A selective history of developmental and mechanical constrains on brain maturation and evolution includes both micro- and macroscopic theories. The general idea regarding the possible existence of overarching laws had its beginning in the early nineteenth century in the work of two prominent scientists; the French zoologist Étienne Geoffroy Saint-Hilaire (1772–1844) and the comparative anatomist George Cuvier (1769–1832). Their multiple debates in 1830 at the Royal Academy of Sciences in Paris examined whether animal structures could be explained by either function (Cuvier) or by morphological laws (Geoffroy). The question was summarized by the zoologist and historian of science E. R. Russell: “Is function the mechanical result of form, or is form merely the manifestation of function or activity? What is the essence of life – organization or activity?” (Russell 1916) The view espoused by Geoffrey, later known as the “doctrine of unity of composition”, argued that function was dependent on structure and that an archetype of a basic structural plan (Bauplan or body map) accounted for homologies across different animal phyla. The word homology was coined only after the Geoffroy-Cuvier debate by Owen to define “the same organ in different animals under every variety of form and function” (Medina 2007). Although, at the time, Geoffroy was judged to be on the losing side of the debate, modern discoveries of evolutionary conserved developmental control genes seemingly support his account of a construction plan that is shared by all bilateral animals (Hirth and Reichert 2007).

Geoffroy’s ideas engendered followers primarily in the persons of Robert Edmond Grant and Étienne Serres. The doctrine of unity of composition of all vertebrates proposed by Geoffroy thus gave rise, in a grander scheme, to a link between ontogeny (i.e., development of an organism from embryo to adult) and phylogeny (i.e., the evolutionary history of a species). Ernst Haeckel (1834–1919), the eminent German biologist and philosopher, summed up previous versions of this idea and proposed that ontogeny repeated forms of the ancestors, a view now called ‘strong’ recapitulation. This way of thinking has fallen into disrepute, in part, due to the fact that Haeckel committed various acts of academic fraud in order to support his theory, e.g., forging diagrams and passing an incomplete dog embryo as that of a human. Although the idea is imprecise and has been refuted in its original form, a ‘weaker’ form is accepted. Indeed, embryonic stages of different species resemble each other more closely than later stages of development (Brüne 2008).

Almost 100 years after the Cuvier-Geoffroy debate, Cornelius Ubbo Ariëns Kappers (1877–1946) introduced the concept of neurobiotaxis (Gk. νευρον, nerve + βίος, life + τάξις, arrangement) as the major law governing vertebrate brain development (Ariëns Kappers 1921). Neurobiotaxis theorizes that nerve cells migrate during development in the direction from which they receive stimuli. This point of view was discredited by Sperry (Sperry 1943) whose work on regeneration of the retinotectal pathways gave rise to the influential “chemoaffinity hypothesis” (Meyer 1998). The most famous antecedent for chemotaxis is the neurotrophic hypothesis of Ramón y Cajal used in explaining the guidance of growth cones towards their final targets (De Castro et al. 2007). Sperry’s hypothesis suggested the existence of unique molecular addresses (“nametags”) and precise connections within the central nervous system. However, proof for a synaptic nametag that matched axonal growth to their targets remained poor and was later superseded by other theories.

Possibly the most influential developmental theory is that of chemical gradients (Linden 2007). This framework evolved from a multidisciplinary perspective that included embryology, computer sciences, and genetics. As with the chemoaffinity hypothesis, major limitations to this mechanism have been noted. Most significant among the objections is the fact that diffusion by itself is not an efficient patterning mechanism. As a zygote divides into a multicellular organism diffusing morphogens face the barriers of multiple cell membranes. The chemoaffinity hypothesis also leaves unaccounted the role of experience-dependent refinement of synaptic connections (Cline 2003).

References to chemical gradients persist till present with various modifications, e.g., the role of neuronal activity during development and the counterbalancing of signals by different chemical mediators (Turing 1952; Linden 2007). It is now known, for example, that gradients of Wnt3 molecules, counterbalanced by WPhrinB1-EphB, control the structuring of elements required to convey spatial information from the eye to its terminal cortical fields (Schmitt et al. 2006). Similarly, opposing gradients of EphA and ephrin-A control the dispersion of clonally related neurons as they assemble into cortical columns (Torii et al. 2009). Computer models emphasize that the crucial conditions for pattern formation are local self-enhancement and long range inhibition (Gierer 1981). The fact that physical-chemical process could be reduced to the forces of attraction and repulsion was probably first theorized during the nineteenth century by du Bois Reymond (Sulloway 1979). Competition lies at the heart of pattern formation. If one competing force is too strong, form disappears into featureless homogeneity. Patterns emerge when the size of the field becomes larger than the range of the activator.

Another influential idea regarding developmental constrains is the rule or law of associative learning espoused by Donald Hebb (1949). His theory about the operation of the brain is often paraphrased as: “Neurons that fire together wire together.” Hebbian learning appears limited to the stabilization of existing synapses within cell assemblies. The resulting pattern of neurons connected through conjoint activation provides for memory traces called engrams. A major limitation of Hebbian precepts and some of the previously mentioned theories is that they apply to the microscopic realm and are foreign to both macroscopic and evolutionary considerations.