonance...... 28, 49 saliency map...... 1, 98 spinal cord...... 38, 39, 43, 45, 48, 72, 75 stage 1...... 77 stage 2...... 11 stage 3...... 9, 11, 18, 34, 45, 48-51, 54, 55, 67, 76, 82, 83 stage 4...... 9, 18, 37, 45, 49, 54, 55, 58, 63, 67, 68, 76, 77 stage 4b...... 63 stage 5...... 37, 63, 68 stage 6...... 37, 63, 67, 77 stage 6b...... 63, 67 stellate...... 8, 16-18, 43, 55 stellate cell ...... 55 stellate neuron ...... 17 stress...... 3, 79 stria of Gennari...... 62 striatum...... 15, 22, 34, 63, 66, 67 superior colliculus ...... 2, 24, 71, 86-88, 91, 92, 100 synapse ...... 8, 82, 84, 95 Talairach...... 14, 27 telencephalon ...... 67 temporal lobe...... 1, 23, 33, 75, 78, 92 thalamic reticular nucleus...... 1, 35, 47, 56, 75, 79, 98 thalamus . . 1, 13, 15, 23, 33-35, 39, 42, 43, 47, 49, 51, 53, 55, 56, 59, 62, 63, 65, 68, 71, 75, 76, 85- 87, 90-92, 96-100 topography...... 35, 92 topology...... 92, 93 System Morphology 10- 109 translation...... 19 trans-...... 59 vestibular system ...... 91, 94, 100 visual cortex ...... 1, 8, 43, 44, 57, 66, 81, 96, 100, 101 Wernicke...... 1, 78, 79 Wernicke’s area...... 77, 79-81 white matter...... 8, 22, 34, 43, 44, 54, 55, 57, 62, 83 Wikipedia...... 22, 57, 84 word serial...... 50 word serial/bit parallel...... 50 xxx...... 1, 2, 8, 11, 14, 15, 17, 22, 35, 39, 40, 47, 60, 62, 67, 72, 81-85, 87, 88, 91, 97-99 [xxx...... 1, 15, 20, 24, 27, 29, 37, 38, 41, 45, 53, 57, 60, 62-64, 73, 76, 85, 91, 100